Age, Neuropathology, and Dementia
n engl j med
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.
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.
Population epidemiologic studies of dementia haverevealed a relentless rise in the incidence of de-mentia into old age,
and clinically diagnosedAlzheimer’s disease is considered to be the majorsubtype of dementia.
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.
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.
The greatest demo-graphic change is the increasing number of per-sons over 85 years of age, in whom most casesof dementia will occur.
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.
Programs that have included personsin the oldest age groups consistently show that these persons have mixed neuropathological fea-tures
and that those who die in their 80s and90s may have pathological features of Alzheimer’sdisease without a diagnosis of dementia duringlife.
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.
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.
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.
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)
and the Geriatric Mental State–Automated Geriatric Examination for ComputerAssisted Taxonomy (GMS-AGECAT)
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
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