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.
Everything in the library, including biomarker, imaging, genetics and laboratory papers.
These dominate the top of the list — which is itself the reason the prevention view exists.
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.
These 1984 criteria describe how to diagnose probable, possible, and definite Alzheimer's disease clinically, noting that no laboratory test can determine the diagnosis and that other causes of dementia must be excluded. They are diagnostic guidance, not a treatment or prevention for the disease.
Summary
Clinical criteria for the diagnosis of Alzheimer's disease include insidious onset and progressive impairment of memory and other cognitive functions. There are no motor, sensory, or coordination deficits early in the disease. The diagnosis cannot be determined by laboratory tests. These tests are important primarily in identifying other possible causes of dementia that must be excluded before the diagnosis of Alzheimer's disease may be made with confidence. Neuropsychological tests provide confirmatory evidence of the diagnosis of dementia and help to assess the course and response to therapy. The criteria proposed are intended to serve as a guide for the diagnosis of probable, possible, and definite Alzheimer's disease; these criteria will be revised as more definitive information become available.
Key findings
There are no motor, sensory, or coordination deficits early in the disease.
The diagnosis cannot be determined by laboratory tests.
These tests are important primarily in identifying other possible causes of dementia that must be excluded before the diagnosis of Alzheimer's disease may be made with confidence.
Neuropsychological tests provide confirmatory evidence of the diagnosis of dementia and help to assess the course and response to therapy.
The criteria proposed are intended to serve as a guide for the diagnosis of probable, possible, and definite Alzheimer's disease; these criteria will be revised as more definitive information become available.
This is the primary Phase 3 Clarity AD trial report for lecanemab. In 1,795 people with early Alzheimer's disease randomized to lecanemab or placebo every two weeks for 18 months, lecanemab slowed decline on the main dementia-severity scale (CDR-SB) by a small but statistically significant amount (change of 1.21 vs 1.66 points, a difference of 0.45 points on an 18-point scale). Infusion reactions occurred in about a quarter of patients, and brain swelling (ARIA-E) occurred in about 1 in 8.
Adjusted mean CDR-SB change: 1.21 (lecanemab) vs 1.66 (placebo); difference −0.45 (less decline with lecanemab)
Infusion-related reactions in 26.4% of participants; ARIA-E (brain swelling/effusion) in 12.6%
Effect size
Adjusted mean CDR-SB change 1.21 (lecanemab) vs. 1.66 (placebo); difference -0.45
Evidence strength
moderate
Study design / n
phase-3-trial · n = 1,795
Limitations
Modest absolute effect size (0.45 points on an 18-point scale) of debated long-term clinical meaningfulness; high rates of infusion reactions (26.4%) and ARIA-E (12.6%); 18-month duration does not establish long-term outcomes.
This 2005 paper introduced the Montreal Cognitive Assessment (MoCA), a brief screening test, and compared it with the MMSE in 94 people with mild cognitive impairment, 93 with mild Alzheimer's and 90 healthy older adults. At a cutoff of 26, the MoCA picked up 90% of the MCI group (MMSE 18%) and all of the mild Alzheimer's group (MMSE 78%), but it also flagged more healthy people: specificity was 87% versus 100% for the MMSE. It is a screening test that signals who needs a fuller assessment, not a diagnosis, and the authors note that MCI itself is "evolving and somewhat controversial".
Summary
Objectives To develop a 10-minute cognitive screening tool (Montreal Cognitive Assessment, MoCA) to assist first-line physicians in detection of mild cognitive impairment (MCI), a clinical state that often progresses to dementia. Design Validation study. Setting A community clinic and an academic center. Participants Ninety-four patients meeting MCI clinical criteria supported by psychometric measures, 93 patients with mild Alzheimer's disease (AD) (Mini-Mental State Examination (MMSE) score > or =17), and 90 healthy elderly controls (NC). Measurements The MoCA and MMSE were administered to all participants, and sensitivity and specificity of both measures were assessed for detection of MCI and mild AD. Results Using a cutoff score 26, the MMSE had a sensitivity of 18% to detect MCI, whereas the MoCA detected 90% of MCI subjects. In the mild AD group, the MMSE had a sensitivity of 78%, whereas the MoCA detected 100%. Specificity was excellent for both MMSE and MoCA (100% and 87%, respectively). Conclusion MCI as an entity is evolving and somewhat controversial. The MoCA is a brief cognitive screening tool with high sensitivity and specificity for detecting MCI as currently conceptualized in patients performing in the normal range on the MMSE.
Key findings
Results Using a cutoff score 26, the MMSE had a sensitivity of 18% to detect MCI, whereas the MoCA detected 90% of MCI subjects.
Presymptomatic Alzheimer's disease can now be identified through blood biomarkers under revised diagnostic criteria, potentially enabling treatment to begin before cognitive symptoms appear. Blood-based biomarkers are incorporated into the diagnostic framework for the first time, providing an additional method for disease identification beyond cerebrospinal fluid and PET imaging.
Summary
This Alzheimer's Association workgroup paper proposes a major update to how Alzheimer's disease is diagnosed: it defines the disease by biological markers (amyloid plaques and tau tangles detected via blood, CSF, or PET) rather than requiring clinical symptoms like memory loss to be present. It also introduces a numeric staging system tracking biomarker and clinical severity together.
Key findings
Alzheimer's disease can now be diagnosed based on biomarker evidence alone, even before symptoms appear
Introduces staging system integrating biological and clinical/functional severity
Incorporates blood-based biomarkers into the diagnostic biomarker categories for the first time
Evidence strength
moderate
Limitations
This is an expert consensus/framework document, not an empirical study with its own participants or effect size.
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 2024 report says there are fewer caregivers than a decade earlier and that each remaining caregiver provides more care. It also reports that unpaid caregivers face an increased risk of emotional distress and of worse mental and physical health. This is an association, not proof that caregiving causes it. The record gives no figures and tests no treatment, so it describes the caregiving burden rather than showing what reduces it.
Summary
These figures reflect a decline in the number of caregivers compared with a decade earlier, as well as an increase in the amount of care provided by each remaining caregiver. Its costs, however, extend to unpaid caregivers' increased risk for emotional distress and negative mental and physical health outcomes.
Key findings
These figures reflect a decline in the number of caregivers compared with a decade earlier, as well as an increase in the amount of care provided by each remaining caregiver.
Its costs, however, extend to unpaid caregivers' increased risk for emotional distress and negative mental and physical health outcomes.
These 2011 expert recommendations revised the 1984 criteria for diagnosing Alzheimer's disease dementia, and were designed to be usable by general healthcare providers without brain scans, spinal-fluid tests or detailed memory testing. The authors state that clinical assessment "will continue to be the cornerstone of the diagnosis in clinical practice"; biomarker evidence was added only "for use in research settings", and they note that "much work lies ahead" to validate it. This is a consensus guideline, not a study that tested patients, and it does not address treatment or prevention.
Summary
The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.
Key findings
On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis.
We also retained the term possible AD dementia, but redefined it in a manner more focused than before.
Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings.
The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia.
Much work lies ahead for validating the biomarker diagnosis of AD dementia.
This 2018 NIA-AA paper proposes, for research use, defining Alzheimer's disease by biology rather than by symptoms alone. Its authors "envision" that this will give a more accurate picture of "the sequence of events that lead to cognitive impairment" and of the "multifactorial etiology of dementia", but this is a stated aim, not a tested result. The paper reports no patient data and offers no test, treatment or cure.
Summary
We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia.
Key findings
We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia.
This report describes the public health impact of Alzheimer's, including costs and effects on family caregivers. It does not test any treatment or prevention, so it does not directly change how the disease is treated or cured.
Summary
This article describes the public health impact of Alzheimer's disease, including prevalence and incidence, mortality and morbidity, use and costs of care, and the overall impact on family caregivers, the dementia workforce and society. These figures reflect a decline in the number of caregivers compared with a decade earlier, as well as an increase in the amount of care provided by each remaining caregiver. Its costs, however, extend to family caregivers' increased risk for emotional distress and negative mental and physical health outcomes - costs that have been aggravated by COVID-19.
Key findings
This article describes the public health impact of Alzheimer's disease, including prevalence and incidence, mortality and morbidity, use and costs of care, and the overall impact on family caregivers, the dementia workforce and society.
These figures reflect a decline in the number of caregivers compared with a decade earlier, as well as an increase in the amount of care provided by each remaining caregiver.
Its costs, however, extend to family caregivers' increased risk for emotional distress and negative mental and physical health outcomes - costs that have been aggravated by COVID-19.
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.
In this phase 3 trial of 1736 people with early symptomatic Alzheimer's disease, donanemab, an antibody designed to clear brain amyloid plaque, slowed decline on a cognitive and functional scale compared with placebo over 76 weeks. The trial reported that 23 of 24 gated outcomes were statistically significant, and it was conducted in people selected for amyloid and low/medium or high tau pathology.
Summary
Importance There are limited efficacious treatments for Alzheimer disease. Objective To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque. Design, setting, and participants Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023). Interventions Participants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met. Main outcomes and measures The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). There were 24 gated outcomes (primary, secondary, and exploratory), including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment). Statistical testing allocated α of .04 to testing low/medium tau population outcomes, with the remainder (.01) for combined population outcomes. Results Among 1736 randomized participants (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] with low/medium tau pathology and 552 [31.8%] with high tau pathology), 1320 (76%) completed the trial. Of the 24 gated outcomes, 23 were statistically significant. The least-squares mean (LSM) change in iADRS score at 76 weeks was -6.02 (95% CI, -7.01 to -5.03) in the donanemab group and -9.27 (95% CI, -10.23 to -8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P Conclusions and relevance Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population. Trial registration ClinicalTrials.gov Identifier: NCT04437511.
Key findings
Results Among 1736 randomized participants (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] with low/medium tau pathology and 552 [31.8%] with high tau pathology), 1320 (76%) completed the trial.
Of the 24 gated outcomes, 23 were statistically significant.
The least-squares mean (LSM) change in iADRS score at 76 weeks was -6.02 (95% CI, -7.01 to -5.03) in the donanemab group and -9.27 (95% CI, -10.23 to -8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P < .001) in the low/medium tau population and -10.2 (95% CI, -11.22 to -9.16) with donanemab and -13.1 (95% CI, -14.10 to -12.13) with placebo (difference, 2.92 [95% CI, 1.51-4.33]; P < .001) in the combined population.
The Neuropsychiatric Inventory (NPI) is a questionnaire, answered by "a caregiver familiar with the patient's behavior", that rates how often and how severely a person with dementia shows 10 behaviours, including delusions, hallucinations, agitation/aggression, depression (dysphoria), anxiety and apathy. Screening questions skip the behaviours that are not present, to keep it short. The authors report it was valid and reliable, though this record gives no figures, and it is a way of measuring symptoms, not a treatment.
Summary
We developed a new instrument, the Neuropsychiatric Inventory (NPI), to assess 10 behavioral disturbances occurring in dementia patients: delusions, hallucinations, dysphoria, anxiety, agitation/aggression, euphoria, disinhibition, irritability/lability, apathy, and aberrant motor activity. The NPI uses a screening strategy to minimize administration time, examining and scoring only those behavioral domains with positive responses to screening questions. Both the frequency and the severity of each behavior are determined. Information for the NPI is obtained from a caregiver familiar with the patient's behavior. Studies reported here demonstrate the content and concurrent validity as well as between-rater, test-retest, and internal consistency reliability; the instrument is both valid and reliable. The NPI has the advantages of evaluating a wider range of psychopathology than existing instruments, soliciting information that may distinguish among different etiologies of dementia, differentiating between severity and frequency of behavioral changes, and minimizing administration time.
Key findings
The NPI uses a screening strategy to minimize administration time, examining and scoring only those behavioral domains with positive responses to screening questions.
Both the frequency and the severity of each behavior are determined.
Information for the NPI is obtained from a caregiver familiar with the patient's behavior.
Studies reported here demonstrate the content and concurrent validity as well as between-rater, test-retest, and internal consistency reliability; the instrument is both valid and reliable.
The NPI has the advantages of evaluating a wider range of psychopathology than existing instruments, soliciting information that may distinguish among different etiologies of dementia, differentiating between severity and frequency of behavioral changes, and minimizing administration time.
This study followed patients discharged after COVID-19 and found some had ongoing problems with lung diffusion, anxiety or depression, fatigue, and kidney function. It does not address Alzheimer's disease treatment, cure or prevention.
Summary
After multivariable adjustment, patients showed an odds ratio (OR) 1·61 (95% CI 0·80-3·25) for scale 4 versus scale 3 and 4·60 (1·85-11·48) for scale 5-6 versus scale 3 for diffusion impairment; OR 0·88 (0·66-1·17) for scale 4 versus scale 3 and OR 1·77 (1·05-2·97) for scale 5-6 versus scale 3 for anxiety or depression, and OR 0·74 (0·58-0·96) for scale 4 versus scale 3 and 2·69 (1·46-4·96) for scale 5-6 versus scale 3 for fatigue or muscle weakness. Of 94 patients with blood antibodies tested at follow-up, the seropositivity (96·2% vs 58·5%) and median titres (19·0 vs 10·0) of the neutralising antibodies were significantly lower compared with at the acute phase. 107 of 822 participants without acute kidney injury and with estimated glomerular filtration rate (eGFR) 90 mL/min per 1·73 m 2 or more at acute phase had eGFR less than 90 mL/min per 1·73 m 2 at follow-up.
Key findings
After multivariable adjustment, patients showed an odds ratio (OR) 1·61 (95% CI 0·80-3·25) for scale 4 versus scale 3 and 4·60 (1·85-11·48) for scale 5-6 versus scale 3 for diffusion impairment; OR 0·88 (0·66-1·17) for scale 4 versus scale 3 and OR 1·77 (1·05-2·97) for scale 5-6 versus scale 3 for anxiety or depression, and OR 0·74 (0·58-0·96) for scale 4 versus scale 3 and 2·69 (1·46-4·96) for scale 5-6 versus scale 3 for fatigue or muscle weakness.
Of 94 patients with blood antibodies tested at follow-up, the seropositivity (96·2% vs 58·5%) and median titres (19·0 vs 10·0) of the neutralising antibodies were significantly lower compared with at the acute phase. 107 of 822 participants without acute kidney injury and with estimated glomerular filtration rate (eGFR) 90 mL/min per 1·73 m 2 or more at acute phase had eGFR less than 90 mL/min per 1·73 m 2 at follow-up.
In 76 people with mild cognitive impairment (MCI) at one Mayo Clinic registry, memory was the main difference from 234 healthy people; their other thinking skills were comparable. Their memory was similar to that of 106 people with mild Alzheimer's disease, but the Alzheimer's group was also worse in other areas. Over time the MCI group declined faster than healthy people but more slowly than the Alzheimer's group. This is an observational study: it gives no conversion rate and tests no treatment.
Summary
Background Subjects with a mild cognitive impairment (MCI) have a memory impairment beyond that expected for age and education yet are not demented. These subjects are becoming the focus of many prediction studies and early intervention trials. Objective To characterize clinically subjects with MCI cross-sectionally and longitudinally. Design A prospective, longitudinal inception cohort. Setting General community clinic. Participants A sample of 76 consecutively evaluated subjects with MCI were compared with 234 healthy control subjects and 106 patients with mild Alzheimer disease (AD), all from a community setting as part of the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry, Rochester, Minn. Main outcome measures The 3 groups of individuals were compared on demographic factors and measures of cognitive function including the Mini-Mental State Examination, Wechsler Adult Intelligence Scale-Revised, Wechsler Memory Scale-Revised, Dementia Rating Scale, Free and Cued Selective Reminding Test, and Auditory Verbal Learning Test. Clinical classifications of dementia and AD were determined according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition and the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria, respectively. Results The primary distinction between control subjects and subjects with MCI was in the area of memory, while other cognitive functions were comparable. However, when the subjects with MCI were compared with the patients with very mild AD, memory performance was similar, but patients with AD were more impaired in other cognitive domains as well. Longitudinal performance demonstrated that the subjects with MCI declined at a rate greater than that of the controls but less rapidly than the patients with mild AD. Conclusions Patients who meet the criteria for MCI can be differentiated from healthy control subjects and those with very mild AD. They appear to constitute a clinical entity that can be characterized for treatment interventions.
Key findings
Participants A sample of 76 consecutively evaluated subjects with MCI were compared with 234 healthy control subjects and 106 patients with mild Alzheimer disease (AD), all from a community setting as part of the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry, Rochester, Minn.
Results The primary distinction between control subjects and subjects with MCI was in the area of memory, while other cognitive functions were comparable.
However, when the subjects with MCI were compared with the patients with very mild AD, memory performance was similar, but patients with AD were more impaired in other cognitive domains as well.
Longitudinal performance demonstrated that the subjects with MCI declined at a rate greater than that of the controls but less rapidly than the patients with mild AD.
These 1984 criteria describe how to diagnose probable, possible, and definite Alzheimer's disease clinically, noting that no laboratory test can determine the diagnosis and that other causes of dementia must be excluded. They are diagnostic guidance, not a treatment or prevention for the disease.
Summary
Clinical criteria for the diagnosis of Alzheimer's disease include insidious onset and progressive impairment of memory and other cognitive functions. There are no motor, sensory, or coordination deficits early in the disease. The diagnosis cannot be determined by laboratory tests. These tests are important primarily in identifying other possible causes of dementia that must be excluded before the diagnosis of Alzheimer's disease may be made with confidence. Neuropsychological tests provide confirmatory evidence of the diagnosis of dementia and help to assess the course and response to therapy. The criteria proposed are intended to serve as a guide for the diagnosis of probable, possible, and definite Alzheimer's disease; these criteria will be revised as more definitive information become available.
Key findings
There are no motor, sensory, or coordination deficits early in the disease.
The diagnosis cannot be determined by laboratory tests.
These tests are important primarily in identifying other possible causes of dementia that must be excluded before the diagnosis of Alzheimer's disease may be made with confidence.
Neuropsychological tests provide confirmatory evidence of the diagnosis of dementia and help to assess the course and response to therapy.
The criteria proposed are intended to serve as a guide for the diagnosis of probable, possible, and definite Alzheimer's disease; these criteria will be revised as more definitive information become available.
This 2005 paper introduced the Montreal Cognitive Assessment (MoCA), a brief screening test, and compared it with the MMSE in 94 people with mild cognitive impairment, 93 with mild Alzheimer's and 90 healthy older adults. At a cutoff of 26, the MoCA picked up 90% of the MCI group (MMSE 18%) and all of the mild Alzheimer's group (MMSE 78%), but it also flagged more healthy people: specificity was 87% versus 100% for the MMSE. It is a screening test that signals who needs a fuller assessment, not a diagnosis, and the authors note that MCI itself is "evolving and somewhat controversial".
Summary
Objectives To develop a 10-minute cognitive screening tool (Montreal Cognitive Assessment, MoCA) to assist first-line physicians in detection of mild cognitive impairment (MCI), a clinical state that often progresses to dementia. Design Validation study. Setting A community clinic and an academic center. Participants Ninety-four patients meeting MCI clinical criteria supported by psychometric measures, 93 patients with mild Alzheimer's disease (AD) (Mini-Mental State Examination (MMSE) score > or =17), and 90 healthy elderly controls (NC). Measurements The MoCA and MMSE were administered to all participants, and sensitivity and specificity of both measures were assessed for detection of MCI and mild AD. Results Using a cutoff score 26, the MMSE had a sensitivity of 18% to detect MCI, whereas the MoCA detected 90% of MCI subjects. In the mild AD group, the MMSE had a sensitivity of 78%, whereas the MoCA detected 100%. Specificity was excellent for both MMSE and MoCA (100% and 87%, respectively). Conclusion MCI as an entity is evolving and somewhat controversial. The MoCA is a brief cognitive screening tool with high sensitivity and specificity for detecting MCI as currently conceptualized in patients performing in the normal range on the MMSE.
Key findings
Results Using a cutoff score 26, the MMSE had a sensitivity of 18% to detect MCI, whereas the MoCA detected 90% of MCI subjects.
These 2011 expert recommendations revised the 1984 criteria for diagnosing Alzheimer's disease dementia, and were designed to be usable by general healthcare providers without brain scans, spinal-fluid tests or detailed memory testing. The authors state that clinical assessment "will continue to be the cornerstone of the diagnosis in clinical practice"; biomarker evidence was added only "for use in research settings", and they note that "much work lies ahead" to validate it. This is a consensus guideline, not a study that tested patients, and it does not address treatment or prevention.
Summary
The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.
Key findings
On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis.
We also retained the term possible AD dementia, but redefined it in a manner more focused than before.
Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings.
The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia.
Much work lies ahead for validating the biomarker diagnosis of AD dementia.
This 2018 NIA-AA paper proposes, for research use, defining Alzheimer's disease by biology rather than by symptoms alone. Its authors "envision" that this will give a more accurate picture of "the sequence of events that lead to cognitive impairment" and of the "multifactorial etiology of dementia", but this is a stated aim, not a tested result. The paper reports no patient data and offers no test, treatment or cure.
Summary
We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia.
Key findings
We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia.
In 76 people with mild cognitive impairment (MCI) at one Mayo Clinic registry, memory was the main difference from 234 healthy people; their other thinking skills were comparable. Their memory was similar to that of 106 people with mild Alzheimer's disease, but the Alzheimer's group was also worse in other areas. Over time the MCI group declined faster than healthy people but more slowly than the Alzheimer's group. This is an observational study: it gives no conversion rate and tests no treatment.
Summary
Background Subjects with a mild cognitive impairment (MCI) have a memory impairment beyond that expected for age and education yet are not demented. These subjects are becoming the focus of many prediction studies and early intervention trials. Objective To characterize clinically subjects with MCI cross-sectionally and longitudinally. Design A prospective, longitudinal inception cohort. Setting General community clinic. Participants A sample of 76 consecutively evaluated subjects with MCI were compared with 234 healthy control subjects and 106 patients with mild Alzheimer disease (AD), all from a community setting as part of the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry, Rochester, Minn. Main outcome measures The 3 groups of individuals were compared on demographic factors and measures of cognitive function including the Mini-Mental State Examination, Wechsler Adult Intelligence Scale-Revised, Wechsler Memory Scale-Revised, Dementia Rating Scale, Free and Cued Selective Reminding Test, and Auditory Verbal Learning Test. Clinical classifications of dementia and AD were determined according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition and the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria, respectively. Results The primary distinction between control subjects and subjects with MCI was in the area of memory, while other cognitive functions were comparable. However, when the subjects with MCI were compared with the patients with very mild AD, memory performance was similar, but patients with AD were more impaired in other cognitive domains as well. Longitudinal performance demonstrated that the subjects with MCI declined at a rate greater than that of the controls but less rapidly than the patients with mild AD. Conclusions Patients who meet the criteria for MCI can be differentiated from healthy control subjects and those with very mild AD. They appear to constitute a clinical entity that can be characterized for treatment interventions.
Key findings
Participants A sample of 76 consecutively evaluated subjects with MCI were compared with 234 healthy control subjects and 106 patients with mild Alzheimer disease (AD), all from a community setting as part of the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry, Rochester, Minn.
Results The primary distinction between control subjects and subjects with MCI was in the area of memory, while other cognitive functions were comparable.
However, when the subjects with MCI were compared with the patients with very mild AD, memory performance was similar, but patients with AD were more impaired in other cognitive domains as well.
Longitudinal performance demonstrated that the subjects with MCI declined at a rate greater than that of the controls but less rapidly than the patients with mild AD.
The Neuropsychiatric Inventory (NPI) is a questionnaire, answered by "a caregiver familiar with the patient's behavior", that rates how often and how severely a person with dementia shows 10 behaviours, including delusions, hallucinations, agitation/aggression, depression (dysphoria), anxiety and apathy. Screening questions skip the behaviours that are not present, to keep it short. The authors report it was valid and reliable, though this record gives no figures, and it is a way of measuring symptoms, not a treatment.
Summary
We developed a new instrument, the Neuropsychiatric Inventory (NPI), to assess 10 behavioral disturbances occurring in dementia patients: delusions, hallucinations, dysphoria, anxiety, agitation/aggression, euphoria, disinhibition, irritability/lability, apathy, and aberrant motor activity. The NPI uses a screening strategy to minimize administration time, examining and scoring only those behavioral domains with positive responses to screening questions. Both the frequency and the severity of each behavior are determined. Information for the NPI is obtained from a caregiver familiar with the patient's behavior. Studies reported here demonstrate the content and concurrent validity as well as between-rater, test-retest, and internal consistency reliability; the instrument is both valid and reliable. The NPI has the advantages of evaluating a wider range of psychopathology than existing instruments, soliciting information that may distinguish among different etiologies of dementia, differentiating between severity and frequency of behavioral changes, and minimizing administration time.
Key findings
The NPI uses a screening strategy to minimize administration time, examining and scoring only those behavioral domains with positive responses to screening questions.
Both the frequency and the severity of each behavior are determined.
Information for the NPI is obtained from a caregiver familiar with the patient's behavior.
Studies reported here demonstrate the content and concurrent validity as well as between-rater, test-retest, and internal consistency reliability; the instrument is both valid and reliable.
The NPI has the advantages of evaluating a wider range of psychopathology than existing instruments, soliciting information that may distinguish among different etiologies of dementia, differentiating between severity and frequency of behavioral changes, and minimizing administration time.
This 2004 review describes mild cognitive impairment (MCI) as "an early, but abnormal, state of cognitive impairment" between normal ageing and very early dementia, and argues it can be diagnosed "in a fashion similar to the clinical diagnoses of dementia and AD", presenting an algorithm to identify people with MCI and sort them into subtypes. It notes that studies have documented an "accelerated rate of progression" to dementia and Alzheimer's in people with MCI, but also that the precise definition has been controversial. It proposes criteria rather than testing them on patients, and it reports no treatment.
Summary
The concept of cognitive impairment intervening between normal ageing and very early dementia has been in the literature for many years. Recently, the construct of mild cognitive impairment (MCI) has been proposed to designate an early, but abnormal, state of cognitive impairment. MCI has generated a great deal of research from both clinical and research perspectives. Numerous epidemiological studies have documented the accelerated rate of progression to dementia and Alzheimer's disease (AD) in MCI subjects and certain predictor variables appear valid. However, there has been controversy regarding the precise definition of the concept and its implementation in various clinical settings. Clinical subtypes of MCI have been proposed to broaden the concept and include prodromal forms of a variety of dementias. It is suggested that the diagnosis of MCI can be made in a fashion similar to the clinical diagnoses of dementia and AD. An algorithm is presented to assist the clinician in identifying subjects and subclassifying them into the various types of MCI. By refining the criteria for MCI, clinical trials can be designed with appropriate inclusion and exclusion restrictions to allow for the investigation of therapeutics tailored for specific targets and populations.
Key findings
It is suggested that the diagnosis of MCI can be made in a fashion similar to the clinical diagnoses of dementia and AD.
In 2011 an international expert workgroup convened by the National Institute on Aging and the Alzheimer's Association proposed research criteria for a "preclinical" stage of Alzheimer's disease, the years when the disease process "is thought to begin" before dementia is diagnosed. The aim was a "common rubric" for long-term studies to test which factors best predict who moves from normal cognition to mild cognitive impairment and dementia; it is an expert proposal, not a study that tested patients. The authors state the criteria are "solely intended for research purposes and do not have any clinical implications at this time," and that the link between the disease process and symptoms still needs to be clarified.
Summary
The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long "preclinical" phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from "normal" cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious.
Key findings
This long "preclinical" phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms.
The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from "normal" cognition to mild cognitive impairment and AD dementia.
We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies.
These recommendations are solely intended for research purposes and do not have any clinical implications at this time.
It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious.
Before this study, the ubiquitinated protein inside the tau- and alpha-synuclein-negative inclusions of frontotemporal lobar degeneration (FTLD-U) and ALS was unknown. The authors report that it is TDP-43, which they found in an abnormal form ("hyper-phosphorylated, ubiquitinated, and cleaved") only in affected brain and spinal cord regions. They conclude it is "the common pathologic substrate linking these neurodegenerative disorders". The study is about FTLD and ALS, not Alzheimer's disease, and it does not test any treatment, test or prevention.
Summary
Ubiquitin-positive, tau- and alpha-synuclein-negative inclusions are hallmarks of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Although the identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease protein in both disorders. Pathologic TDP-43 was hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders.
Key findings
Although the identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease protein in both disorders.
This is the primary Phase 3 Clarity AD trial report for lecanemab. In 1,795 people with early Alzheimer's disease randomized to lecanemab or placebo every two weeks for 18 months, lecanemab slowed decline on the main dementia-severity scale (CDR-SB) by a small but statistically significant amount (change of 1.21 vs 1.66 points, a difference of 0.45 points on an 18-point scale). Infusion reactions occurred in about a quarter of patients, and brain swelling (ARIA-E) occurred in about 1 in 8.
Adjusted mean CDR-SB change: 1.21 (lecanemab) vs 1.66 (placebo); difference −0.45 (less decline with lecanemab)
Infusion-related reactions in 26.4% of participants; ARIA-E (brain swelling/effusion) in 12.6%
Effect size
Adjusted mean CDR-SB change 1.21 (lecanemab) vs. 1.66 (placebo); difference -0.45
Evidence strength
moderate
Study design / n
phase-3-trial · n = 1,795
Limitations
Modest absolute effect size (0.45 points on an 18-point scale) of debated long-term clinical meaningfulness; high rates of infusion reactions (26.4%) and ARIA-E (12.6%); 18-month duration does not establish long-term outcomes.
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.
This study found that revised criteria for behavioural variant frontotemporal dementia improved diagnostic accuracy compared with older criteria in a sample with known frontotemporal lobar degeneration. It concerns diagnosis of a different dementia type and does not report a treatment or cure.
Summary
Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration.
Key findings
Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment.
In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration.
This 1993 report from an international workshop convened by the NINDS with support from AIREN set out research criteria for diagnosing vascular dementia, intended "as a guide for case definition in neuroepidemiologic studies" at three levels of certainty: definite, probable and possible. The criteria stress that vascular dementia takes many forms, that a secure diagnosis needs a link in time between stroke and the start of dementia, and that brain imaging and memory-and-thinking tests should support the diagnosis. The authors say the criteria "await testing and validation and will be revised as more information becomes available"; the report studied no patients and gives no accuracy figures.
Summary
Criteria for the diagnosis of vascular dementia (VaD) that are reliable, valid, and readily applicable in a variety of settings are urgently needed for both clinical and research purposes. To address this need, the Neuroepidemiology Branch of the National Institute of Neurological Disorders and Stroke (NINDS) convened an International Workshop with support from the Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN), resulting in research criteria for the diagnosis of VaD. Compared with other current criteria, these guidelines emphasize (1) the heterogeneity of vascular dementia syndromes and pathologic subtypes including ischemic and hemorrhagic strokes, cerebral hypoxic-ischemic events, and senile leukoencephalopathic lesions; (2) the variability in clinical course, which may be static, remitting, or progressive; (3) specific clinical findings early in the course (eg, gait disorder, incontinence, or mood and personality changes) that support a vascular rather than a degenerative cause; (4) the need to establish a temporal relationship between stroke and dementia onset for a secure diagnosis; (5) the importance of brain imaging to support clinical findings; (6) the value of neuropsychological testing to document impairments in multiple cognitive domains; and (7) a protocol for neuropathologic evaluations and correlative studies of clinical, radiologic, and neuropsychological features. These criteria are intended as a guide for case definition in neuroepidemiologic studies, stratified by levels of certainty (definite, probable, and possible). They await testing and validation and will be revised as more information becomes available.
Key findings
Compared with other current criteria, these guidelines emphasize (1) the heterogeneity of vascular dementia syndromes and pathologic subtypes including ischemic and hemorrhagic strokes, cerebral hypoxic-ischemic events, and senile leukoencephalopathic lesions; (2) the variability in clinical course, which may be static, remitting, or progressive; (3) specific clinical findings early in the course (eg, gait disorder, incontinence, or mood and personality changes) that support a vascular rather than a degenerative cause; (4) the need to establish a temporal relationship between stroke and dementia onset for a secure diagnosis; (5) the importance of brain imaging to support clinical findings; (6) the value of neuropsychological testing to document impairments in multiple cognitive domains; and (7) a protocol for neuropathologic evaluations and correlative studies of clinical, radiologic, and neuropsychological features.
This 1998 international workshop consensus set out research diagnostic criteria for three syndromes of frontotemporal lobar degeneration: frontotemporal dementia, progressive nonfluent aphasia and semantic dementia. Each has listed core and supportive features, with broad inclusion and exclusion rules for the condition as a whole. The authors describe these disorders as accounting for "a substantial proportion" of degenerative dementia beginning before age 65. The paper is expert agreement, not a test of accuracy or of any treatment, and it is about FTD rather than Alzheimer's disease.
Summary
Objective To improve clinical recognition and provide research diagnostic criteria for three clinical syndromes associated with frontotemporal lobar degeneration. Methods Consensus criteria for the three prototypic syndromes-frontotemporal dementia, progressive nonfluent aphasia, and semantic dementia-were developed by members of an international workshop on frontotemporal lobar degeneration. These criteria build on earlier published clinical diagnostic guidelines for frontotemporal dementia produced by some of the workshop members. Results The consensus criteria specify core and supportive features for each of the three prototypic clinical syndromes and provide broad inclusion and exclusion criteria for the generic entity of frontotemporal lobar degeneration. The criteria are presented in lists, and operational definitions for features are provided in the text. Conclusions The criteria ought to provide the foundation for research work into the neuropsychology, neuropathology, genetics, molecular biology, and epidemiology of these important clinical disorders that account for a substantial proportion of cases of primary degenerative dementia occurring before the age of 65 years.
Key findings
Objective To improve clinical recognition and provide research diagnostic criteria for three clinical syndromes associated with frontotemporal lobar degeneration.
Results The consensus criteria specify core and supportive features for each of the three prototypic clinical syndromes and provide broad inclusion and exclusion criteria for the generic entity of frontotemporal lobar degeneration.
In families with inherited frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) linked to chromosome 9p21, this study found an expanded GGGGCC repeat in the C9ORF72 gene. In the authors' clinical series it was the most common genetic abnormality: 11.7% of familial FTD and 23.5% of familial ALS. The authors call it "a major cause of both FTD and ALS", though the study concerns those diseases rather than Alzheimer's and tests no treatment or prevention.
Summary
Several families have been reported with autosomal-dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here, we report an expansion of a noncoding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p. This same repeat expansion was identified in the majority of our families with a combined FTD/ALS phenotype and TDP-43-based pathology. Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (23.5%). The repeat expansion leads to the loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS.
Key findings
Here, we report an expansion of a noncoding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p.
Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS.
This paper develops and evaluates a brain image registration method for measuring atrophy in elderly and neurodegenerative brains, including in frontotemporal dementia and Alzheimer's disease. It is a technical imaging methods study and does not test any treatment, cure or prevention.
Summary
One of the most challenging problems in modern neuroimaging is detailed characterization of neurodegeneration. Quantifying spatial and longitudinal atrophy patterns is an important component of this process. These spatiotemporal signals will aid in discriminating between related diseases, such as frontotemporal dementia (FTD) and Alzheimer's disease (AD), which manifest themselves in the same at-risk population. Here, we develop a novel symmetric image normalization method (SyN) for maximizing the cross-correlation within the space of diffeomorphic maps and provide the Euler-Lagrange equations necessary for this optimization. We then turn to a careful evaluation of our method. Our evaluation uses gold standard, human cortical segmentation to contrast SyN's performance with a related elastic method and with the standard ITK implementation of Thirion's Demons algorithm. The new method compares favorably with both approaches, in particular when the distance between the template brain and the target brain is large. We then report the correlation of volumes gained by algorithmic cortical labelings of FTD and control subjects with those gained by the manual rater. This comparison shows that, of the three methods tested, SyN's volume measurements are the most strongly correlated with volume measurements gained by expert labeling. This study indicates that SyN, with cross-correlation, is a reliable method for normalizing and making anatomical measurements in volumetric MRI of patients and at-risk elderly individuals.
Key findings
This study indicates that SyN, with cross-correlation, is a reliable method for normalizing and making anatomical measurements in volumetric MRI of patients and at-risk elderly individuals.
This 2005 consensus report from the DLB Consortium revised the criteria for diagnosing dementia with Lewy bodies, giving more weight to REM sleep behavior disorder, severe neuroleptic sensitivity and reduced dopamine transporter activity on brain imaging, and it weighs both Lewy-related and Alzheimer-type brain changes when judging how likely a DLB diagnosis is. On treatment, it says evidence on specific interventions is limited; the data it cites suggest only a partial motor response to levodopa, severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations and sleep with cholinesterase inhibitors.
Summary
The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.
Key findings
The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome.
This 1985 laboratory study purified the protein at the core of the amyloid plaques found in the brains of people with Alzheimer disease and older people with Down syndrome, and found it is made of clumps of a small protein of "about 40 residues (4 kDa)". It reported that this protein is "almost identical" to the amyloid deposited in brain blood-vessel walls, apart from "ragged" starting ends, which the authors say "indicates a common origin" for the two, and it found "no similarities in amino acid sequences" with scrapie. It describes what plaques are made of, gives no number of brains studied, and does not test whether amyloid causes dementia or how to treat it.
Summary
We have purified and characterized the cerebral amyloid protein that forms the plaque core in Alzheimer disease and in aged individuals with Down syndrome. The protein consists of multimeric aggregates of a polypeptide of about 40 residues (4 kDa). The amino acid composition, molecular mass, and NH2-terminal sequence of this amyloid protein are almost identical to those described for the amyloid deposited in the congophilic angiopathy of Alzheimer disease and Down syndrome, but the plaque core proteins have ragged NH2 termini. The shared 4-kDa subunit indicates a common origin for the amyloids of the plaque core and of the congophilic angiopathy. There are superficial resemblances between the solubility characteristics of the plaque core and some of the properties of scrapie infectivity, but there are no similarities in amino acid sequences between the plaque core and scrapie polypeptides.
Key findings
We have purified and characterized the cerebral amyloid protein that forms the plaque core in Alzheimer disease and in aged individuals with Down syndrome.
The protein consists of multimeric aggregates of a polypeptide of about 40 residues (4 kDa).
The amino acid composition, molecular mass, and NH2-terminal sequence of this amyloid protein are almost identical to those described for the amyloid deposited in the congophilic angiopathy of Alzheimer disease and Down syndrome, but the plaque core proteins have ragged NH2 termini.
The shared 4-kDa subunit indicates a common origin for the amyloids of the plaque core and of the congophilic angiopathy.
There are superficial resemblances between the solubility characteristics of the plaque core and some of the properties of scrapie infectivity, but there are no similarities in amino acid sequences between the plaque core and scrapie polypeptides.
This 1982 paper introduced the Global Deterioration Scale, a tool for assessing primary degenerative dementia and "delineation of its stages." The authors report using it "successfully for more than 5 years" and validating it against behavioral, neuroanatomic, and neurophysiologic measures, but the record we hold gives no patient numbers or validation statistics. It is a way to rate how advanced decline is, not a test that confirms a cause or a treatment.
Summary
Cognitive decline associated with old age and consistent with the diagnosis of primary degenerative dementia is a unique clinical syndrome with characteristic phenomena and progression. The authors describe a Global Deterioration Scale for the assessment of primary degenerative dementia and delineation of its stages. The authors have used the Global Deterioration Scale successfully for more than 5 years and have validated it against behavioral, neuroanatomic, and neurophysiologic measures in patients with primary degenerative dementia.
Key findings
Cognitive decline associated with old age and consistent with the diagnosis of primary degenerative dementia is a unique clinical syndrome with characteristic phenomena and progression.
In 30 people with late-onset Alzheimer's disease, each from a different affected family, half of their APOE gene copies were the type 4 form (allele frequency 0.50), compared with 0.16 in 91 age-matched unrelated controls (P = 0.014). In separate laboratory tests, apolipoprotein E in spinal fluid bound tightly to synthetic beta-amyloid, the main component of Alzheimer's plaques, and the protein was found in plaques and tangles. The authors only "suggested" a role for the E4 form in familial late-onset disease: this small study measured how common the allele was, not any individual's risk, and it tested no treatment.
Summary
Apolipoprotein E is immunochemically localized to the senile plaques, vascular amyloid, and neurofibrillary tangles of Alzheimer disease. In vitro, apolipoprotein E in cerebrospinal fluid binds to synthetic beta A4 peptide (the primary constituent of the senile plaque) with high avidity. Amino acids 12-28 of the beta A4 peptide are required. The gene for apolipoprotein E is located on chromosome 19q13.2, within the region previously associated with linkage of late-onset familial Alzheimer disease. Analysis of apolipoprotein E alleles in Alzheimer disease and controls demonstrated that there was a highly significant association of apolipoprotein E type 4 allele (APOE-epsilon 4) and late-onset familial Alzheimer disease. The allele frequency of the APOE-epsilon 4 in 30 random affected patients, each from a different Alzheimer disease family, was 0.50 +/- 0.06; the allele frequency of APOE-epsilon 4 in 91 age-matched unrelated controls was 0.16 +/- 0.03 (Z = 2.44, P = 0.014). A functional role of the apolipoprotein E-E4 isoform in the pathogenesis of late-onset familial Alzheimer disease is suggested.
Key findings
The gene for apolipoprotein E is located on chromosome 19q13.2, within the region previously associated with linkage of late-onset familial Alzheimer disease.
Analysis of apolipoprotein E alleles in Alzheimer disease and controls demonstrated that there was a highly significant association of apolipoprotein E type 4 allele (APOE-epsilon 4) and late-onset familial Alzheimer disease.
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 2001 review by an international expert group defines mild cognitive impairment as memory loss greater than expected for age in people who do not meet criteria for clinically probable Alzheimer's disease, and says such people progress to probable AD at a considerably accelerated rate compared with healthy peers of the same age. It notes that the term was used inconsistently and suggests subclassifications. It states that no treatments were recommended for MCI at the time, though clinical trials were under way.
Summary
The field of aging and dementia is focusing on the characterization of the earliest stages of cognitive impairment. Recent research has identified a transitional state between the cognitive changes of normal aging and Alzheimer's disease (AD), known as mild cognitive impairment (MCI). Mild cognitive impairment refers to the clinical condition between normal aging and AD in which persons experience memory loss to a greater extent than one would expect for age, yet they do not meet currently accepted criteria for clinically probable AD. When these persons are observed longitudinally, they progress to clinically probable AD at a considerably accelerated rate compared with healthy age-matched individuals. Consequently, this condition has been recognized as suitable for possible therapeutic intervention, and several multicenter international treatment trials are under way. Because this is a topic of intense interest, a group of experts on aging and MCI from around the world in the fields of neurology, psychiatry, geriatrics, neuropsychology, neuroimaging, neuropathology, clinical trials, and ethics was convened to summarize the current state of the field of MCI. Participants reviewed the world scientific literature on aging and MCI and summarized the various topics with respect to available evidence on MCI. Diagnostic criteria and clinical outcomes of these subjects are available in the literature. Mild cognitive impairment is believed to be a high-risk condition for the development of clinically probable AD. Heterogeneity in the use of the term was recognized, and subclassifications were suggested. While no treatments are recommended for MCI currently, clinical trials regarding potential therapies are under way. Recommendations concerning ethical issues in the diagnosis and the management of subjects with MCI were made.
Key findings
When these persons are observed longitudinally, they progress to clinically probable AD at a considerably accelerated rate compared with healthy age-matched individuals.
This 2011 genetic study identified a large GGGGCC repeat expansion in the C9ORF72 gene as the cause of ALS and frontotemporal dementia linked to chromosome 9p21. In Finland it accounted for 46.0% of familial and 21.1% of sporadic ALS, and it was found in one-third of familial ALS cases of European descent, which the authors called the most common genetic cause of these diseases identified to date. The study concerns ALS and FTD, not Alzheimer's disease, gives no FTD-only figures, and does not test any treatment.
Summary
The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.
Key findings
We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region.
Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause.
CERAD built short, standardised sets of clinical and memory/thinking tests for Alzheimer's disease and gave them to more than 350 people with a clinical diagnosis of AD and 275 controls at 16 university centres. The tests told apart people without dementia from those with mild and moderate dementia, picked up decline in language, memory, praxis and general intellectual status after one year, and gave consistent results between raters and on retesting. The authors cautioned that validation was still limited and that diagnoses were awaiting confirmation at postmortem examination, so this paper shows that the tests were usable and consistent, not that they diagnose AD.
Summary
The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) has developed brief, comprehensive, and reliable batteries of clinical and neuropsychological tests for assessment of patients with the clinical diagnosis of Alzheimer's disease (AD). We administered these batteries in a standardized manner to more than 350 subjects with a diagnosis of AD and 275 control subjects who were enrolled in a nationwide registry by a consortium of 16 university medical centers. The tests selected for this study measured the primary cognitive manifestations of AD across a range of severity of the disorder, and discriminated between normal subjects and those with mild and moderate dementia. The batteries also detected deterioration of language, memory, praxis, and general intellectual status in subjects returning for reassessment 1 year later. Interrater and test-retest reliabilities were substantial. Long-term observations of this cohort are in progress in an effort to validate the clinical and neuropsychological assessments and to confirm the diagnosis by postmortem examinations. Although information on validation is limited thus far, the CERAD batteries appear to fill a need for a standardized, easily administered, and reliable instrument for evaluating persons with AD in multicenter research studies as well as in clinical practice.
Key findings
The tests selected for this study measured the primary cognitive manifestations of AD across a range of severity of the disorder, and discriminated between normal subjects and those with mild and moderate dementia.
The batteries also detected deterioration of language, memory, praxis, and general intellectual status in subjects returning for reassessment 1 year later.
Interrater and test-retest reliabilities were substantial.
Long-term observations of this cohort are in progress in an effort to validate the clinical and neuropsychological assessments and to confirm the diagnosis by postmortem examinations.
Although information on validation is limited thus far, the CERAD batteries appear to fill a need for a standardized, easily administered, and reliable instrument for evaluating persons with AD in multicenter research studies as well as in clinical practice.
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 review describes the clinical features that help distinguish Parkinson's disease from other parkinsonian disorders, noting that because there is no definitive test, the disease must be diagnosed based on clinical criteria. It covers motor and non-motor symptoms used in diagnosis, but does not address treating, curing, or preventing Alzheimer's disease.
Summary
Objective Parkinson's disease (PD) is a progressive neurological disorder characterised by a large number of motor and non-motor features that can impact on function to a variable degree. This review describes the clinical characteristics of PD with emphasis on those features that differentiate the disease from other parkinsonian disorders. Methods A MedLine search was performed to identify studies that assess the clinical characteristics of PD. Search terms included "Parkinson's disease", "diagnosis" and "signs and symptoms". Results Because there is no definitive test for the diagnosis of PD, the disease must be diagnosed based on clinical criteria. Rest tremor, bradykinesia, rigidity and loss of postural reflexes are generally considered the cardinal signs of PD. The presence and specific presentation of these features are used to differentiate PD from related parkinsonian disorders. Other clinical features include secondary motor symptoms (eg, hypomimia, dysarthria, dysphagia, sialorrhoea, micrographia, shuffling gait, festination, freezing, dystonia, glabellar reflexes), non-motor symptoms (eg, autonomic dysfunction, cognitive/neurobehavioral abnormalities, sleep disorders and sensory abnormalities such as anosmia, paresthesias and pain). Absence of rest tremor, early occurrence of gait difficulty, postural instability, dementia, hallucinations, and the presence of dysautonomia, ophthalmoparesis, ataxia and other atypical features, coupled with poor or no response to levodopa, suggest diagnoses other than PD. Conclusions A thorough understanding of the broad spectrum of clinical manifestations of PD is essential to the proper diagnosis of the disease. Genetic mutations or variants, neuroimaging abnormalities and other tests are potential biomarkers that may improve diagnosis and allow the identification of persons at risk.
Key findings
Results Because there is no definitive test for the diagnosis of PD, the disease must be diagnosed based on clinical criteria.
This large analysis of many studies confirmed that carrying the APOE epsilon4 version of the apolipoprotein E gene raises the risk of Alzheimer's disease, with two copies raising risk far more than one, while the epsilon2 version was linked to lower risk. The strength of the epsilon4 link was weaker in African American and Hispanic groups, and the study did not test any treatment or prevention.
Summary
Objective To examine more closely the association between apolipoprotein E (APOE) genotype and Alzheimer disease (AD) by age and sex in populations of various ethnic and racial denominations. Data sources Forty research teams contributed data on APOE genotype, sex, age at disease onset, and ethnic background for 5930 patients who met criteria for probable or definite AD and 8607 controls without dementia who were recruited from clinical, community, and brain bank sources. Main outcome measures Odds ratios (ORs) and 95% confidence intervals (CIs) for AD, adjusted for age and study and stratified by major ethnic group (Caucasian, African American, Hispanic, and Japanese) and source, were computed for APOE genotypes epsilon2/epsilon2, epsilon2/epsilon3, epsilon2/epsilon4, epsilon3/epsilon4, and epsilon4/epsilon4 relative to the epsilon3/epsilon3 group. The influence of age and sex on the OR for each genotype was assessed using logistic regression procedures. Results Among Caucasian subjects from clinic- or autopsy-based studies, the risk of AD was significantly increased for people with genotypes epsilon2/epsilon4 (OR=2.6, 95% CI=1.6-4.0), epsilon3/epsilon4 (OR=3.2, 95% CI=2.8-3.8), and epsilon4/epsilon4 (OR=14.9, 95% CI= 10.8-20.6); whereas, the ORs were decreased for people with genotypes epsilon2/epsilon2 (OR=0.6, 95% CI=0.2-2.0) and epsilon2/epsilon3 (OR=0.6, 95% CI=0.5-0.8). The APOE epsilon4-AD association was weaker among African Americans and Hispanics, but there was significant heterogeneity in ORs among studies of African Americans (P Conclusions The APOE epsilon4 allele represents a major risk factor for AD in all ethnic groups studied, across all ages between 40 and 90 years, and in both men and women. The association between APOE epsilon4 and AD in African Americans requires clarification, and the attenuated effect of APOE epsilon4 in Hispanics should be investigated further.
Key findings
Results Among Caucasian subjects from clinic- or autopsy-based studies, the risk of AD was significantly increased for people with genotypes epsilon2/epsilon4 (OR=2.6, 95% CI=1.6-4.0), epsilon3/epsilon4 (OR=3.2, 95% CI=2.8-3.8), and epsilon4/epsilon4 (OR=14.9, 95% CI= 10.8-20.6); whereas, the ORs were decreased for people with genotypes epsilon2/epsilon2 (OR=0.6, 95% CI=0.2-2.0) and epsilon2/epsilon3 (OR=0.6, 95% CI=0.5-0.8).
The APOE epsilon4-AD association was weaker among African Americans and Hispanics, but there was significant heterogeneity in ORs among studies of African Americans (P<.03).
This 2017 consensus report from the DLB Consortium updates its earlier, widely used criteria for diagnosing dementia with Lewy bodies. It separates clinical features from diagnostic biomarkers, gives more weight to REM sleep behavior disorder and MIBG myocardial scintigraphy, and adjusts the pathology criteria to take account of co-existing Alzheimer disease brain changes. It states that its treatment recommendations are largely based on expert opinion because randomized controlled trials in DLB are few.
Summary
The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123 iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.
Key findings
Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss.
Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few.
Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder.
During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies.
There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.
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 proposal revised the diagnostic criteria for Alzheimer's disease to capture the earliest stages before full-blown dementia, centering on early and significant episodic memory impairment plus at least one abnormal biomarker from MRI, PET, or cerebrospinal fluid analysis of amyloid beta or tau proteins. The authors note that validation studies are needed to optimize the criteria's sensitivity, specificity, and accuracy.
Summary
The NINCDS-ADRDA and the DSM-IV-TR criteria for Alzheimer's disease (AD) are the prevailing diagnostic standards in research; however, they have now fallen behind the unprecedented growth of scientific knowledge. Distinctive and reliable biomarkers of AD are now available through structural MRI, molecular neuroimaging with PET, and cerebrospinal fluid analyses. This progress provides the impetus for our proposal of revised diagnostic criteria for AD. Our framework was developed to capture both the earliest stages, before full-blown dementia, as well as the full spectrum of the illness. These new criteria are centred on a clinical core of early and significant episodic memory impairment. They stipulate that there must also be at least one or more abnormal biomarkers among structural neuroimaging with MRI, molecular neuroimaging with PET, and cerebrospinal fluid analysis of amyloid beta or tau proteins. The timeliness of these criteria is highlighted by the many drugs in development that are directed at changing pathogenesis, particularly at the production and clearance of amyloid beta as well as at the hyperphosphorylation state of tau. Validation studies in existing and prospective cohorts are needed to advance these criteria and optimise their sensitivity, specificity, and accuracy.
Key findings
These new criteria are centred on a clinical core of early and significant episodic memory impairment.
This paper introduced the Frontal Assessment Battery, a roughly 10-minute bedside test with six parts covering abilities such as mental flexibility, inhibitory control and sensitivity to interference. It was tried in 42 healthy people and 121 patients with Parkinson's disease, multiple system atrophy, corticobasal degeneration, progressive supranuclear palsy or frontotemporal dementia, and scores tracked closely with an established dementia rating scale (rho = 0.82). No one in the study had Alzheimer's disease, so this paper alone does not show how well the test works in Alzheimer's.
Summary
Objective To devise a short bedside cognitive and behavioral battery to assess frontal lobe functions. Methods The designed battery consists of six subtests exploring the following: conceptualization, mental flexibility, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy. It takes approximately 10 minutes to administer. The authors studied 42 normal subjects and 121 patients with various degrees of frontal lobe dysfunction (PD, n = 24; multiple system atrophy, n = 6; corticobasal degeneration, n = 21; progressive supranuclear palsy, n = 47; frontotemporal dementia, n = 23). Results The Frontal Assessment Battery scores correlated with the Mattis Dementia Rating Scale scores (rho = 0.82, p Conclusion The Frontal Assessment Battery is easy to administer at bedside and is sensitive to frontal lobe dysfunction.
Key findings
Results The Frontal Assessment Battery scores correlated with the Mattis Dementia Rating Scale scores (rho = 0.82, p Conclusion The Frontal Assessment Battery is easy to administer at bedside and is sensitive to frontal lobe dysfunction.
This consensus report devised a protocol for evaluating cortical Lewy body frequency and classifying cases into brainstem predominant, limbic, and neocortical subtypes, and recommended procedures for sampling and storing frozen tissue for neurochemical assays. It notes that the precise relationship between dementia with Lewy bodies and Alzheimer's disease remains uncertain.
Summary
We identified optimal staining methods for each of these and devised a protocol for the evaluation of cortical LB frequency based on a brain sampling procedure consistent with CERAD. This allows cases to be classified into brainstem predominant, limbic (transitional), and neocortical subtypes, using a simple scoring system based on the relative distribution of semiquantitative LB counts. Alzheimer pathology is also frequently present in DLB, usually as diffuse or neuritic plaques, neocortical neurofibrillary tangles being much less common. The precise nosological relationship between DLB and AD remains uncertain, as does that between DLB and patients with Parkinson's disease who subsequently develop neuropsychiatric features. Finally, we recommend procedures for the selective sampling and storage of frozen tissue for a variety of neurochemical assays, which together with developments in molecular genetics, should assist future refinements of diagnosis and classification.
Key findings
We identified optimal staining methods for each of these and devised a protocol for the evaluation of cortical LB frequency based on a brain sampling procedure consistent with CERAD.
This allows cases to be classified into brainstem predominant, limbic (transitional), and neocortical subtypes, using a simple scoring system based on the relative distribution of semiquantitative LB counts.
Alzheimer pathology is also frequently present in DLB, usually as diffuse or neuritic plaques, neocortical neurofibrillary tangles being much less common.
The precise nosological relationship between DLB and AD remains uncertain, as does that between DLB and patients with Parkinson's disease who subsequently develop neuropsychiatric features.
Finally, we recommend procedures for the selective sampling and storage of frozen tissue for a variety of neurochemical assays, which together with developments in molecular genetics, should assist future refinements of diagnosis and classification.
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.
In 273 brains from people who died of disorders other than Parkinson's disease, the authors found Lewy bodies in 3.8% of people in their sixth decade, rising to 12.8% in their ninth. They interpret these "incidental" cases as probably presymptomatic Parkinson's disease, a reading based on post-mortem findings rather than on following anyone in life, and they propose, without testing it here, that early-life internal mechanisms may matter more than environmental agents. The paper is about Parkinson's disease, not Alzheimer's, and it does not test any treatment or prevention.
Summary
The Lewy body is a distinctive neuronal inclusion that is always found in the substantia nigra and other specific brain regions in Parkinson's disease. It is mainly composed of structurally altered neurofilament, and occurs wherever there is excessive loss of neurons. It occurs in some elderly individuals and rarely in other degenerative diseases of the central nervous system. In 273 brains of patients dying from disorders other than Parkinson's disease, the age-specific prevalence of Lewy bodies increased from 3.8% to 12.8% between the sixth and ninth decades. Associated pathological findings suggest that these cases of incidental Lewy body disease are presymptomatic cases of Parkinson's disease, and confirm the importance of age (time) in the evolution of the disease. In view of the common and widespread occurrence of this disorder we propose that endogenous mechanisms operating in early life may be more important than environmental agents in the pathogenesis of Lewy bodies and Parkinson's disease.
Key findings
Associated pathological findings suggest that these cases of incidental Lewy body disease are presymptomatic cases of Parkinson's disease, and confirm the importance of age (time) in the evolution of the disease.
This study followed patients discharged after COVID-19 and found some had ongoing problems with lung diffusion, anxiety or depression, fatigue, and kidney function. It does not address Alzheimer's disease treatment, cure or prevention.
Summary
After multivariable adjustment, patients showed an odds ratio (OR) 1·61 (95% CI 0·80-3·25) for scale 4 versus scale 3 and 4·60 (1·85-11·48) for scale 5-6 versus scale 3 for diffusion impairment; OR 0·88 (0·66-1·17) for scale 4 versus scale 3 and OR 1·77 (1·05-2·97) for scale 5-6 versus scale 3 for anxiety or depression, and OR 0·74 (0·58-0·96) for scale 4 versus scale 3 and 2·69 (1·46-4·96) for scale 5-6 versus scale 3 for fatigue or muscle weakness. Of 94 patients with blood antibodies tested at follow-up, the seropositivity (96·2% vs 58·5%) and median titres (19·0 vs 10·0) of the neutralising antibodies were significantly lower compared with at the acute phase. 107 of 822 participants without acute kidney injury and with estimated glomerular filtration rate (eGFR) 90 mL/min per 1·73 m 2 or more at acute phase had eGFR less than 90 mL/min per 1·73 m 2 at follow-up.
Key findings
After multivariable adjustment, patients showed an odds ratio (OR) 1·61 (95% CI 0·80-3·25) for scale 4 versus scale 3 and 4·60 (1·85-11·48) for scale 5-6 versus scale 3 for diffusion impairment; OR 0·88 (0·66-1·17) for scale 4 versus scale 3 and OR 1·77 (1·05-2·97) for scale 5-6 versus scale 3 for anxiety or depression, and OR 0·74 (0·58-0·96) for scale 4 versus scale 3 and 2·69 (1·46-4·96) for scale 5-6 versus scale 3 for fatigue or muscle weakness.
Of 94 patients with blood antibodies tested at follow-up, the seropositivity (96·2% vs 58·5%) and median titres (19·0 vs 10·0) of the neutralising antibodies were significantly lower compared with at the acute phase. 107 of 822 participants without acute kidney injury and with estimated glomerular filtration rate (eGFR) 90 mL/min per 1·73 m 2 or more at acute phase had eGFR less than 90 mL/min per 1·73 m 2 at follow-up.
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.
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.