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01/26/2013

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original article
Th
new england journal
o
medicine
n engl j med
360;22
nejm.org may
28, 2009
2302
Age, Neuropathology, and Dementia
George M. Savva, Ph.D., Stephen B. Wharton, F.R.C.Path., Paul G. Ince, M.D.,Gillian Forster, B.Sc., Fiona E. Matthews, Ph.D., and Carol Brayne, M.D.,for the Medical Research Council Cognitive Function and Ageing Study
From the Department of Public Healthand Primary Care, Institute of PublicHealth, University of Cambridge, Cam-bridge (G.M.S., C.B.); the Academic Unitof Pathology, University of Sheffield, Shef-field (S.B.W., P.G.I., G.F.); and the Medi-cal Research Council Biostatistics Unit,Institute of Public Health, Cambridge(F.E.M.) — all in the United Kingdom.Address reprint requests to Dr. Whartonat the Academic Unit of Pathology, Uni-versity of Sheffield, Medical School,Beech Hill Rd., Sheffield S10 2RX, UnitedKingdom, or at s.wharton@sheffield.ac.uk.Drs. Savva and Wharton contributedequally to this article.N Engl J Med 2009;360:2302-09.
Copyright © 2009 Massachusetts Medical Society.
Abstract
Background
Research in Alzheimer’s disease is focused mainly on younger old persons, whereasstudies involving very old persons report attenuated relationships between the path-ological features of Alzheimer’s disease and dementia.
Methods
We assessed 456 brains donated to the population-based Medical Research CouncilCognitive Function and Ageing Study from persons 69 to 103 years of age at death.We used a standard neuropathological protocol that included measures of the path-ological features of Alzheimer’s disease, cerebral atrophy, and cerebrovascular dis-ease. Neuropathological variables were dichotomized to represent no burden or amild burden of pathological lesions as compared with a moderate or severe burden.Logistic regression was used to estimate the effect of age on the relationship be-tween neuropathological features and dementia.
Results
The difference in the prevalence of moderate and severe Alzheimer’s-type patho-logical changes between persons with and those without dementia decreased withincreasing age. The association between neocortical neuritic plaques and dementia was strong at 75 years of age (odds ratio, 8.63; 95% confidence interval [CI], 3.81to 19.60) and reduced at 95 years of age (odds ratio, 2.48; 95% CI, 0.92 to 4.14), andsimilar attenuations with advancing age were observed in the association betweenother pathological changes related to Alzheimer’s disease and dementia in all brainareas. In contrast, neocortical cerebral atrophy maintained a relationship with agein persons with dementia at both 75 years of age (odds ratio, 5.11; 95% CI, 1.94 to13.46) and 95 years of age (odds ratio, 6.10; 95% CI, 2.80 to 13.28) and thus distin-guished the cohort with dementia from the cohort without dementia.
Conclusions
The association between the pathological features of Alzheimer’s disease and de-mentia is stronger in younger old persons than in older old persons. Age must betaken into account when assessing the likely effect of interventions against demen-tia on the population.
Downloaded from www.nejm.org on June 14, 2010 . Copyright © 2009 Massachusetts Medical Society. All rights reserved.
 
Age, Neuropathology, and Dementia
n engl j med
360;22
nejm.org may
28, 2009
2303
D
uring the 20th century, interest
in the dementias focused on specific dis-orders defined by criteria that were devel-oped for patients who had onset of dementia be-fore the age of 65 years, which had come to beconsidered by many as pathologically distinct fromlate-onset dementia.
1
In the second half of that century, the distinction between early-onset andlate-onset dementias was challenged by the real-ization that the hallmarks of Alzheimer’s diseasein older persons were indistinguishable from thosein younger persons with Alzheimer’s disease.
2
 Population epidemiologic studies of dementia haverevealed a relentless rise in the incidence of de-mentia into old age,
3
and clinically diagnosedAlzheimer’s disease is considered to be the majorsubtype of dementia.
4
The role of Alzheimer’s dis-ease in very old persons has become less clear sincethe contribution of vascular and other pathologi-cal changes has been recognized.
5,6
Research in dementia is driven by the expecta-tion that understanding the genetic and molecu-lar findings underlying clinical subtypes of de-mentia will result in major prevention strategiesfor the whole population.
7
The greatest demo-graphic change is the increasing number of per-sons over 85 years of age, in whom most casesof dementia will occur.
8
It is therefore important to know whether research findings in younger oldpersons, often in tertiary research settings, arerelevant to older old persons in the population.Only a small number of brain-donation programsare linked to longitudinal, population-based stud-ies of aging.
9
Programs that have included personsin the oldest age groups consistently show that these persons have mixed neuropathological fea-tures
10,11
and that those who die in their 80s and90s may have pathological features of Alzheimer’sdisease without a diagnosis of dementia duringlife.
12
Current diagnostic criteria that seek to de-fine Alzheimer’s disease, vascular dementia, andLewy body dementia may not apply as well to theoldest old as to the younger old, in whom they  were generated.The relationship between underlying biology and clinical phenotype in the oldest old meritsfurther examination, because current diagnosis,treatment, and management are predominantly shaped by research based on the younger old.
13
 Here we explore the effect of age on the relation-ship between the classic neuropathological fea-tures of dementia and the clinical manifestationof dementia in a population-based cohort of theelderly.
Methods
Population selection and interview phases
The Medical Research Council Cognitive Functionand Ageing Study (CFAS) is a multicenter, prospec-tive, population-based study of older people inthe United Kingdom. The study design and dataon the prevalence and incidence of dementia havebeen previously reported and have been used inthe development of international and national poli-cies on dementia.
5,8,10,14,15
The population baseused was derived from lists of primary care phy-sicians in specific geographic areas that includedinstitutions that cared for elderly people. In fiveurban and rural centers in England and Wales,random samples of approximately 2500 personsaged 64 years or older underwent a screening in-terview that included the Mini–Mental State Exam-ination (MMSE)
16
and the Geriatric Mental StateAutomated Geriatric Examination for ComputerAssisted Taxonomy (GMS-AGECAT)
17
items relatedto organic disorders. The response rate was 82%.Detailed assessment was conducted in a subsam-ple of approximately 20% of subjects stratifiedaccording to the MMSE and the AGECAT organic-ity scores. The screening and assessment process was repeated after 2 years, and a further 20% of those not previously included were added to theassessment group. This assessment group was fol-lowed up again 6 years after baseline, and the en-tire remaining cohort was assessed 10 years afterbaseline. Additional interviews at 1, 3, and 8 years were conducted in samples of the assessment group. In a sixth center, 5200 people underwent similar assessments at baseline, 1 or 2 years, 3 or4 years, 5 or 6 years, 8 years, and 10 years.Those who took part in assessment interviews were asked whether they and their families were willing to consider brain donation after the re-spondent’s death. The analysis presented here wasbased on 456 brains donated up to July 2004 (dataset version 3.1).
Diagnosis of dementia
Dementia status at death was determined on thebasis of all information available for each respon-dent. This information was based on interviews
Downloaded from www.nejm.org on June 14, 2010 . Copyright © 2009 Massachusetts Medical Society. All rights reserved.
 
Th
new england journal
o
medicine
n engl j med
360;22
nejm.org may
28, 2009
2304
during the last years of life, including the fullGMS-AGECAT diagnostic algorithm
17
that wasequivalent to that in the
Diagnostic and StatisticalManual of Mental Disorders,
third edition, revised(DSM-III-R), interviews with informants after therespondent’s death when this was possible, anddeath certification. Dementia was diagnosed be-fore death in 243 of the 456 respondents, and 183 were determined not to have dementia. Sufficient information for a diagnosis of dementia was not available for an additional 30 respondents, who were excluded from the analysis. The approach tothe diagnosis of dementia in the CFAS is describedin the Supplementary Appendix, available with thefull text of this article at NEJM.org.
Neuropathological assessment
Assessment by neuropathologists who were un-aware of all clinical data was conducted accord-ing to a modified Consortium to Establish a Reg-istry for Alzheimer’s Disease (CERAD) protocol(www.cfas.ac.uk).
10,18
Neuropathological lesionsof Alzheimer’s disease, diffuse plaques, neuriticplaques, and neurofibrillary tangles in the ento-rhinal, hippocampal, frontal, temporal, parietal,and occipital cortexes were classified into fourcategories (none, mild, moderate, and severe). Cor-tical atrophy was assessed macroscopically in eachbrain area, without knowledge of microscopicalfindings, and classified as absent, mild, moderate,or severe. Lewy bodies and hemorrhages, region-al infarcts (>1 cm in diameter), and small-vesseldisease (severe arteriosclerosis, lacunes, microin-farcts, or severe white-matter attenuation) werescored according to the CERAD protocol. Somesubjects had more than one of the vascular path-ological changes that were assessed. Inter-raterreliability for cerebral atrophy, tangles, plaques,Lewy bodies, and amyloid angiopathy was validatedamong contributing pathologists at the begin-ning of the study by circulating photographs of macroscopic findings and slides of microscopi-cal findings.
10
Statistical Analysis
Variables were dichotomized so that moderate andsevere scores were considered to represent a sig-nificant burden of pathological lesions, as com-pared with no score and mild scores, which rep-resented no burden or a low burden. In accordance with the CERAD protocol, maximum neocorticalscores for each lesion and for atrophy were used.Logistic regression was used to model the effect of age on the relationship between neuropatho-logical lesions and dementia. Each dichotomizedpathological indicator was considered as an out-come, and the effects of age and dementia and theirinteraction were included in the model. Age at death was modeled as a continuous variable toestimate the association between pathology anddementia at different ages and to test for interac-tions. For analysis of the relationship between theprevalence of lesions and dementia at death, thesubjects were divided into five age groups: under80, 80 to 84, 85 to 89, 90 to 94, and over 94 yearsof age.Sensitivity analyses were conducted for the ef-fects of potential confounders. These analyses in-cluded sex, level of education, social class, timesince last interview, and center, as well as the in-teraction of each of these with dementia. Furtheranalyses included only those participants whoreceived an assessment 1 year before death andexcluded all those with prevalent dementia at baseline.
Results
Sample Characteristics
The sex, age, and dementia status of the membersof the cohort at death are given in
Table 1
. Morethan 63% of donors were 85 years of age or olderat death; 59% were women. Among those who hadnot received a diagnosis of dementia, there was nosignificant association between age and MMSEscore at the most recent assessment before death.Among those who died with dementia, the MMSEscore was lower (indicating poorer function) in theolder groups. The time since the last interview  was similar in all age groups. Among those whodied without dementia, the causes of death weresimilar in those who had an autopsy and those whodid not (the cause of death was cancer in 23% and24% of respondents, respectively, and cardiovas-cular disease in 45% and 44%).
Age and Alzheimer’s disease–typepathological lesions
The distribution of each pathological lesion accord-ing to age group and dementia status is shown in
Table 1
in the Supplementary Appendix. The mod-eled and observed prevalence rates of pathologi-cal changes are shown in Figure 1. Among persons without dementia, the prevalence of moderate or
Downloaded from www.nejm.org on June 14, 2010 . Copyright © 2009 Massachusetts Medical Society. All rights reserved.

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