You can call any of these for free. You do not need a diagnosis, an appointment, or a crisis to call — questions and plain exhaustion are reasons enough.
Alzheimer's Association 24/7 Helpline800-272-390024 hours a day, 365 days a yearFree, confidential support and information for people with dementia, caregivers, families and the public. Master's-level clinicians. Also Spanish.
988 Suicide & Crisis Lifeline98824/7Call or text 988, or chat at 988lifeline.org. For anyone in emotional distress or a mental-health crisis, including caregivers.
Alzheimer's Foundation of America (AFA) Helpline866-232-84849:00 am - 9:00 pm ET, seven days a weekLicensed social workers providing support, info and referrals. Also text message and web chat.Text: 646-586-5283
In a medical emergency, call 911.
More numbers, and what each line does, on the help page.
Which of the 7080 studies in our library other researchers actually build on — measured
two different ways, because the obvious way is misleading on its own.
Read this before the table
Raw citation count rewards being old. A paper published in 2010 has had fifteen years to
collect citations; one published last year has had months. Raw counts also reward being in a big, busy field.
Ranking only by raw count tells you mostly which papers are oldest and most famous — which you probably
already knew.
RCR (Relative Citation Ratio) is the fairer number. It is calculated by the NIH and is
normalised for both field and year: it compares a paper against other papers of the same age in the same
research area. An RCR of 1.0 is exactly average for NIH-funded work in that field and year.
2.0 means roughly twice the citations a typical comparable paper gets; 0.5 means about half.
So: RCR is our primary ranking and answers "most influential for its age and field".
Raw count is the secondary ranking and answers "most cited in absolute terms". Both columns
are shown in every table so you can see where they disagree — and they disagree a lot.
All numbers retrieved 2026-09-27. Citation
counts change daily; a number here is a reading taken on that date, not a permanent property of the paper.
What we could and could not measure
Of 7080 unique studies in the library (after removing duplicates by PubMed ID, then
DOI, then title):
7043 have a citation count from iCite.
6917 have an RCR. RCR cannot be computed until a paper has been out long
enough to accumulate a citation history, so 126 indexed papers —
nearly all of them very recent — have a citation count but no RCR yet.
7060 have a count from OpenAlex, 6998 from
Semantic Scholar.
17 are not indexed in any of the three. These are regulatory
documents, company announcements and conference presentations rather than journal articles.
A paper with no citation data is not a paper with zero citations. It is a paper these
indexes do not cover. Those rows read not indexed below and are never counted
as 0, never averaged in, and never imputed.
The three sources disagree, and we show that rather than hide it
On the 7040 papers where both iCite and OpenAlex returned a number, they gave a
different answer for 6894 of them. The median gap is a factor of
1.3×, and the widest is 728.0×.
That is normal. Each index covers a different set of journals and counts references differently — OpenAlex
indexes preprints and book chapters that iCite does not, for instance. We store every source's number
separately and never average them. The ranking columns below are labelled with the source they come
from; the other sources' numbers are in the downloadable data.
This view keeps only the 1464 studies about something that
can in principle be changed — diet, physical activity, sleep, hearing, blood pressure, alcohol, vaccination,
medicines and multidomain lifestyle programmes — and removes papers whose subject is a biomarker assay, a
brain scan, a genome-wide scan or laboratory biology. Those are important, but a heavily-cited amyloid
biomarker paper does not answer the question "what is worth studying about things people can change".
Most influential — ranked by RCR
40 with an RCR
Field- and time-normalised. 1.0 is the NIH-funded average for that field and year.
Source: iCite (NIH), retrieved 2026-09-27.
This Global Burden of Disease analysis estimates how many people had dementia worldwide in 2019 and forecasts the number for 2050. It attributes the projected rise mainly to population growth and population ageing: growth contributed most in sub-Saharan Africa, and ageing contributed most in east Asia. The authors say the country-level estimates can inform national planning, and they call for scaling up interventions on modifiable risk factors alongside research on biological mechanisms. It is a projection of case numbers, not a test of any treatment.
Summary
Projected increases in cases could largely be attributed to population growth and population ageing, although their relative importance varied by world region, with population growth contributing most to the increases in sub-Saharan Africa and population ageing contributing most to the increases in east Asia. Interpretation Growth in the number of individuals living with dementia underscores the need for public health planning efforts and policy to address the needs of this group. Country-level estimates can be used to inform national planning efforts and decisions. Multifaceted approaches, including scaling up interventions to address modifiable risk factors and investing in research on biological mechanisms, will be key in addressing the expected increases in the number of individuals affected by dementia. Funding Bill & Melinda Gates Foundation and Gates Ventures.
Key findings
Projected increases in cases could largely be attributed to population growth and population ageing, although their relative importance varied by world region, with population growth contributing most to the increases in sub-Saharan Africa and population ageing contributing most to the increases in east Asia.
Interpretation Growth in the number of individuals living with dementia underscores the need for public health planning efforts and policy to address the needs of this group.
Country-level estimates can be used to inform national planning efforts and decisions.
Multifaceted approaches, including scaling up interventions to address modifiable risk factors and investing in research on biological mechanisms, will be key in addressing the expected increases in the number of individuals affected by dementia.
Funding Bill & Melinda Gates Foundation and Gates Ventures.
This 2021 Lancet overview (a review, not a new study) reports that dementia prevalence is projected to double in Europe and triple worldwide by 2050, that Alzheimer's risk is 60–80% heritable with APOE the strongest of more than 40 genetic risk loci, and that PET scans and blood tests for amyloid β and phosphorylated tau "show great promise". It says multidomain lifestyle trials "suggest cognitive benefits" in people at increased risk of dementia, but also that lifestyle factors "do not directly affect Alzheimer's disease pathology". Anti-amyloid, anti-tau and anti-inflammatory drugs were in advanced trials when it was written.
Summary
In this Seminar, we highlight the main developments in the field of Alzheimer's disease. The most recent data indicate that, by 2050, the prevalence of dementia will double in Europe and triple worldwide, and that estimate is 3 times higher when based on a biological (rather than clinical) definition of Alzheimer's disease. The earliest phase of Alzheimer's disease (cellular phase) happens in parallel with accumulating amyloid β, inducing the spread of tau pathology. The risk of Alzheimer's disease is 60-80% dependent on heritable factors, with more than 40 Alzheimer's disease-associated genetic risk loci already identified, of which the APOE alleles have the strongest association with the disease. Novel biomarkers include PET scans and plasma assays for amyloid β and phosphorylated tau, which show great promise for clinical and research use. Multidomain lifestyle-based prevention trials suggest cognitive benefits in participants with increased risk of dementia. Lifestyle factors do not directly affect Alzheimer's disease pathology, but can still contribute to a positive outcome in individuals with Alzheimer's disease. Promising pharmacological treatments are poised at advanced stages of clinical trials and include anti-amyloid β, anti-tau, and anti-inflammatory strategies.
Key findings
The most recent data indicate that, by 2050, the prevalence of dementia will double in Europe and triple worldwide, and that estimate is 3 times higher when based on a biological (rather than clinical) definition of Alzheimer's disease.
Multidomain lifestyle-based prevention trials suggest cognitive benefits in participants with increased risk of dementia.
Obesity is described as a major health challenge that raises the risk of many diseases, including dementia. Long-term prevention and treatment strategies have not been successful, and the review calls for combining individual approaches with environmental and societal changes.
Summary
The prevalence of obesity has increased worldwide in the past ~50 years, reaching pandemic levels. Obesity represents a major health challenge because it substantially increases the risk of diseases such as type 2 diabetes mellitus, fatty liver disease, hypertension, myocardial infarction, stroke, dementia, osteoarthritis, obstructive sleep apnoea and several cancers, thereby contributing to a decline in both quality of life and life expectancy. Obesity is also associated with unemployment, social disadvantages and reduced socio-economic productivity, thus increasingly creating an economic burden. Thus far, obesity prevention and treatment strategies - both at the individual and population level - have not been successful in the long term. Lifestyle and behavioural interventions aimed at reducing calorie intake and increasing energy expenditure have limited effectiveness because complex and persistent hormonal, metabolic and neurochemical adaptations defend against weight loss and promote weight regain. Reducing the obesity burden requires approaches that combine individual interventions with changes in the environment and society. Therefore, a better understanding of the remarkable regional differences in obesity prevalence and trends might help to identify societal causes of obesity and provide guidance on which are the most promising intervention strategies.
Key findings
Obesity is also associated with unemployment, social disadvantages and reduced socio-economic productivity, thus increasingly creating an economic burden.
This large genetic study found 75 risk loci for Alzheimer's disease and related dementias and built a genetic risk score linked to future risk or progression from mild cognitive impairment. It identifies genetic risk factors only and reports no treatment, cure or prevention.
Summary
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
Key findings
We found 75 risk loci, of which 42 were new at the time of analysis.
We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia.
Evidence strength
low
Limitations
Some cases were identified by family-history ‘proxy’ status rather than a confirmed clinical diagnosis, which can introduce some misclassification compared with using only clinically diagnosed cases.
In an early 1.5 T MRI study of 12 people with Alzheimer's disease, 4 with multi-infarct dementia and 9 age-matched controls, small bright spots in the deep white matter appeared in about 60% of both the Alzheimer's patients and the controls and were unrelated to high blood pressure or other vascular risk factors. A more extensive smooth "halo" of brightness around the ventricles was more common in Alzheimer's patients (p = .024), and the authors suggest it "may be of diagnostic importance". This is a very small imaging comparison: it does not test a diagnostic rule, a treatment or any way of preventing the disease.
Summary
The type, frequency, and extent of MR signal abnormalities in Alzheimer's disease and normal aging are a subject of controversy. With a 1.5-MR unit we studied 12 Alzheimer patients, four subjects suffering from multiinfarct dementia and nine age-matched controls. Punctate or early confluent high-signal abnormalities in the deep white matter, noted in 60% of both Alzheimer patients and controls, were unrelated to the presence of hypertension or other vascular risk factors. A significant number of Alzheimer patients exhibited a more extensive smooth "halo" of periventricular hyperintensity when compared with controls (p = .024). Widespread deep white-matter hyperintensity (two patients) and extensive, irregular periventricular hyperintensity (three patients) were seen in multiinfarct dementia. Areas of high signal intensity affecting hippocampal and sylvian cortex were also present in five Alzheimer and two multiinfarct dementia patients, but absent in controls. Discrete, small foci of deep white-matter hyperintensity are not characteristic of Alzheimer's disease nor do they appear to imply a vascular cause for the dementing illness. The frequently observed "halo" of periventricular hyperintensity in Alzheimer's disease may be of diagnostic importance. High-signal abnormalities in specific cortical regions are likely to reflect disease processes localized to those structures.
Key findings
A significant number of Alzheimer patients exhibited a more extensive smooth "halo" of periventricular hyperintensity when compared with controls (p = .024).
This review states that the cause of Parkinson's disease is multifactorial and involves genetic and environmental factors, with risk factors such as pesticides and protective factors such as physical activity and tendency to smoke postulated but causality complicated by the long prodromal period. It notes that chronic neurodegenerative diseases such as Parkinson's disease and dementia are gaining higher public health priority, with multipronged prevention strategies mentioned, but reports no treatment or cure for Alzheimer's disease.
Summary
The epidemiology of Parkinson's disease shows marked variations in time, geography, ethnicity, age, and sex. Internationally, prevalence has increased over and above demographic changes. There are several potential reasons for this increase, including the decline in other competing causes of death. Whether incidence is increasing, especially in women or in many low-income and middle-income countries where there is a shortage of high-quality data, is less certain. Parkinson's disease is more common in older people and men, and a variety of environmental factors have been suggested to explain why, including exposure to neurotoxic agents. Within countries, there appear to be ethnic differences in disease risk, although these differences might reflect differential access to health care. The cause of Parkinson's disease is multifactorial, and involves genetic and environmental factors. Both risk factors (eg, pesticides) and protective factors (eg, physical activity and tendency to smoke) have been postulated to have a role in Parkinson's disease, although elucidating causality is complicated by the long prodromal period. Following the establishment of public health strategies to prevent cardiovascular diseases and some cancers, chronic neurodegenerative diseases such as Parkinson's disease and dementia are gaining a deserved higher priority. Multipronged prevention strategies are required that tackle population-based primary prevention, high-risk targeted secondary prevention, and Parkinson's disease-modifying therapies for tertiary prevention. Future international collaborations will be required to triangulate evidence from basic, applied, and epidemiological research, thereby enhancing the understanding and prevention of Parkinson's disease at a global level.
Key findings
The cause of Parkinson's disease is multifactorial, and involves genetic and environmental factors.
Both risk factors (eg, pesticides) and protective factors (eg, physical activity and tendency to smoke) have been postulated to have a role in Parkinson's disease, although elucidating causality is complicated by the long prodromal period.
Following the establishment of public health strategies to prevent cardiovascular diseases and some cancers, chronic neurodegenerative diseases such as Parkinson's disease and dementia are gaining a deserved higher priority.
Multipronged prevention strategies are required that tackle population-based primary prevention, high-risk targeted secondary prevention, and Parkinson's disease-modifying therapies for tertiary prevention.
Future international collaborations will be required to triangulate evidence from basic, applied, and epidemiological research, thereby enhancing the understanding and prevention of Parkinson's disease at a global level.
This systematic review estimated global dementia prevalence and projected rising numbers, especially in low- and middle-income countries. It offers a basis for planning care resources but does not evaluate any treatment or cure.
Summary
Background The evidence base on the prevalence of dementia is expanding rapidly, particularly in countries with low and middle incomes. A reappraisal of global prevalence and numbers is due, given the significant implications for social and public policy and planning. Methods In this study we provide a systematic review of the global literature on the prevalence of dementia (1980-2009) and metaanalysis to estimate the prevalence and numbers of those affected, aged ≥60 years in 21 Global Burden of Disease regions. Results Age-standardized prevalence for those aged ≥60 years varied in a narrow band, 5%-7% in most world regions, with a higher prevalence in Latin America (8.5%), and a distinctively lower prevalence in the four sub-Saharan African regions (2%-4%). It was estimated that 35.6 million people lived with dementia worldwide in 2010, with numbers expected to almost double every 20 years, to 65.7 million in 2030 and 115.4 million in 2050. In 2010, 58% of all people with dementia lived in countries with low or middle incomes, with this proportion anticipated to rise to 63% in 2030 and 71% in 2050. Conclusion The detailed estimates in this study constitute the best current basis for policymaking, planning, and allocation of health and welfare resources in dementia care. The age-specific prevalence of dementia varies little between world regions, and may converge further. Future projections of numbers of people with dementia may be modified substantially by preventive interventions (lowering incidence), improvements in treatment and care (prolonging survival), and disease-modifying interventions (preventing or slowing progression). All countries need to commission nationally representative surveys that are repeated regularly to monitor trends.
Key findings
A reappraisal of global prevalence and numbers is due, given the significant implications for social and public policy and planning.
Results Age-standardized prevalence for those aged ≥60 years varied in a narrow band, 5%-7% in most world regions, with a higher prevalence in Latin America (8.5%), and a distinctively lower prevalence in the four sub-Saharan African regions (2%-4%).
This review describes inflammageing as a risk factor for several conditions including dementia, but states that whether modulating inflammation beneficially affects the clinical course of non-cardiovascular health problems is controversial. It does not establish that treating inflammation prevents or cures Alzheimer's disease.
Summary
Most older individuals develop inflammageing, a condition characterized by elevated levels of blood inflammatory markers that carries high susceptibility to chronic morbidity, disability, frailty, and premature death. Potential mechanisms of inflammageing include genetic susceptibility, central obesity, increased gut permeability, changes to microbiota composition, cellular senescence, NLRP3 inflammasome activation, oxidative stress caused by dysfunctional mitochondria, immune cell dysregulation, and chronic infections. Inflammageing is a risk factor for cardiovascular diseases (CVDs), and clinical trials suggest that this association is causal. Inflammageing is also a risk factor for chronic kidney disease, diabetes mellitus, cancer, depression, dementia, and sarcopenia, but whether modulating inflammation beneficially affects the clinical course of non-CVD health problems is controversial. This uncertainty is an important issue to address because older patients with CVD are often affected by multimorbidity and frailty - which affect clinical manifestations, prognosis, and response to treatment - and are associated with inflammation by mechanisms similar to those in CVD. The hypothesis that inflammation affects CVD, multimorbidity, and frailty by inhibiting growth factors, increasing catabolism, and interfering with homeostatic signalling is supported by mechanistic studies but requires confirmation in humans. Whether early modulation of inflammageing prevents or delays the onset of cardiovascular frailty should be tested in clinical trials.
Key findings
Inflammageing is a risk factor for cardiovascular diseases (CVDs), and clinical trials suggest that this association is causal.
This uncertainty is an important issue to address because older patients with CVD are often affected by multimorbidity and frailty - which affect clinical manifestations, prognosis, and response to treatment - and are associated with inflammation by mechanisms similar to those in CVD.
In a randomised trial of 120 older adults, aerobic exercise training grew the front part of the hippocampus, a memory region that normally shrinks with age, by about 2% and improved spatial memory; in the control group hippocampal volume declined, and two other brain regions were unchanged. Larger gains went with higher blood levels of BDNF, a growth factor. The trial measured brain size and memory in ageing, not dementia or Alzheimer's disease.
Summary
The hippocampus shrinks in late adulthood, leading to impaired memory and increased risk for dementia. Hippocampal and medial temporal lobe volumes are larger in higher-fit adults, and physical activity training increases hippocampal perfusion, but the extent to which aerobic exercise training can modify hippocampal volume in late adulthood remains unknown. Here we show, in a randomized controlled trial with 120 older adults, that aerobic exercise training increases the size of the anterior hippocampus, leading to improvements in spatial memory. Exercise training increased hippocampal volume by 2%, effectively reversing age-related loss in volume by 1 to 2 y. We also demonstrate that increased hippocampal volume is associated with greater serum levels of BDNF, a mediator of neurogenesis in the dentate gyrus. Hippocampal volume declined in the control group, but higher preintervention fitness partially attenuated the decline, suggesting that fitness protects against volume loss. Caudate nucleus and thalamus volumes were unaffected by the intervention. These theoretically important findings indicate that aerobic exercise training is effective at reversing hippocampal volume loss in late adulthood, which is accompanied by improved memory function.
Key findings
The hippocampus shrinks in late adulthood, leading to impaired memory and increased risk for dementia.
We also demonstrate that increased hippocampal volume is associated with greater serum levels of BDNF, a mediator of neurogenesis in the dentate gyrus.
Hippocampal volume declined in the control group, but higher preintervention fitness partially attenuated the decline, suggesting that fitness protects against volume loss.
These theoretically important findings indicate that aerobic exercise training is effective at reversing hippocampal volume loss in late adulthood, which is accompanied by improved memory function.
Evidence strength
high
Study design / n
randomized controlled trial
Limitations
This trial was in healthy older adults, not people with Alzheimer's disease or MCI, so it shows exercise can grow the hippocampus and improve memory in normal aging, not that it can reverse hippocampal loss once Alzheimer's pathology is present.
In this two-year randomised trial in at-risk older people, a combined programme of diet, exercise, cognitive training and vascular risk monitoring produced a small, statistically significant advantage over control in the yearly change of a cognitive test-battery score (difference 0·022 per year; 95% CI 0·002–0·042). The authors say this "suggest[s]" such a programme "could improve or maintain cognitive functioning"; the record reports no dementia outcomes. Adverse events were more common with the intervention (7% vs 1%), mostly musculoskeletal pain.
Summary
Background Modifiable vascular and lifestyle-related risk factors have been associated with dementia risk in observational studies. Between-group difference in the change of NTB total score per year was 0·022 (95% CI 0·002-0·042, p=0·030). 153 (12%) individuals dropped out overall. Adverse events occurred in 46 (7%) participants in the intervention group compared with six (1%) participants in the control group; the most common adverse event was musculoskeletal pain (32 [5%] individuals for intervention vs no individuals for control). Interpretation Findings from this large, long-term, randomised controlled trial suggest that a multidomain intervention could improve or maintain cognitive functioning in at-risk elderly people from the general population.
Key findings
Background Modifiable vascular and lifestyle-related risk factors have been associated with dementia risk in observational studies.
Between-group difference in the change of NTB total score per year was 0·022 (95% CI 0·002-0·042, p=0·030). 153 (12%) individuals dropped out overall.
Adverse events occurred in 46 (7%) participants in the intervention group compared with six (1%) participants in the control group; the most common adverse event was musculoskeletal pain (32 [5%] individuals for intervention vs no individuals for control).
Interpretation Findings from this large, long-term, randomised controlled trial suggest that a multidomain intervention could improve or maintain cognitive functioning in at-risk elderly people from the general population.
In a genome-wide meta-analysis of 94,437 people with or without clinically diagnosed late-onset Alzheimer's disease, researchers confirmed 20 known genetic risk locations and found five new ones (IQCK, ACE, ADAM10, ADAMTS1 and WWOX). They also confirmed the immune-system variant HLA-DR15 as a risk factor. The genes point to immunity, lipid metabolism, tau-binding proteins and amyloid processing, and the authors say more rare variants remain to be found. These are statistical associations with risk: the study tests no treatment and does not show that any of these genes causes the disease.
Summary
Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10 -7 ), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
Key findings
We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia.
Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD.
Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD.
Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10 -7 ), indicating that additional rare variants remain to be identified.
We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
Evidence strength
high
Study design / n
meta-analysis · n = 94,437
Limitations
This is a genetic association study of diagnosed cases versus controls; it identifies statistical links between DNA locations and Alzheimer's risk but does not by itself establish how these genes cause disease.
This 2011 American Heart Association/American Stroke Association statement for healthcare professionals defines "vascular contributions to cognitive impairment and dementia" (VCI) as the whole spectrum of cognitive problems "associated with all forms of cerebral vascular brain injury-not solely stroke," from mild cognitive impairment through to dementia. It is a definition and practitioner guide, not a study with participants or measured results, so it does not by itself show that any treatment or risk-factor control prevents dementia.
Summary
This statement serves as an overall guide for practitioners to gain a better understanding of VCI and dementia, prevention, and treatment. Results The construct of VCI has been introduced to capture the entire spectrum of cognitive disorders associated with all forms of cerebral vascular brain injury-not solely stroke-ranging from mild cognitive impairment through fully developed dementia.
Key findings
This statement serves as an overall guide for practitioners to gain a better understanding of VCI and dementia, prevention, and treatment.
Results The construct of VCI has been introduced to capture the entire spectrum of cognitive disorders associated with all forms of cerebral vascular brain injury-not solely stroke-ranging from mild cognitive impairment through fully developed dementia.
This consensus study estimates how many people have dementia worldwide and projects that the number will grow substantially by 2040, especially in developing countries. It provides no information about treating, curing or preventing Alzheimer's disease.
Summary
Background 100 years after the first description, Alzheimer's disease is one of the most disabling and burdensome health conditions worldwide. We used the Delphi consensus method to determine dementia prevalence for each world region. Methods 12 international experts were provided with a systematic review of published studies on dementia and were asked to provide prevalence estimates for every WHO world region, for men and women combined, in 5-year age bands from 60 to 84 years, and for those aged 85 years and older. UN population estimates and projections were used to estimate numbers of people with dementia in 2001, 2020, and 2040. We estimated incidence rates from prevalence, remission, and mortality. Findings Evidence from well-planned, representative epidemiological surveys is scarce in many regions. We estimate that 24.3 million people have dementia today, with 4.6 million new cases of dementia every year (one new case every 7 seconds). The number of people affected will double every 20 years to 81.1 million by 2040. Most people with dementia live in developing countries (60% in 2001, rising to 71% by 2040). Rates of increase are not uniform; numbers in developed countries are forecast to increase by 100% between 2001 and 2040, but by more than 300% in India, China, and their south Asian and western Pacific neighbours. Interpretation We believe that the detailed estimates in this paper constitute the best currently available basis for policymaking, planning, and allocation of health and welfare resources.
Key findings
We estimate that 24.3 million people have dementia today, with 4.6 million new cases of dementia every year (one new case every 7 seconds).
The number of people affected will double every 20 years to 81.1 million by 2040.
Most people with dementia live in developing countries (60% in 2001, rising to 71% by 2040).
Rates of increase are not uniform; numbers in developed countries are forecast to increase by 100% between 2001 and 2040, but by more than 300% in India, China, and their south Asian and western Pacific neighbours.
Interpretation We believe that the detailed estimates in this paper constitute the best currently available basis for policymaking, planning, and allocation of health and welfare resources.
This analysis estimated the global burden of dementia and found that a portion of it could be attributed to modifiable risk factors like high BMI, high fasting plasma glucose, smoking, and high intake of sugar-sweetened beverages. It highlights the potential for prevention by addressing these factors.
Summary
We aimed to present the first detailed analysis of the global prevalence, mortality, and overall burden of dementia as captured by the Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2016, and highlight the most important messages for clinicians and neurologists. Overall, 28·8 million (95% UI 24·5-34·0) DALYs were attributed to dementia; 6·4 million (95% UI 3·4-10·5) of these could be attributed to the modifiable GBD risk factors of high BMI, high fasting plasma glucose, smoking, and a high intake of sugar-sweetened beverages.
Key findings
We aimed to present the first detailed analysis of the global prevalence, mortality, and overall burden of dementia as captured by the Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2016, and highlight the most important messages for clinicians and neurologists.
Overall, 28·8 million (95% UI 24·5-34·0) DALYs were attributed to dementia; 6·4 million (95% UI 3·4-10·5) of these could be attributed to the modifiable GBD risk factors of high BMI, high fasting plasma glucose, smoking, and a high intake of sugar-sweetened beverages.
This Global Burden of Disease analysis estimates how many people had dementia worldwide in 2019 and forecasts the number for 2050. It attributes the projected rise mainly to population growth and population ageing: growth contributed most in sub-Saharan Africa, and ageing contributed most in east Asia. The authors say the country-level estimates can inform national planning, and they call for scaling up interventions on modifiable risk factors alongside research on biological mechanisms. It is a projection of case numbers, not a test of any treatment.
Summary
Projected increases in cases could largely be attributed to population growth and population ageing, although their relative importance varied by world region, with population growth contributing most to the increases in sub-Saharan Africa and population ageing contributing most to the increases in east Asia. Interpretation Growth in the number of individuals living with dementia underscores the need for public health planning efforts and policy to address the needs of this group. Country-level estimates can be used to inform national planning efforts and decisions. Multifaceted approaches, including scaling up interventions to address modifiable risk factors and investing in research on biological mechanisms, will be key in addressing the expected increases in the number of individuals affected by dementia. Funding Bill & Melinda Gates Foundation and Gates Ventures.
Key findings
Projected increases in cases could largely be attributed to population growth and population ageing, although their relative importance varied by world region, with population growth contributing most to the increases in sub-Saharan Africa and population ageing contributing most to the increases in east Asia.
Interpretation Growth in the number of individuals living with dementia underscores the need for public health planning efforts and policy to address the needs of this group.
Country-level estimates can be used to inform national planning efforts and decisions.
Multifaceted approaches, including scaling up interventions to address modifiable risk factors and investing in research on biological mechanisms, will be key in addressing the expected increases in the number of individuals affected by dementia.
Funding Bill & Melinda Gates Foundation and Gates Ventures.
In an early 1.5 T MRI study of 12 people with Alzheimer's disease, 4 with multi-infarct dementia and 9 age-matched controls, small bright spots in the deep white matter appeared in about 60% of both the Alzheimer's patients and the controls and were unrelated to high blood pressure or other vascular risk factors. A more extensive smooth "halo" of brightness around the ventricles was more common in Alzheimer's patients (p = .024), and the authors suggest it "may be of diagnostic importance". This is a very small imaging comparison: it does not test a diagnostic rule, a treatment or any way of preventing the disease.
Summary
The type, frequency, and extent of MR signal abnormalities in Alzheimer's disease and normal aging are a subject of controversy. With a 1.5-MR unit we studied 12 Alzheimer patients, four subjects suffering from multiinfarct dementia and nine age-matched controls. Punctate or early confluent high-signal abnormalities in the deep white matter, noted in 60% of both Alzheimer patients and controls, were unrelated to the presence of hypertension or other vascular risk factors. A significant number of Alzheimer patients exhibited a more extensive smooth "halo" of periventricular hyperintensity when compared with controls (p = .024). Widespread deep white-matter hyperintensity (two patients) and extensive, irregular periventricular hyperintensity (three patients) were seen in multiinfarct dementia. Areas of high signal intensity affecting hippocampal and sylvian cortex were also present in five Alzheimer and two multiinfarct dementia patients, but absent in controls. Discrete, small foci of deep white-matter hyperintensity are not characteristic of Alzheimer's disease nor do they appear to imply a vascular cause for the dementing illness. The frequently observed "halo" of periventricular hyperintensity in Alzheimer's disease may be of diagnostic importance. High-signal abnormalities in specific cortical regions are likely to reflect disease processes localized to those structures.
Key findings
A significant number of Alzheimer patients exhibited a more extensive smooth "halo" of periventricular hyperintensity when compared with controls (p = .024).
This 2021 Lancet overview (a review, not a new study) reports that dementia prevalence is projected to double in Europe and triple worldwide by 2050, that Alzheimer's risk is 60–80% heritable with APOE the strongest of more than 40 genetic risk loci, and that PET scans and blood tests for amyloid β and phosphorylated tau "show great promise". It says multidomain lifestyle trials "suggest cognitive benefits" in people at increased risk of dementia, but also that lifestyle factors "do not directly affect Alzheimer's disease pathology". Anti-amyloid, anti-tau and anti-inflammatory drugs were in advanced trials when it was written.
Summary
In this Seminar, we highlight the main developments in the field of Alzheimer's disease. The most recent data indicate that, by 2050, the prevalence of dementia will double in Europe and triple worldwide, and that estimate is 3 times higher when based on a biological (rather than clinical) definition of Alzheimer's disease. The earliest phase of Alzheimer's disease (cellular phase) happens in parallel with accumulating amyloid β, inducing the spread of tau pathology. The risk of Alzheimer's disease is 60-80% dependent on heritable factors, with more than 40 Alzheimer's disease-associated genetic risk loci already identified, of which the APOE alleles have the strongest association with the disease. Novel biomarkers include PET scans and plasma assays for amyloid β and phosphorylated tau, which show great promise for clinical and research use. Multidomain lifestyle-based prevention trials suggest cognitive benefits in participants with increased risk of dementia. Lifestyle factors do not directly affect Alzheimer's disease pathology, but can still contribute to a positive outcome in individuals with Alzheimer's disease. Promising pharmacological treatments are poised at advanced stages of clinical trials and include anti-amyloid β, anti-tau, and anti-inflammatory strategies.
Key findings
The most recent data indicate that, by 2050, the prevalence of dementia will double in Europe and triple worldwide, and that estimate is 3 times higher when based on a biological (rather than clinical) definition of Alzheimer's disease.
Multidomain lifestyle-based prevention trials suggest cognitive benefits in participants with increased risk of dementia.
Obesity is described as a major health challenge that raises the risk of many diseases, including dementia. Long-term prevention and treatment strategies have not been successful, and the review calls for combining individual approaches with environmental and societal changes.
Summary
The prevalence of obesity has increased worldwide in the past ~50 years, reaching pandemic levels. Obesity represents a major health challenge because it substantially increases the risk of diseases such as type 2 diabetes mellitus, fatty liver disease, hypertension, myocardial infarction, stroke, dementia, osteoarthritis, obstructive sleep apnoea and several cancers, thereby contributing to a decline in both quality of life and life expectancy. Obesity is also associated with unemployment, social disadvantages and reduced socio-economic productivity, thus increasingly creating an economic burden. Thus far, obesity prevention and treatment strategies - both at the individual and population level - have not been successful in the long term. Lifestyle and behavioural interventions aimed at reducing calorie intake and increasing energy expenditure have limited effectiveness because complex and persistent hormonal, metabolic and neurochemical adaptations defend against weight loss and promote weight regain. Reducing the obesity burden requires approaches that combine individual interventions with changes in the environment and society. Therefore, a better understanding of the remarkable regional differences in obesity prevalence and trends might help to identify societal causes of obesity and provide guidance on which are the most promising intervention strategies.
Key findings
Obesity is also associated with unemployment, social disadvantages and reduced socio-economic productivity, thus increasingly creating an economic burden.
This consensus study estimates how many people have dementia worldwide and projects that the number will grow substantially by 2040, especially in developing countries. It provides no information about treating, curing or preventing Alzheimer's disease.
Summary
Background 100 years after the first description, Alzheimer's disease is one of the most disabling and burdensome health conditions worldwide. We used the Delphi consensus method to determine dementia prevalence for each world region. Methods 12 international experts were provided with a systematic review of published studies on dementia and were asked to provide prevalence estimates for every WHO world region, for men and women combined, in 5-year age bands from 60 to 84 years, and for those aged 85 years and older. UN population estimates and projections were used to estimate numbers of people with dementia in 2001, 2020, and 2040. We estimated incidence rates from prevalence, remission, and mortality. Findings Evidence from well-planned, representative epidemiological surveys is scarce in many regions. We estimate that 24.3 million people have dementia today, with 4.6 million new cases of dementia every year (one new case every 7 seconds). The number of people affected will double every 20 years to 81.1 million by 2040. Most people with dementia live in developing countries (60% in 2001, rising to 71% by 2040). Rates of increase are not uniform; numbers in developed countries are forecast to increase by 100% between 2001 and 2040, but by more than 300% in India, China, and their south Asian and western Pacific neighbours. Interpretation We believe that the detailed estimates in this paper constitute the best currently available basis for policymaking, planning, and allocation of health and welfare resources.
Key findings
We estimate that 24.3 million people have dementia today, with 4.6 million new cases of dementia every year (one new case every 7 seconds).
The number of people affected will double every 20 years to 81.1 million by 2040.
Most people with dementia live in developing countries (60% in 2001, rising to 71% by 2040).
Rates of increase are not uniform; numbers in developed countries are forecast to increase by 100% between 2001 and 2040, but by more than 300% in India, China, and their south Asian and western Pacific neighbours.
Interpretation We believe that the detailed estimates in this paper constitute the best currently available basis for policymaking, planning, and allocation of health and welfare resources.
This systematic review estimated global dementia prevalence and projected rising numbers, especially in low- and middle-income countries. It offers a basis for planning care resources but does not evaluate any treatment or cure.
Summary
Background The evidence base on the prevalence of dementia is expanding rapidly, particularly in countries with low and middle incomes. A reappraisal of global prevalence and numbers is due, given the significant implications for social and public policy and planning. Methods In this study we provide a systematic review of the global literature on the prevalence of dementia (1980-2009) and metaanalysis to estimate the prevalence and numbers of those affected, aged ≥60 years in 21 Global Burden of Disease regions. Results Age-standardized prevalence for those aged ≥60 years varied in a narrow band, 5%-7% in most world regions, with a higher prevalence in Latin America (8.5%), and a distinctively lower prevalence in the four sub-Saharan African regions (2%-4%). It was estimated that 35.6 million people lived with dementia worldwide in 2010, with numbers expected to almost double every 20 years, to 65.7 million in 2030 and 115.4 million in 2050. In 2010, 58% of all people with dementia lived in countries with low or middle incomes, with this proportion anticipated to rise to 63% in 2030 and 71% in 2050. Conclusion The detailed estimates in this study constitute the best current basis for policymaking, planning, and allocation of health and welfare resources in dementia care. The age-specific prevalence of dementia varies little between world regions, and may converge further. Future projections of numbers of people with dementia may be modified substantially by preventive interventions (lowering incidence), improvements in treatment and care (prolonging survival), and disease-modifying interventions (preventing or slowing progression). All countries need to commission nationally representative surveys that are repeated regularly to monitor trends.
Key findings
A reappraisal of global prevalence and numbers is due, given the significant implications for social and public policy and planning.
Results Age-standardized prevalence for those aged ≥60 years varied in a narrow band, 5%-7% in most world regions, with a higher prevalence in Latin America (8.5%), and a distinctively lower prevalence in the four sub-Saharan African regions (2%-4%).
In a randomised trial of 120 older adults, aerobic exercise training grew the front part of the hippocampus, a memory region that normally shrinks with age, by about 2% and improved spatial memory; in the control group hippocampal volume declined, and two other brain regions were unchanged. Larger gains went with higher blood levels of BDNF, a growth factor. The trial measured brain size and memory in ageing, not dementia or Alzheimer's disease.
Summary
The hippocampus shrinks in late adulthood, leading to impaired memory and increased risk for dementia. Hippocampal and medial temporal lobe volumes are larger in higher-fit adults, and physical activity training increases hippocampal perfusion, but the extent to which aerobic exercise training can modify hippocampal volume in late adulthood remains unknown. Here we show, in a randomized controlled trial with 120 older adults, that aerobic exercise training increases the size of the anterior hippocampus, leading to improvements in spatial memory. Exercise training increased hippocampal volume by 2%, effectively reversing age-related loss in volume by 1 to 2 y. We also demonstrate that increased hippocampal volume is associated with greater serum levels of BDNF, a mediator of neurogenesis in the dentate gyrus. Hippocampal volume declined in the control group, but higher preintervention fitness partially attenuated the decline, suggesting that fitness protects against volume loss. Caudate nucleus and thalamus volumes were unaffected by the intervention. These theoretically important findings indicate that aerobic exercise training is effective at reversing hippocampal volume loss in late adulthood, which is accompanied by improved memory function.
Key findings
The hippocampus shrinks in late adulthood, leading to impaired memory and increased risk for dementia.
We also demonstrate that increased hippocampal volume is associated with greater serum levels of BDNF, a mediator of neurogenesis in the dentate gyrus.
Hippocampal volume declined in the control group, but higher preintervention fitness partially attenuated the decline, suggesting that fitness protects against volume loss.
These theoretically important findings indicate that aerobic exercise training is effective at reversing hippocampal volume loss in late adulthood, which is accompanied by improved memory function.
Evidence strength
high
Study design / n
randomized controlled trial
Limitations
This trial was in healthy older adults, not people with Alzheimer's disease or MCI, so it shows exercise can grow the hippocampus and improve memory in normal aging, not that it can reverse hippocampal loss once Alzheimer's pathology is present.
This 2011 American Heart Association/American Stroke Association statement for healthcare professionals defines "vascular contributions to cognitive impairment and dementia" (VCI) as the whole spectrum of cognitive problems "associated with all forms of cerebral vascular brain injury-not solely stroke," from mild cognitive impairment through to dementia. It is a definition and practitioner guide, not a study with participants or measured results, so it does not by itself show that any treatment or risk-factor control prevents dementia.
Summary
This statement serves as an overall guide for practitioners to gain a better understanding of VCI and dementia, prevention, and treatment. Results The construct of VCI has been introduced to capture the entire spectrum of cognitive disorders associated with all forms of cerebral vascular brain injury-not solely stroke-ranging from mild cognitive impairment through fully developed dementia.
Key findings
This statement serves as an overall guide for practitioners to gain a better understanding of VCI and dementia, prevention, and treatment.
Results The construct of VCI has been introduced to capture the entire spectrum of cognitive disorders associated with all forms of cerebral vascular brain injury-not solely stroke-ranging from mild cognitive impairment through fully developed dementia.
This review describes inflammageing as a risk factor for several conditions including dementia, but states that whether modulating inflammation beneficially affects the clinical course of non-cardiovascular health problems is controversial. It does not establish that treating inflammation prevents or cures Alzheimer's disease.
Summary
Most older individuals develop inflammageing, a condition characterized by elevated levels of blood inflammatory markers that carries high susceptibility to chronic morbidity, disability, frailty, and premature death. Potential mechanisms of inflammageing include genetic susceptibility, central obesity, increased gut permeability, changes to microbiota composition, cellular senescence, NLRP3 inflammasome activation, oxidative stress caused by dysfunctional mitochondria, immune cell dysregulation, and chronic infections. Inflammageing is a risk factor for cardiovascular diseases (CVDs), and clinical trials suggest that this association is causal. Inflammageing is also a risk factor for chronic kidney disease, diabetes mellitus, cancer, depression, dementia, and sarcopenia, but whether modulating inflammation beneficially affects the clinical course of non-CVD health problems is controversial. This uncertainty is an important issue to address because older patients with CVD are often affected by multimorbidity and frailty - which affect clinical manifestations, prognosis, and response to treatment - and are associated with inflammation by mechanisms similar to those in CVD. The hypothesis that inflammation affects CVD, multimorbidity, and frailty by inhibiting growth factors, increasing catabolism, and interfering with homeostatic signalling is supported by mechanistic studies but requires confirmation in humans. Whether early modulation of inflammageing prevents or delays the onset of cardiovascular frailty should be tested in clinical trials.
Key findings
Inflammageing is a risk factor for cardiovascular diseases (CVDs), and clinical trials suggest that this association is causal.
This uncertainty is an important issue to address because older patients with CVD are often affected by multimorbidity and frailty - which affect clinical manifestations, prognosis, and response to treatment - and are associated with inflammation by mechanisms similar to those in CVD.
In this two-year randomised trial in at-risk older people, a combined programme of diet, exercise, cognitive training and vascular risk monitoring produced a small, statistically significant advantage over control in the yearly change of a cognitive test-battery score (difference 0·022 per year; 95% CI 0·002–0·042). The authors say this "suggest[s]" such a programme "could improve or maintain cognitive functioning"; the record reports no dementia outcomes. Adverse events were more common with the intervention (7% vs 1%), mostly musculoskeletal pain.
Summary
Background Modifiable vascular and lifestyle-related risk factors have been associated with dementia risk in observational studies. Between-group difference in the change of NTB total score per year was 0·022 (95% CI 0·002-0·042, p=0·030). 153 (12%) individuals dropped out overall. Adverse events occurred in 46 (7%) participants in the intervention group compared with six (1%) participants in the control group; the most common adverse event was musculoskeletal pain (32 [5%] individuals for intervention vs no individuals for control). Interpretation Findings from this large, long-term, randomised controlled trial suggest that a multidomain intervention could improve or maintain cognitive functioning in at-risk elderly people from the general population.
Key findings
Background Modifiable vascular and lifestyle-related risk factors have been associated with dementia risk in observational studies.
Between-group difference in the change of NTB total score per year was 0·022 (95% CI 0·002-0·042, p=0·030). 153 (12%) individuals dropped out overall.
Adverse events occurred in 46 (7%) participants in the intervention group compared with six (1%) participants in the control group; the most common adverse event was musculoskeletal pain (32 [5%] individuals for intervention vs no individuals for control).
Interpretation Findings from this large, long-term, randomised controlled trial suggest that a multidomain intervention could improve or maintain cognitive functioning in at-risk elderly people from the general population.
In a genome-wide meta-analysis of 94,437 people with or without clinically diagnosed late-onset Alzheimer's disease, researchers confirmed 20 known genetic risk locations and found five new ones (IQCK, ACE, ADAM10, ADAMTS1 and WWOX). They also confirmed the immune-system variant HLA-DR15 as a risk factor. The genes point to immunity, lipid metabolism, tau-binding proteins and amyloid processing, and the authors say more rare variants remain to be found. These are statistical associations with risk: the study tests no treatment and does not show that any of these genes causes the disease.
Summary
Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10 -7 ), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
Key findings
We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia.
Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD.
Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD.
Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10 -7 ), indicating that additional rare variants remain to be identified.
We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
Evidence strength
high
Study design / n
meta-analysis · n = 94,437
Limitations
This is a genetic association study of diagnosed cases versus controls; it identifies statistical links between DNA locations and Alzheimer's risk but does not by itself establish how these genes cause disease.
In this Framingham Study cohort, elevated plasma homocysteine levels measured at baseline and eight years earlier were associated with an increased risk of newly diagnosed dementia and Alzheimer's disease over a median follow-up of eight years. The study identifies homocysteine as a risk factor but does not test whether lowering it prevents dementia.
Summary
Background In cross-sectional studies, elevated plasma homocysteine levels have been associated with poor cognition and dementia. Studies of newly diagnosed dementia are required in order to establish whether the elevated homocysteine levels precede the onset of dementia or result from dementia-related nutritional and vitamin deficiencies. Methods A total of 1092 subjects without dementia (667 women and 425 men; mean age, 76 years) from the Framingham Study constituted our study sample. We examined the relation of the plasma total homocysteine level measured at base line and that measured eight years earlier to the risk of newly diagnosed dementia on follow-up. We used multivariable proportional-hazards regression to adjust for age, sex, apolipoprotein E genotype, vascular risk factors other than homocysteine, and plasma levels of folate and vitamins B12 and B6. Results Over a median follow-up period of eight years, dementia developed in 111 subjects, including 83 given a diagnosis of Alzheimer's disease. The multivariable-adjusted relative risk of dementia was 1.4 (95 percent confidence interval, 1.1 to 1.9) for each increase of 1 SD in the log-transformed homocysteine value either at base line or eight years earlier. The relative risk of Alzheimer's disease was 1.8 (95 percent confidence interval, 1.3 to 2.5) per increase of 1 SD at base line and 1.6 (95 percent confidence interval, 1.2 to 2.1) per increase of 1 SD eight years before base line. With a plasma homocysteine level greater than 14 micromol per liter, the risk of Alzheimer's disease nearly doubled. Conclusions An increased plasma homocysteine level is a strong, independent risk factor for the development of dementia and Alzheimer's disease.
Key findings
Background In cross-sectional studies, elevated plasma homocysteine levels have been associated with poor cognition and dementia.
Studies of newly diagnosed dementia are required in order to establish whether the elevated homocysteine levels precede the onset of dementia or result from dementia-related nutritional and vitamin deficiencies.
Results Over a median follow-up period of eight years, dementia developed in 111 subjects, including 83 given a diagnosis of Alzheimer's disease.
This review provides evidence-based guidance for prescribing exercise as therapy across 26 chronic diseases including dementia. It discusses exercise as a therapy, not a cure or proven prevention for Alzheimer's disease.
Summary
This review provides the reader with the up-to-date evidence-based basis for prescribing exercise as medicine in the treatment of 26 different diseases: psychiatric diseases (depression, anxiety, stress, schizophrenia); neurological diseases (dementia, Parkinson's disease, multiple sclerosis); metabolic diseases (obesity, hyperlipidemia, metabolic syndrome, polycystic ovarian syndrome, type 2 diabetes, type 1 diabetes); cardiovascular diseases (hypertension, coronary heart disease, heart failure, cerebral apoplexy, and claudication intermittent); pulmonary diseases (chronic obstructive pulmonary disease, asthma, cystic fibrosis); musculo-skeletal disorders (osteoarthritis, osteoporosis, back pain, rheumatoid arthritis); and cancer. The effect of exercise therapy on disease pathogenesis and symptoms are given and the possible mechanisms of action are discussed. We have interpreted the scientific literature and for each disease, we provide the reader with our best advice regarding the optimal type and dose for prescription of exercise.
Key findings
This review provides the reader with the up-to-date evidence-based basis for prescribing exercise as medicine in the treatment of 26 different diseases: psychiatric diseases (depression, anxiety, stress, schizophrenia); neurological diseases (dementia, Parkinson's disease, multiple sclerosis); metabolic diseases (obesity, hyperlipidemia, metabolic syndrome, polycystic ovarian syndrome, type 2 diabetes, type 1 diabetes); cardiovascular diseases (hypertension, coronary heart disease, heart failure, cerebral apoplexy, and claudication intermittent); pulmonary diseases (chronic obstructive pulmonary disease, asthma, cystic fibrosis); musculo-skeletal disorders (osteoarthritis, osteoporosis, back pain, rheumatoid arthritis); and cancer.
The effect of exercise therapy on disease pathogenesis and symptoms are given and the possible mechanisms of action are discussed.
We have interpreted the scientific literature and for each disease, we provide the reader with our best advice regarding the optimal type and dose for prescription of exercise.
Caregivers who reported feeling mental or emotional strain from caregiving had a 63% higher adjusted mortality risk than non-caregivers. Caregivers who did not report strain showed no elevated mortality risk, so the danger was caregiving under strain rather than caregiving itself.
Summary
This prospective study followed 392 older spousal caregivers and 427 non-caregivers for an average of 4.5 years. It found that caregivers who reported feeling mental or emotional strain from caregiving had a notably higher risk of dying during the study period than people who weren't caregiving — caregiving itself wasn't the danger, but caregiving under strain was.
Key findings
103 of 819 participants (12.6%) died over the ~4.5-year follow-up
Caregivers experiencing strain had a 63% higher adjusted mortality risk than non-caregivers (RR 1.63, 95% CI 1.00-2.65)
Caregivers who did not report strain, and non-caregiving spouses of disabled partners, showed no elevated mortality risk
Effect size
RR 1.63 (95% CI 1.00-2.65) for strained caregivers vs. non-caregivers
Evidence strength
high
Study design / n
cohort · n = 819
Limitations
Observational cohort; strain was self-reported; caregivers without strain and non-caregiving spouses of disabled partners showed no elevated risk, so the effect is specific to reported strain, not caregiving per se.
This 2006 Lancet review describes mild cognitive impairment as cognitive decline greater than expected for a person's age and education that does not notably interfere with daily life, affecting 3% to 19% of over-65s in population studies. It reports that some people stay stable or return to normal, but more than half progress to dementia within five years, and that the amnestic subtype carries a high risk of Alzheimer's disease. The authors suggest that identifying MCI could allow secondary prevention by controlling risk factors such as systolic hypertension, a proposal rather than a tested result.
Summary
Mild cognitive impairment is a syndrome defined as cognitive decline greater than expected for an individual's age and education level but that does not interfere notably with activities of daily life. Prevalence in population-based epidemiological studies ranges from 3% to 19% in adults older than 65 years. Some people with mild cognitive impairment seem to remain stable or return to normal over time, but more than half progress to dementia within 5 years. Mild cognitive impairment can thus be regarded as a risk state for dementia, and its identification could lead to secondary prevention by controlling risk factors such as systolic hypertension. The amnestic subtype of mild cognitive impairment has a high risk of progression to Alzheimer's disease, and it could constitute a prodromal stage of this disorder. Other definitions and subtypes of mild cognitive impairment need to be studied as potential prodromes of Alzheimer's disease and other types of dementia.
Key findings
Prevalence in population-based epidemiological studies ranges from 3% to 19% in adults older than 65 years.
Some people with mild cognitive impairment seem to remain stable or return to normal over time, but more than half progress to dementia within 5 years.
Mild cognitive impairment can thus be regarded as a risk state for dementia, and its identification could lead to secondary prevention by controlling risk factors such as systolic hypertension.
The amnestic subtype of mild cognitive impairment has a high risk of progression to Alzheimer's disease, and it could constitute a prodromal stage of this disorder.
Other definitions and subtypes of mild cognitive impairment need to be studied as potential prodromes of Alzheimer's disease and other types of dementia.
This large genetic study found 75 risk loci for Alzheimer's disease and related dementias and built a genetic risk score linked to future risk or progression from mild cognitive impairment. It identifies genetic risk factors only and reports no treatment, cure or prevention.
Summary
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
Key findings
We found 75 risk loci, of which 42 were new at the time of analysis.
We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia.
Evidence strength
low
Limitations
Some cases were identified by family-history ‘proxy’ status rather than a confirmed clinical diagnosis, which can introduce some misclassification compared with using only clinically diagnosed cases.
This analysis estimated the global burden of dementia and found that a portion of it could be attributed to modifiable risk factors like high BMI, high fasting plasma glucose, smoking, and high intake of sugar-sweetened beverages. It highlights the potential for prevention by addressing these factors.
Summary
We aimed to present the first detailed analysis of the global prevalence, mortality, and overall burden of dementia as captured by the Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2016, and highlight the most important messages for clinicians and neurologists. Overall, 28·8 million (95% UI 24·5-34·0) DALYs were attributed to dementia; 6·4 million (95% UI 3·4-10·5) of these could be attributed to the modifiable GBD risk factors of high BMI, high fasting plasma glucose, smoking, and a high intake of sugar-sweetened beverages.
Key findings
We aimed to present the first detailed analysis of the global prevalence, mortality, and overall burden of dementia as captured by the Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2016, and highlight the most important messages for clinicians and neurologists.
Overall, 28·8 million (95% UI 24·5-34·0) DALYs were attributed to dementia; 6·4 million (95% UI 3·4-10·5) of these could be attributed to the modifiable GBD risk factors of high BMI, high fasting plasma glucose, smoking, and a high intake of sugar-sweetened beverages.
This population study found that type 2 diabetes almost doubled the risk of dementia and Alzheimer's disease, with the highest risk in patients treated with insulin. It identifies diabetes as a possible contributor to dementia but does not test whether treating diabetes prevents or cures Alzheimer's disease.
Summary
Objective To determine the influence of type 2 diabetes mellitus on the risk of dementia and AD. Background Both dementia and diabetes are frequent disorders in elderly people. Methods Prospective population-based cohort study among 6,370 elderly subjects. At baseline study participants were examined for presence of diabetes mellitus. Nondemented participants were followed up, on average, for 2.1 years. Incident dementia was diagnosed using a three-step screening and comprehensive diagnostic workup. To complete the follow-up, medical files were studied of persons who could not be reexamined. We estimated relative risks with proportional hazard regression, adjusting for age, sex, and possible confounders. Results During the follow-up, 126 patients became demented, of whom 89 had AD. Diabetes mellitus almost doubled the risk of dementia (relative risk [RR] 1.9 [1.3 to 2.8]) and AD (RR 1.9 [1.2 to 3.1]). Patients treated with insulin were at highest risk of dementia (RR 4.3 [1.7 to 10.5]). Conclusion The diabetes attributable risk for dementia of 8.8% suggests that diabetes may have contributed to the clinical syndrome in a substantial proportion of all dementia patients.
Key findings
Results During the follow-up, 126 patients became demented, of whom 89 had AD.
Conclusion The diabetes attributable risk for dementia of 8.8% suggests that diabetes may have contributed to the clinical syndrome in a substantial proportion of all dementia patients.
This now-retired American Academy of Neurology guideline (marked "[RETIRED]" in its title) systematically reviewed MCI research. It reported prevalence rising from 6.7% at ages 60–64 to 25.2% at 80–84, and found that 14.9% of people over 65 with MCI developed dementia within 2 years. It found "no high-quality evidence" for any drug treatment: clinicians may choose not to offer cholinesterase inhibitors, and must discuss the lack of evidence if they do. It recommended regular exercise, which was "likely to improve cognitive measures" over 6 months, and recommended monitoring cognition over time.
Summary
Objective To update the 2001 American Academy of Neurology (AAN) guideline on mild cognitive impairment (MCI). Methods The guideline panel systematically reviewed MCI prevalence, prognosis, and treatment articles according to AAN evidence classification criteria, and based recommendations on evidence and modified Delphi consensus. Results MCI prevalence was 6.7% for ages 60-64, 8.4% for 65-69, 10.1% for 70-74, 14.8% for 75-79, and 25.2% for 80-84. Cumulative dementia incidence was 14.9% in individuals with MCI older than age 65 years followed for 2 years. No high-quality evidence exists to support pharmacologic treatments for MCI. In patients with MCI, exercise training (6 months) is likely to improve cognitive measures and cognitive training may improve cognitive measures. Major recommendations Clinicians should assess for MCI with validated tools in appropriate scenarios (Level B). Clinicians should evaluate patients with MCI for modifiable risk factors, assess for functional impairment, and assess for and treat behavioral/neuropsychiatric symptoms (Level B). Clinicians should monitor cognitive status of patients with MCI over time (Level B). Cognitively impairing medications should be discontinued where possible and behavioral symptoms treated (Level B). Clinicians may choose not to offer cholinesterase inhibitors (Level B); if offering, they must first discuss lack of evidence (Level A). Clinicians should recommend regular exercise (Level B). Clinicians may recommend cognitive training (Level C). Clinicians should discuss diagnosis, prognosis, long-term planning, and the lack of effective medicine options (Level B), and may discuss biomarker research with patients with MCI and families (Level C).
Key findings
Results MCI prevalence was 6.7% for ages 60-64, 8.4% for 65-69, 10.1% for 70-74, 14.8% for 75-79, and 25.2% for 80-84.
This 2006 systematic review of 14 long-term population studies, "of variable methodological quality", found that dementia was more common in people with diabetes in 7 of 10 studies, including Alzheimer's disease (8 of 13) and vascular dementia (6 of 9). It gives no single estimate of how much higher the risk is. Most studies lacked data on blood-sugar control, diabetes complications, high blood pressure and stroke, so the review cannot say whether diabetes itself or these related conditions explain the link. The authors call for better studies and do not show that treating diabetes prevents dementia.
Summary
The relation between diabetes and major types of dementia is controversial. This systematic review examines the incidence of dementia in people with diabetes mellitus. We identified 14 eligible longitudinal population-based studies of variable methodological quality. The incidence of "any dementia" was higher in individuals with diabetes than in those without diabetes in seven of ten studies reporting this aggregate outcome. This high risk included both Alzheimer's disease and vascular dementia (eight of 13 studies and six of nine studies respectively). Detailed data on modulating and mediating effects of glycaemic control, microvascular complications, and comorbidity (eg, hypertension and stroke) were generally absent. The findings of mechanistic studies suggest that vascular disease and alterations in glucose, insulin, and amyloid metabolism underlie the pathophysiology, but which of these mechanisms are clinically relevant is unclear. Further high quality studies need to be initiated, with objective diabetes assessment, together with reliable methods to establish the contribution of vascular disease and other comorbidity to dementia.
Key findings
The findings of mechanistic studies suggest that vascular disease and alterations in glucose, insulin, and amyloid metabolism underlie the pathophysiology, but which of these mechanisms are clinically relevant is unclear.
In this randomized, placebo-controlled trial within the Women's Health Initiative, 61 postmenopausal women were diagnosed with probable dementia over an average of about 4 years: 40 in the estrogen-plus-progestin group and 21 in the placebo group. The authors estimate this means "an additional 23 cases of dementia per 10 000 women per year", and say that these findings, "coupled with previously reported WHI data", support the conclusion that the risks of estrogen plus progestin outweigh the benefits. The record does not report results for mild cognitive impairment or for estrogen taken alone.
Summary
Objective To evaluate the effect of estrogen plus progestin on the incidence of dementia and mild cognitive impairment compared with placebo. Results The mean (SD) time between the date of randomization into WHI and the last Modified Mini-Mental State Examination (3MSE) for all WHIMS participants was 4.05 (1.19) years. Overall, 61 women were diagnosed with probable dementia, 40 (66%) in the estrogen plus progestin group compared with 21 (34%) in the placebo group. This increased risk would result in an additional 23 cases of dementia per 10 000 women per year. These findings, coupled with previously reported WHI data, support the conclusion that the risks of estrogen plus progestin outweigh the benefits.
Key findings
Objective To evaluate the effect of estrogen plus progestin on the incidence of dementia and mild cognitive impairment compared with placebo.
Results The mean (SD) time between the date of randomization into WHI and the last Modified Mini-Mental State Examination (3MSE) for all WHIMS participants was 4.05 (1.19) years.
Overall, 61 women were diagnosed with probable dementia, 40 (66%) in the estrogen plus progestin group compared with 21 (34%) in the placebo group.
This increased risk would result in an additional 23 cases of dementia per 10 000 women per year.
These findings, coupled with previously reported WHI data, support the conclusion that the risks of estrogen plus progestin outweigh the benefits.
This narrative review defines vascular cognitive impairment as changes in thinking "attributable to cerebrovascular causes", from subtle deficits to dementia. It notes that vascular damage often coexists with Alzheimer's disease. It sets out to examine how damaged blood vessels disrupt their support of nerve and glial cells, especially in the brain's white matter, and it highlights "the importance of midlife vascular risk factor control in the prevention of late-life dementia." It is an expert review, not a trial, so that prevention point is the author's emphasis rather than a tested result.
Summary
Vascular cognitive impairment defines alterations in cognition, ranging from subtle deficits to full-blown dementia, attributable to cerebrovascular causes. Often coexisting with Alzheimer's disease, mixed vascular and neurodegenerative dementia has emerged as the leading cause of age-related cognitive impairment. Central to the disease mechanism is the crucial role that cerebral blood vessels play in brain health, not only for the delivery of oxygen and nutrients, but also for the trophic signaling that inextricably links the well-being of neurons and glia to that of cerebrovascular cells. This review will examine how vascular damage disrupts these vital homeostatic interactions, focusing on the hemispheric white matter, a region at heightened risk for vascular damage, and on the interplay between vascular factors and Alzheimer's disease. Finally, preventative and therapeutic prospects will be examined, highlighting the importance of midlife vascular risk factor control in the prevention of late-life dementia.
Key findings
Vascular cognitive impairment defines alterations in cognition, ranging from subtle deficits to full-blown dementia, attributable to cerebrovascular causes.
Often coexisting with Alzheimer's disease, mixed vascular and neurodegenerative dementia has emerged as the leading cause of age-related cognitive impairment.
Central to the disease mechanism is the crucial role that cerebral blood vessels play in brain health, not only for the delivery of oxygen and nutrients, but also for the trophic signaling that inextricably links the well-being of neurons and glia to that of cerebrovascular cells.
This review will examine how vascular damage disrupts these vital homeostatic interactions, focusing on the hemispheric white matter, a region at heightened risk for vascular damage, and on the interplay between vascular factors and Alzheimer's disease.
Finally, preventative and therapeutic prospects will be examined, highlighting the importance of midlife vascular risk factor control in the prevention of late-life dementia.
This survey of adults aged 60 and over in China estimated that, after adjusting for age and sex, 6·0% had dementia (3·9% Alzheimer's disease, 1·6% vascular dementia and 0·5% other types). A further 15·5% had mild cognitive impairment, which the authors put at about 38·77 million people. It is a one-time snapshot of how common these conditions were, not a test of what causes or prevents them. The risk-factor and care findings named in its title are not in the summary we hold.
Summary
Findings Overall age-adjusted and sex-adjusted prevalence was estimated to be 6·0% (95% CI 5·8-6·3) for dementia, 3·9% (3·8-4·1) for Alzheimer's disease, 1·6% (1·5-1·7) for vascular dementia, and 0·5% (0·5-0·6) for other dementias. Overall MCI prevalence was estimated to be 15·5% (15·2-15·9), representing 38·77 million (37·95-39·62) people in China.
Key findings
Findings Overall age-adjusted and sex-adjusted prevalence was estimated to be 6·0% (95% CI 5·8-6·3) for dementia, 3·9% (3·8-4·1) for Alzheimer's disease, 1·6% (1·5-1·7) for vascular dementia, and 0·5% (0·5-0·6) for other dementias.
Overall MCI prevalence was estimated to be 15·5% (15·2-15·9), representing 38·77 million (37·95-39·62) people in China.
Arterial stiffness is described as a growing condition linked to increased risk of cardiovascular events, dementia, and death. The review discusses lifestyle changes and therapies that reduce arterial stiffness, which might help lower these risks.
Summary
Arterial stiffness is a growing epidemic associated with increased risk of cardiovascular events, dementia, and death. Decreased compliance of the central vasculature alters arterial pressure and flow dynamics and impacts cardiac performance and coronary perfusion. This article reviews the structural, cellular, and genetic contributors to arterial stiffness, including the roles of the scaffolding proteins, extracellular matrix, inflammatory molecules, endothelial cell function, and reactive oxidant species. Additional influences of atherosclerosis, glucose regulation, chronic renal disease, salt, and changes in neurohormonal regulation are discussed. A review of the hemodynamic impact of arterial stiffness follows. A number of lifestyle changes and therapies that reduce arterial stiffness are presented, including weight loss, exercise, salt reduction, alcohol consumption, and neuroendocrine-directed therapies, such as those targeting the renin-angiotensin aldosterone system, natriuretic peptides, insulin modulators, as well as novel therapies that target advanced glycation end products.
Key findings
Arterial stiffness is a growing epidemic associated with increased risk of cardiovascular events, dementia, and death.
High blood pressure is presented as the strongest risk factor for cardiovascular disease and is also linked to dementia. The review suggests that preventing age-related increases in blood pressure could reduce vascular consequences usually attributed to aging.
Summary
Fragmented investigation has masked the overall picture for causes of cardiovascular disease (CVD). Among the risk factors for CVD, high blood pressure (BP) is associated with the strongest evidence for causation and it has a high prevalence of exposure. Biologically, normal levels of BP are considerably lower than what has typically been characterized as normal in research and clinical practice. We propose that CVD is primarily caused by a right-sided shift in the population distribution of BP. Our view that BP is the predominant risk factor for CVD is based on conceptual postulates that have been tested in observational investigations and clinical trials. Large cohort studies have demonstrated that high BP is an important risk factor for heart failure, atrial fibrillation, chronic kidney disease, heart valve diseases, aortic syndromes, and dementia, in addition to coronary heart disease and stroke. In multivariate modeling, the presumed attributable risk of high BP for stroke and coronary heart disease has increased steadily with progressive use of lower values for normal BP. Meta-analysis of BP-lowering randomized controlled trials has demonstrated a benefit which is almost identical to that predicted from BP risk relationships in cohort studies. Prevention of age-related increases in BP would, in large part, reduce the vascular consequences usually attributed to aging, and together with intensive treatment of established hypertension would eliminate a large proportion of the population burden of BP-related CVD.
Key findings
Fragmented investigation has masked the overall picture for causes of cardiovascular disease (CVD).
Among the risk factors for CVD, high blood pressure (BP) is associated with the strongest evidence for causation and it has a high prevalence of exposure.
Large cohort studies have demonstrated that high BP is an important risk factor for heart failure, atrial fibrillation, chronic kidney disease, heart valve diseases, aortic syndromes, and dementia, in addition to coronary heart disease and stroke.
Meta-analysis of BP-lowering randomized controlled trials has demonstrated a benefit which is almost identical to that predicted from BP risk relationships in cohort studies.
Swedish researchers followed 382 people without dementia from age 70 to 85. Those who developed dementia at 79–85 had higher blood pressure at age 70 (average systolic 178 vs 164 mm Hg), and higher diastolic pressure at 70 was also seen in those who went on to develop Alzheimer's disease. Their blood pressure then fell in the years before dementia began, and the authors say it is still unknown whether that fall is a cause or a consequence of the brain disease. This is an observational association: the study tested no treatment and does not show that high or low blood pressure causes dementia.
Summary
Background Vascular causes of dementia may be more common than supposed. Vascular factors may also have a role in late-onset Alzheimer's disease, but the role of hypertension in the development of dementia is unclear. Methods As part of the Longitudinal Population Study of 70-year-olds in Göteborg, Sweden, we analysed the relation between blood pressure and the development of dementia in the age intervals 70-75, 75-79, and 79-85 years in those non-demented at age 70 (n = 382). The sample was followed up for 15 years and examined repeatedly with a comprehensive investigation, including a psychiatric and physical examination. a Findings Participants who developed dementia at age 79-85 had higher systolic blood pressure at age 70 (mean 178 vs 164 mm Hg, p = 0.034) and higher diastolic blood pressure at ages 70 (101 vs 92, p = 0.004) and 75 (97 vs 90, p = 0.022) than those who did not develop dementia. For subtypes of dementia, higher diastolic blood pressure was recorded at age 70 (101, p = 0.019) for those developing Alzheimer's disease and at age 75 (101, p = 0.015) for those developing vascular dementia than for those who did not develop dementia. Participants with white-matter lesions on computed tomography at age 85 had higher blood pressure at age 70 than those without such lesions. Blood pressure declined in the years before dementia onset and was then similar to or lower than that in non-demented individuals. Interpretation Previously increased blood pressure may increase the risk for dementia by inducing small-vessel disease and white-matter lesions. To what extent the decline in blood pressure before dementia onset is a consequence or a cause of the brain disease remains to be elucidated.
Key findings
For subtypes of dementia, higher diastolic blood pressure was recorded at age 70 (101, p = 0.019) for those developing Alzheimer's disease and at age 75 (101, p = 0.015) for those developing vascular dementia than for those who did not develop dementia.
Participants with white-matter lesions on computed tomography at age 85 had higher blood pressure at age 70 than those without such lesions.
Blood pressure declined in the years before dementia onset and was then similar to or lower than that in non-demented individuals.
Interpretation Previously increased blood pressure may increase the risk for dementia by inducing small-vessel disease and white-matter lesions.
To what extent the decline in blood pressure before dementia onset is a consequence or a cause of the brain disease remains to be elucidated.
Based on in-home assessments of 856 people aged 71 and older drawn from the nationally representative Health and Retirement Study, this study estimated that 13.9% of that age group in the USA (about 3.4 million people) had dementia in 2002, and 9.7% (about 2.4 million) had Alzheimer's disease. Dementia was far more common with age: 5.0% at ages 71–79 against 37.4% at 90 and older. These are weighted national estimates from a single snapshot, intended for planning care needs; the study did not test any cause or treatment.
Summary
Aim To estimate the prevalence of Alzheimer's disease (AD) and other dementias in the USA using a nationally representative sample. Methods The Aging, Demographics, and Memory Study sample was composed of 856 individuals aged 71 years and older from the nationally representative Health and Retirement Study (HRS) who were evaluated for dementia using a comprehensive in-home assessment. An expert consensus panel used this information to assign a diagnosis of normal cognition, cognitive impairment but not demented, or dementia (and dementia subtype). Using sampling weights derived from the HRS, we estimated the national prevalence of dementia, AD and vascular dementia by age and gender. Results The prevalence of dementia among individuals aged 71 and older was 13.9%, comprising about 3.4 million individuals in the USA in 2002. The corresponding values for AD were 9.7% and 2.4 million individuals. Dementia prevalence increased with age, from 5.0% of those aged 71-79 years to 37.4% of those aged 90 and older. Conclusions Dementia prevalence estimates from this first nationally representative population-based study of dementia in the USA to include subjects from all regions of the country can provide essential information for effective planning for the impending healthcare needs of the large and increasing number of individuals at risk for dementia as our population ages.
Key findings
Results The prevalence of dementia among individuals aged 71 and older was 13.9%, comprising about 3.4 million individuals in the USA in 2002.
This systematic review examined the prevalence and risk factors for dementia before and after stroke. It aimed to clarify conflicting data to help inform patients, carers, and service planning.
Summary
Background Reliable data on the prevalence and predictors of post-stroke dementia are needed to inform patients and carers, plan services and clinical trials, ascertain the overall burden of stroke, and understand its causes. However, published data on the prevalence and risk factors for pre-stroke and post-stroke dementia are conflicting. We undertook this systematic review to assess the heterogeneity in the reported rates and to identify risk factors for pre-stroke and post-stroke dementia. Methods Studies published between 1950 and May 1, 2009, were identified from bibliographic databases, reference lists, and journal contents pages. Studies were included if they were on patients with symptomatic stroke, were published in English, reported on a series of consecutive eligible patients or volunteers in prospective cohort studies, included all stroke or all ischaemic stroke, measured dementia by standard criteria, and followed up patients for at least 3 months after stroke. Pooled rates of dementia were stratified by study setting, inclusion or exclusion of pre-stroke dementia, and by first, any, or recurrent stroke. Pooled odds ratios were calculated for factors associated with pre-stroke and post-stroke dementia. Findings We identified 22 hospital-based and eight population-based eligible cohorts (7511 patients) described in 73 papers. The pooled prevalence of pre-stroke dementia was higher (14.4%, 95% CI 12.0-16.8) in hospital-based studies than in population-based studies (9.1%, 6.9-11.3). Although post-stroke ( Interpretation After study methods and case mix are taken into account, reported estimates of the prevalence of dementia are consistent: 10% of patients had dementia before first stroke, 10% developed new dementia soon after first stroke, and more than a third had dementia after recurrent stroke. The strong association of post-stroke dementia with multiple strokes and the prognostic value of other stroke characteristics highlight the central causal role of stroke itself as opposed to the underlying vascular risk factors and, thus, the likely effect of optimum acute stroke care and secondary prevention in reducing the burden of dementia. Funding None.
Key findings
Background Reliable data on the prevalence and predictors of post-stroke dementia are needed to inform patients and carers, plan services and clinical trials, ascertain the overall burden of stroke, and understand its causes.
Pooled odds ratios were calculated for factors associated with pre-stroke and post-stroke dementia.
In a mouse model of Alzheimer's, vaccination with amyloid-beta protected the mice from learning and memory deficits and partially reduced amyloid buildup. This is an early animal study, so it does not yet show whether such a vaccine would prevent or treat Alzheimer's in people.
Summary
Vaccinations with amyloid-beta peptide (A beta) can dramatically reduce amyloid deposition in a transgenic mouse model of Alzheimer's disease. To determine if the vaccinations had deleterious or beneficial functional consequences, we tested eight months of A beta vaccination in a different transgenic model for Alzheimer's disease in which mice develop learning deficits as amyloid accumulates. Here we show that vaccination with A beta protects transgenic mice from the learning and age-related memory deficits that normally occur in this mouse model for Alzheimer's disease. During testing for potential deleterious effects of the vaccine, all mice performed superbly on the radial-arm water-maze test of working memory. Later, at an age when untreated transgenic mice show memory deficits, the A beta-vaccinated transgenic mice showed cognitive performance superior to that of the control transgenic mice and, ultimately, performed as well as nontransgenic mice. The A beta-vaccinated mice also had a partial reduction in amyloid burden at the end of the study. This therapeutic approach may thus prevent and, possibly, treat Alzheimer's dementia.
Key findings
Here we show that vaccination with A beta protects transgenic mice from the learning and age-related memory deficits that normally occur in this mouse model for Alzheimer's disease.
During testing for potential deleterious effects of the vaccine, all mice performed superbly on the radial-arm water-maze test of working memory.
Later, at an age when untreated transgenic mice show memory deficits, the A beta-vaccinated transgenic mice showed cognitive performance superior to that of the control transgenic mice and, ultimately, performed as well as nontransgenic mice.
The A beta-vaccinated mice also had a partial reduction in amyloid burden at the end of the study.
This therapeutic approach may thus prevent and, possibly, treat Alzheimer's dementia.
Evidence strength
low
Limitations
This is a mouse model study; protecting genetically engineered mice from memory deficits does not guarantee the same approach will be safe or effective in human Alzheimer's disease, which the subsequent two decades of human trials have shown is a much harder problem.
This report describes LATE-NC, a common TDP-43 proteinopathy that can mimic Alzheimer's-type dementia and was found in about 25% of brains in community-based autopsy cohorts. It shares some genetic risk factors with both frontotemporal lobar degeneration and Alzheimer's disease, but also has disease-specific mechanisms.
Summary
LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer's-type dementia in retrospective autopsy studies. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer's disease, but also suggests disease-specific underlying mechanisms.
Key findings
LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer's-type dementia in retrospective autopsy studies.
In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment.
Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions.
The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer's disease, but also suggests disease-specific underlying mechanisms.
In a 2015 summary prepared at the World Dementia Council's request, the Alzheimer's Association concluded that regular physical activity and managing diabetes, obesity, smoking and high blood pressure reduce the risk of cognitive decline and may reduce the risk of dementia. It judged that a healthy diet and lifelong learning or cognitive training may also reduce the risk of cognitive decline, but made no dementia claim for those two. These are the Association's population-level judgements with no risk estimates attached, not results of a new trial, and they do not single out Alzheimer's disease.
Summary
An estimated 47 million people worldwide are living with dementia in 2015, and this number is projected to triple by 2050. In the absence of a disease-modifying treatment or cure, reducing the risk of developing dementia takes on added importance. In 2014, the World Dementia Council (WDC) requested the Alzheimer's Association evaluate and report on the state of the evidence on modifiable risk factors for cognitive decline and dementia. This report is a summary of the Association's evaluation, which was presented at the October 2014 WDC meeting. The Association believes there is sufficient evidence to support the link between several modifiable risk factors and a reduced risk for cognitive decline, and sufficient evidence to suggest that some modifiable risk factors may be associated with reduced risk of dementia. Specifically, the Association believes there is sufficiently strong evidence, from a population-based perspective, to conclude that regular physical activity and management of cardiovascular risk factors (diabetes, obesity, smoking, and hypertension) reduce the risk of cognitive decline and may reduce the risk of dementia. The Association also believes there is sufficiently strong evidence to conclude that a healthy diet and lifelong learning/cognitive training may also reduce the risk of cognitive decline.
Key findings
The Association believes there is sufficient evidence to support the link between several modifiable risk factors and a reduced risk for cognitive decline, and sufficient evidence to suggest that some modifiable risk factors may be associated with reduced risk of dementia.
Specifically, the Association believes there is sufficiently strong evidence, from a population-based perspective, to conclude that regular physical activity and management of cardiovascular risk factors (diabetes, obesity, smoking, and hypertension) reduce the risk of cognitive decline and may reduce the risk of dementia.
The Association also believes there is sufficiently strong evidence to conclude that a healthy diet and lifelong learning/cognitive training may also reduce the risk of cognitive decline.
In this randomized trial in Perth, Australia, 170 adults aged 50 or older who reported memory problems but did not have dementia were assigned either to a 24-week home-based physical activity program or to education and usual care. At the end of the program, the exercise group scored 1.3 points better than the usual-care group on the ADAS-Cog memory-and-thinking test (95% CI −2.38 to −0.22; scale 0–70), which the authors call "a modest improvement in cognition over an 18-month follow-up period." Several other thinking and mood measures did not change significantly, 138 of 170 participants completed the 18-month assessment, and the trial did not measure whether anyone developed dementia.
Summary
Context Many observational studies have shown that physical activity reduces the risk of cognitive decline; however, evidence from randomized trials is lacking. Objective To determine whether physical activity reduces the rate of cognitive decline among older adults at risk. Design and setting Randomized controlled trial of a 24-week physical activity intervention conducted between 2004 and 2007 in metropolitan Perth, Western Australia. Assessors of cognitive function were blinded to group membership. Participants We recruited volunteers who reported memory problems but did not meet criteria for dementia. Three hundred eleven individuals aged 50 years or older were screened for eligibility, 89 were not eligible, and 52 refused to participate. A total of 170 participants were randomized and 138 participants completed the 18-month assessment. Intervention Participants were randomly allocated to an education and usual care group or to a 24-week home-based program of physical activity. Main outcome measure Change in Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores (possible range, 0-70) over 18 months. Results In an intent-to-treat analysis, participants in the intervention group improved 0.26 points (95% confidence interval, -0.89 to 0.54) and those in the usual care group deteriorated 1.04 points (95% confidence interval, 0.32 to 1.82) on the ADAS-Cog at the end of the intervention. The absolute difference of the outcome measure between the intervention and control groups was -1.3 points (95% confidence interval,-2.38 to -0.22) at the end of the intervention. At 18 months, participants in the intervention group improved 0.73 points (95% confidence interval, -1.27 to 0.03) on the ADAS-Cog, and those in the usual care group improved 0.04 points (95% confidence interval, -0.46 to 0.88). Word list delayed recall and Clinical Dementia Rating sum of boxes improved modestly as well, whereas word list total immediate recall, digit symbol coding, verbal fluency, Beck depression score, and Medical Outcomes 36-Item Short-Form physical and mental component summaries did not change significantly. Conclusions In this study of adults with subjective memory impairment, a 6-month program of physical activity provided a modest improvement in cognition over an 18-month follow-up period. Trial registration anzctr.org.au Identifier: ACTRN12605000136606.
Key findings
Context Many observational studies have shown that physical activity reduces the risk of cognitive decline; however, evidence from randomized trials is lacking.
Results In an intent-to-treat analysis, participants in the intervention group improved 0.26 points (95% confidence interval, -0.89 to 0.54) and those in the usual care group deteriorated 1.04 points (95% confidence interval, 0.32 to 1.82) on the ADAS-Cog at the end of the intervention.
Word list delayed recall and Clinical Dementia Rating sum of boxes improved modestly as well, whereas word list total immediate recall, digit symbol coding, verbal fluency, Beck depression score, and Medical Outcomes 36-Item Short-Form physical and mental component summaries did not change significantly.
This report on menopausal hormone therapy found a complex pattern of risks and benefits, with some outcomes like breast cancer and heart disease showing increased risk during the intervention phase. It did not focus on dementia outcomes.
Summary
Results During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% CI, 0.95-1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01-1.53). Results for other outcomes were similar to CEE plus MPA. For CEE alone, younger women (aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P Conclusions and relevance Menopausal hormone therapy has a complex pattern of risks and benefits.
Key findings
Results During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% CI, 0.95-1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01-1.53).
Results for other outcomes were similar to CEE plus MPA.
For CEE alone, younger women (aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P Conclusions and relevance Menopausal hormone therapy has a complex pattern of risks and benefits.
This 2018 review separates mild, slowly progressing thinking changes, which it says occur with diabetes at all ages, from mild cognitive impairment and dementia, which occur "primarily in older individuals (>65 years of age)" and are its focus. It reports that the risk of clinically diagnosed Alzheimer's and of vascular dementia is increased in association with diabetes, while the brain's burden of Alzheimer's hallmark tangles and plaques is not, and it concludes that in most patients the cognitive problems probably have "multiple aetiologies". It tests no treatment, and says targeted treatment and prevention will depend on further research linking laboratory and clinical work.
Summary
Cognitive dysfunction is increasingly recognized as an important comorbidity of diabetes mellitus. Different stages of diabetes-associated cognitive dysfunction exist, each with different cognitive features, affected age groups and prognoses and probably with different underlying mechanisms. Relatively subtle, slowly progressive cognitive decrements occur in all age groups. More severe stages, particularly mild cognitive impairment and dementia, with progressive deficits, occur primarily in older individuals (>65 years of age). Patients in the latter group are the most relevant for patient management and are the focus of this Review. Here, we review the evolving insights from studies on risk factors, brain imaging and neuropathology, which provide important clues on mechanisms of both the subtle cognitive decrements and the more severe stages of cognitive dysfunction. In the majority of patients, the cognitive phenotype is probably defined by multiple aetiologies. Although both the risk of clinically diagnosed Alzheimer disease and that of vascular dementia is increased in association with diabetes, the cerebral burden of the prototypical pathologies of Alzheimer disease (such as neurofibrillary tangles and neuritic plaques) is not. A major challenge for researchers is to pinpoint from the spectrum of diabetes-related disease processes those that affect the brain and contribute to development of dementia beyond the pathologies of Alzheimer disease. Observations from experimental models can help to meet that challenge, but this requires further improving the synergy between experimental and clinical scientists. The development of targeted treatment and preventive strategies will therefore depend on these translational efforts.
Key findings
In the majority of patients, the cognitive phenotype is probably defined by multiple aetiologies.
Although both the risk of clinically diagnosed Alzheimer disease and that of vascular dementia is increased in association with diabetes, the cerebral burden of the prototypical pathologies of Alzheimer disease (such as neurofibrillary tangles and neuritic plaques) is not.
A major challenge for researchers is to pinpoint from the spectrum of diabetes-related disease processes those that affect the brain and contribute to development of dementia beyond the pathologies of Alzheimer disease.
Observations from experimental models can help to meet that challenge, but this requires further improving the synergy between experimental and clinical scientists.
The development of targeted treatment and preventive strategies will therefore depend on these translational efforts.
This review notes that high blood pressure is a risk factor for dementia, among other diseases, and that lowering blood pressure through diet and treatment can help. It supports managing blood pressure as a way to reduce dementia risk, but does not test a specific Alzheimer's treatment.
Summary
High blood pressure is one of the most important risk factors for ischaemic heart disease, stroke, other cardiovascular diseases, chronic kidney disease and dementia. Mean blood pressure and the prevalence of raised blood pressure have declined substantially in high-income regions since at least the 1970s. By contrast, blood pressure has risen in East, South and Southeast Asia, Oceania and sub-Saharan Africa. Given these trends, the prevalence of hypertension is now higher in low-income and middle-income countries than in high-income countries. In 2015, an estimated 8.5 million deaths were attributable to systolic blood pressure >115 mmHg, 88% of which were in low-income and middle-income countries. Measures such as increasing the availability and affordability of fresh fruits and vegetables, lowering the sodium content of packaged and prepared food and staples such as bread, and improving the availability of dietary salt substitutes can help lower blood pressure in the entire population. The use and effectiveness of hypertension treatment vary substantially across countries. Factors influencing this variation include a country's financial resources, the extent of health insurance and health facilities, how frequently people interact with physicians and non-physician health personnel, whether a clear and widely adopted clinical guideline exists and the availability of medicines. Scaling up treatment coverage and improving its community effectiveness can substantially reduce the health burden of hypertension.
Key findings
In 2015, an estimated 8.5 million deaths were attributable to systolic blood pressure >115 mmHg, 88% of which were in low-income and middle-income countries.
Measures such as increasing the availability and affordability of fresh fruits and vegetables, lowering the sodium content of packaged and prepared food and staples such as bread, and improving the availability of dietary salt substitutes can help lower blood pressure in the entire population.
The use and effectiveness of hypertension treatment vary substantially across countries.
Factors influencing this variation include a country's financial resources, the extent of health insurance and health facilities, how frequently people interact with physicians and non-physician health personnel, whether a clear and widely adopted clinical guideline exists and the availability of medicines.
Scaling up treatment coverage and improving its community effectiveness can substantially reduce the health burden of hypertension.
In 639 adults from the Baltimore Longitudinal Study of Aging whose hearing was measured by audiometry, dementia risk rose with worse hearing over a median 11.9 years: 1.27 times per 10-dB loss (95% CI 1.06–1.50), across 58 dementia cases. For Alzheimer disease alone (37 cases) the trend was similar but not conclusive (1.20 per 10 dB; 95% CI 0.94–1.53). This is an association. The authors say it is still open whether hearing loss is an early marker of dementia or a risk factor that could be modified.
Summary
Objective To determine whether hearing loss is associated with incident all-cause dementia and Alzheimer disease (AD). Design Prospective study of 639 individuals who underwent audiometric testing and were dementia free in 1990 to 1994. Hearing loss was defined by a pure-tone average of hearing thresholds at 0.5, 1, 2, and 4 kHz in the better-hearing ear (normal, 70 dB [n = 6]). Diagnosis of incident dementia was made by consensus diagnostic conference. Cox proportional hazards models were used to model time to incident dementia according to severity of hearing loss and were adjusted for age, sex, race, education, diabetes mellitus, smoking, and hypertension. Setting Baltimore Longitudinal Study of Aging. Participants Six hundred thirty-nine individuals aged 36 to 90 years. Main outcome measure Incident cases of all-cause dementia and AD until May 31, 2008. Results During a median follow-up of 11.9 years, 58 cases of incident all-cause dementia were diagnosed, of which 37 cases were AD. The risk of incident all-cause dementia increased log linearly with the severity of baseline hearing loss (1.27 per 10-dB loss; 95% confidence interval, 1.06-1.50). Compared with normal hearing, the hazard ratio (95% confidence interval) for incident all-cause dementia was 1.89 (1.00-3.58) for mild hearing loss, 3.00 (1.43-6.30) for moderate hearing loss, and 4.94 (1.09-22.40) for severe hearing loss. The risk of incident AD also increased with baseline hearing loss (1.20 per 10 dB of hearing loss) but with a wider confidence interval (0.94-1.53). Conclusions Hearing loss is independently associated with incident all-cause dementia. Whether hearing loss is a marker for early-stage dementia or is actually a modifiable risk factor for dementia deserves further study.
Key findings
Objective To determine whether hearing loss is associated with incident all-cause dementia and Alzheimer disease (AD).
Results During a median follow-up of 11.9 years, 58 cases of incident all-cause dementia were diagnosed, of which 37 cases were AD.
Compared with normal hearing, the hazard ratio (95% confidence interval) for incident all-cause dementia was 1.89 (1.00-3.58) for mild hearing loss, 3.00 (1.43-6.30) for moderate hearing loss, and 4.94 (1.09-22.40) for severe hearing loss.
Conclusions Hearing loss is independently associated with incident all-cause dementia.
In this Rotterdam population study of 284 people with dementia (207 with Alzheimer's disease) and 1,698 without, signs of hardened arteries, measured by neck-artery ultrasound and an ankle-arm blood-pressure ratio, were more common in those with dementia. People with severe atherosclerosis had about three times the odds of having Alzheimer's disease as people with none (odds ratio 3.0, 95% CI 1.5–6.0). Dementia was more common still in people who carried the APOE ε4 gene variant and had moderate-to-severe atherosclerosis (odds ratio 4.5 for all dementia). The study looked at people at one point in time, so it shows a link, not that atherosclerosis causes Alzheimer's or that treating it would prevent the disease.
Summary
Background Vascular disorders have been implicated in dementia, but whether atherosclerosis is related to the most frequent type of dementia, Alzheimer's disease, is not known. The apolipoprotein-E genotype has been associated with Alzheimer's disease, and we postulate that it plays a part, together with atherosclerosis, in the aetiology of Alzheimer's disease. We investigated the frequency of dementia and its subtypes in relation to atherosclerosis and apolipoprotein E. Methods We did a population-based study of 284 patients with dementia, 207 of whom had Alzheimer's disease, and 1698 individuals who were not demented. Indicators of atherosclerosis included vessel wall thickness and plaques of the carotid arteries, assessed by ultrasonography, and the ratio of ankle-to-brachial systolic blood pressure as a measure of generalised atherosclerosis. Based on these indicators participants were scored from 0 (no atherosclerosis) to 3 (severe atherosclerosis) for degree of atherosclerosis. Apolipoprotein-E polymorphisms were assessed in 246 patients and in 928 controls. Findings All indicators of atherosclerosis were associated with dementia (odds ratios ranging from 1.3 to 1.9) and its major subtypes Alzheimer's disease (odds ratios 1.3-1.8) and vascular dementia (odds ratios 1.9-3.2). The frequencies of all dementia. Alzheimer's disease, and vascular dementia increased with the degree of atherosclerosis. The odds ratio for Alzheimer's disease in those with severe atherosclerosis compared with those without atherosclerosis was 3.0 (95% CI 1.5-6.0; p = 0.001). In participants with the apolipoprotein-E epsilon 4 genotype and an atherosclerosis score of 2 or 3 the odds ratio for all dementia was 4.5 (2.0-10.1; p Interpretation These findings suggest that dementia and its two major subtypes Alzheimer's disease and vascular dementia are associated with atherosclerosis and that there is an interaction between apolipoprotein E and atherosclerosis in the aetiology of Alzheimer's disease.
Key findings
The apolipoprotein-E genotype has been associated with Alzheimer's disease, and we postulate that it plays a part, together with atherosclerosis, in the aetiology of Alzheimer's disease.
Findings All indicators of atherosclerosis were associated with dementia (odds ratios ranging from 1.3 to 1.9) and its major subtypes Alzheimer's disease (odds ratios 1.3-1.8) and vascular dementia (odds ratios 1.9-3.2).
The odds ratio for Alzheimer's disease in those with severe atherosclerosis compared with those without atherosclerosis was 3.0 (95% CI 1.5-6.0; p = 0.001).
In participants with the apolipoprotein-E epsilon 4 genotype and an atherosclerosis score of 2 or 3 the odds ratio for all dementia was 4.5 (2.0-10.1; p < 0.001), for Alzheimer's disease was 3.9 (1.6-9.6; p = 0.002), and for vascular dementia was 19.8 (4.1-95.0; p < 0.001).
In 11 cognitively normal people aged 50–65 who carried two copies of the APOE ε4 gene variant and had a family history of Alzheimer's, PET scans showed lower glucose use in the same posterior cingulate, parietal, temporal and prefrontal regions previously seen to decline in patients with probable Alzheimer's, compared with 22 matched non-carriers. The authors read this as "preclinical evidence" that ε4 is a risk factor, and suggested PET "may offer a relatively rapid way of testing future treatments to prevent Alzheimer's disease". It is a small group comparison of brain metabolism: it doesn't show who goes on to develop dementia, and it doesn't test any treatment.
Summary
Background Variants of the apolipoprotein E allele appear to account for most cases of late-onset Alzheimer's disease, and persons with two copies of the epsilon 4 allele appear to have an especially high risk of dementia. Positron-emission tomography (PET) has identified specific regions of the brain in which the rate of glucose metabolism declines progressively in patients with probable Alzheimer's disease. We used PET to investigate whether these same regions of the brain are affected in subjects homozygous for the epsilon 4 allele before the onset of cognitive impairment. Methods Apolipoprotein E genotypes were established in 235 volunteers 50 to 65 years of age who reported a family history of probable Alzheimer's disease. Neurologic and psychiatric evaluations, a battery of neuropsychological tests, magnetic resonance imaging, and PET were performed in 11 epsilon 4 homozygotes and 22 controls without the epsilon 4 allele who were matched for sex, age, and level of education. An automated method was used to generate an aggregate surface-projection map that compared regional rates of glucose metabolism in the two groups. Results The epsilon 4 homozygotes were cognitively normal. They had significantly reduced rates of glucose metabolism in the same posterior cingulate, parietal, temporal, and prefrontal regions as in previously studied patients with probable Alzheimer's disease. They also had reduced rates of glucose metabolism in additional prefrontal regions, which may be preferentially affected during normal aging. Conclusions In late middle age, cognitively normal subjects who are homozygous for the epsilon 4 allele for apolipoprotein E have reduced glucose metabolism in the same regions of the brain as in patients with probable Alzheimer's disease. These findings provide preclinical evidence that the presence of the epsilon 4 allele is a risk factor for Alzheimer's disease. PET may offer a relatively rapid way of testing future treatments to prevent Alzheimer's disease.
Key findings
Results The epsilon 4 homozygotes were cognitively normal.
They had significantly reduced rates of glucose metabolism in the same posterior cingulate, parietal, temporal, and prefrontal regions as in previously studied patients with probable Alzheimer's disease.
These findings provide preclinical evidence that the presence of the epsilon 4 allele is a risk factor for Alzheimer's disease.
In mice, the Alzheimer's risk gene form APOE4, or having no APOE at all, made the brain's blood-vessel barrier leaky through an inflammatory pathway involving a protein called cyclophilin A (CypA) in the cells around small vessels. The APOE2 and APOE3 forms did not do this. The authors report that this vessel damage came before damage to nerve cells, and that APOE3, but not APOE4, switched the pathway off. They suggest CypA as a possible treatment target, but this is animal research with no numbers in our record, and it does not show that blocking CypA helps people with or at risk of Alzheimer's.
Summary
Human apolipoprotein E has three isoforms: APOE2, APOE3 and APOE4. APOE4 is a major genetic risk factor for Alzheimer's disease and is associated with Down's syndrome dementia and poor neurological outcome after traumatic brain injury and haemorrhage. Neurovascular dysfunction is present in normal APOE4 carriers and individuals with APOE4-associated disorders. In mice, lack of Apoe leads to blood-brain barrier (BBB) breakdown, whereas APOE4 increases BBB susceptibility to injury. How APOE genotype affects brain microcirculation remains elusive. Using different APOE transgenic mice, including mice with ablation and/or inhibition of cyclophilin A (CypA), here we show that expression of APOE4 and lack of murine Apoe, but not APOE2 and APOE3, leads to BBB breakdown by activating a proinflammatory CypA-nuclear factor-κB-matrix-metalloproteinase-9 pathway in pericytes. This, in turn, leads to neuronal uptake of multiple blood-derived neurotoxic proteins, and microvascular and cerebral blood flow reductions. We show that the vascular defects in Apoe-deficient and APOE4-expressing mice precede neuronal dysfunction and can initiate neurodegenerative changes. Astrocyte-secreted APOE3, but not APOE4, suppressed the CypA-nuclear factor-κB-matrix-metalloproteinase-9 pathway in pericytes through a lipoprotein receptor. Our data suggest that CypA is a key target for treating APOE4-mediated neurovascular injury and the resulting neuronal dysfunction and degeneration.
Key findings
APOE4 is a major genetic risk factor for Alzheimer's disease and is associated with Down's syndrome dementia and poor neurological outcome after traumatic brain injury and haemorrhage.
Our data suggest that CypA is a key target for treating APOE4-mediated neurovascular injury and the resulting neuronal dysfunction and degeneration.
A library that never mentions these is less trustworthy, not more. A correction usually
means a number or a figure was fixed — it does not mean the paper was withdrawn. A retraction does.
Retracted
Retraction Note: A specific amyloid-β protein assembly in the brain impairs memory.Nature, 2024 ·
retraction notice
· PubMed 38914864
This is the retraction notice. It retracts: Nature. 2006 Mar 16;440(7082):352-7. doi: 10.1038/nature04533.
Corrected after publication
Blood phosphorylated tau for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis.The Lancet Neurology, 2025
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Long-Term Effect of Intensive vs Standard Blood Pressure Control on Mild Cognitive Impairment and Probable Dementia in SPRINT.Neurology, 2025
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Correction published: Neurology. 2025 May 27;104(10):e213686. doi: 10.1212/WNL.0000000000213686.
APOE4 homozygozity represents a distinct genetic form of Alzheimer's disease.Nature Medicine, 2024
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Correction published: JAMA Netw Open. 2024 Jun 3;7(6):e2424366. doi: 10.1001/jamanetworkopen.2024.24366.
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· PubMed 41081870
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· PubMed 25961184
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