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.
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
· PubMed 40818474
Long-Term Effect of Intensive vs Standard Blood Pressure Control on Mild Cognitive Impairment and Probable Dementia in SPRINT.Neurology, 2025
· PubMed 39819096
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
· PubMed 38710950
Health System, Community-Based, or Usual Dementia Care for Persons With Dementia and Caregivers: The D-CARE Randomized Clinical Trial.JAMA, 2025
· PubMed 39878968
Correction published: JAMA. 2025 May 6;333(17):1549. doi: 10.1001/jama.2025.4753.
Modified titration of donanemab reduces ARIA risk and maintains amyloid reduction.Alzheimer's & Dementia, 2025
· PubMed 40172303
Cholinesterase inhibitors and memantine are associated with a reduced mortality in nursing home residents with dementia: a longitudinal observational study.Alzheimer's Research & Therapy, 2024
· PubMed 38812028
Correction published: Alzheimers Res Ther. 2024 Aug 5;16(1):178. doi: 10.1186/s13195-024-01548-y.
Consumption of Olive Oil and Diet Quality and Risk of Dementia-Related Death.JAMA Network Open, 2024
· PubMed 38709531
Correction published: JAMA Netw Open. 2024 Jun 3;7(6):e2424366. doi: 10.1001/jamanetworkopen.2024.24366.
Sleep disorders and the risk of cognitive decline or dementia: an updated systematic review and meta-analysis of longitudinal studies.Journal of Neurology, 2025
· PubMed 41081870
Mediterranean Diet and Age-Related Cognitive Decline: A Randomized Clinical Trial.JAMA Internal Medicine, 2015
· PubMed 25961184
Correction published: JAMA Intern Med. 2018 Dec 1;178(12):1731-1732. doi: 10.1001/jamainternmed.2018.6460.
Association of Daily Step Count and Intensity With Incident Dementia in 78 430 Adults Living in the UK.JAMA Neurology, 2022
· PubMed 36066874
Correction published: JAMA Neurol. 2022 Oct 1;79(10):1086. doi: 10.1001/jamaneurol.2022.3612.
Blood pressure lowering and prevention of dementia: an individual patient data meta-analysis.European Heart Journal, 2022
· PubMed 36282295
Correction published: Eur Heart J. 2026 Sep 02:ehag701. doi: 10.1093/eurheartj/ehag701.
The efficacy of cognitive stimulation, cognitive training, and cognitive rehabilitation for people living with dementia: a systematic review and meta-analysis.GeroScience, 2024
· PubMed 39485657
Citation counts measure attention from other researchers. They are not a measure of
whether a finding is correct, whether it replicated, or whether it should change anything you do. Papers are
sometimes heavily cited because they were controversial or later disputed — one of the papers in this
library has been retracted and is still cited.
Nothing on this page is health advice, and a high rank here is not evidence that a
treatment or a behaviour works. For what the studies actually found, read the
research summaries. For decisions about care, talk to a clinician.