Elsevier

The Lancet

Volume 357, Issue 9251, 20 January 2001, Pages 169-175
The Lancet

Articles
Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales

https://doi.org/10.1016/S0140-6736(00)03589-3Get rights and content

Summary

Background

We have undertaken a large unselected, community-based neuropathology study in an elderly (70–103 years) UK population in relation to prospectively evaluated dementia status. The study tests the assumption that dementing disorders as defined by current diagnostic protocols underlie this syndrome in the community at large.

Methods

Respondents in the Medical Research Council Cognitive Function and Ageing Study were approached for consent to examine the brain at necropsy. Dementia status was assigned by use of the automated geriatric examination for computer-assisted taxonomy algorithm. Neuropathological features were standardised by use of the protocol of the Consortium to Establish a Registry of Alzheimer's Disease, which assesses the severity and distribution of Alzheimer-type pathology, vascular lesions, and other potential causes of dementia. A statistical model of dementia risk related predominantly to Alzheimer-type and vascular pathology was developed by multivariate logistic regression.

Findings

We report on the first 209 individuals who have come to necropsy. The median age at death was 85 years for men, and 86 years for women. Cerebrovascular (78%) and Alzheimer-type (70%) pathology were common. Dementia was present in 100 (48%), of whom 64% had features indicating probable or definite Alzheimer's disease. However, 33% of the 109 non-demented people had equivalent densities of neocortical neuritic plaques. Some degree of neocortical neurofibrillary pathology was found in 61% of demented and 34% of non-demented individuals. Vascular lesions were equally common in both groups, although the proportion with multiple vascular pathology was higher in the demented group (46% vs 33%).

Interpretation

Alzheimer-type and vascular pathology were the major pathological correlates of cognitive decline in this elderly sample, as expected, but most patients had mixed disease. There were no clear thresholds of these features that predicted dementia status. The findings therefore challenge conventional dementia diagnostic criteria in this setting. Additional factors must determine whether moderate burdens of cerebral Alzheimer-type pathology and vascular lesions are associated with cognitive failure.

Introduction

Epidemiological, clinical, and neuropathological studies of dementia in elderly people have proliferated in the past three decades. Most have used a model of dementia based on neuropathological definitions of Alzheimer's disease,1, 2 vascular dementia, 3 dementia with Lewy bodies, 4 and other less frequent ‘causes’ of dementia. The disease entities that have emerged from these studies are defined within consensus guidelines for the burden of pathology required to achieve a particular degree of certainty of diagnosis. This situation can lead to circularity in the design of studies: for example, for studies of Alzheimer's disease, only patients with abundant neuritic plaques may be selected. This process then reinforces the concept of Alzheimer's disease as an amyloidosis and contributes to theories of causation such as the amyloid cascade hypothesis.5

Despite all this work, there are important unanswered questions about the pathology of dementia. What is the relative prevalence of these different types of pathology in community populations? How do they interact as substrates for dementia? How are the processes that lead to dementia distinct from normal effects of ageing? Most clinicopathological studies in more developed countries suggest that Alzheimer's disease is the commonest cause of dementia, with vascular disease the second most common cause. Other studies have suggested that dementia with Lewy bodies is more frequent than vascular dementia. 6, 7 Yet another has suggested that vascular disease predominates over all other causes in the oldest age-group.8

Community-based studies have been few but instructive. For example, the ɛ4 allele of the apolipoprotein E gene is associated with increased Alzheimer-type pathology in both demented and nondemented individuals.9 In another study, only 60% of individuals with sufficient Alzheimer-type pathology to warrant a neuropathological diagnosis of Alzheimer's disease1 were demented.10 The severity of Alzheimer-type pathology associated with dementia was inversely correlated with the presence of cerebral ischaemic lesions-in demented individuals with ischaemic lesions the burden of neocortical neurofibrillary tangles was an eighth of that in patients without ischaemic lesions.10 Such studies suggest that the relation between lesion burden and cognitive status, and the interactions between lesions, may differ in the wider community from those in selected secondary referral cohorts of demented people.

The Medical Research Council Cognitive Function and Ageing Study (MRC CFAS) 11 is a large multicentre, community-based, prospective study of prevalent and incident dementia, which has a strategy of necropsy. A large sample of brains from elderly people is available, with a strategy to enrich the number of demented individuals. The non-demented cohort was based on a random sample of the rest of the general population. We report standardised neuropathological findings in the first 209 individuals coming to necropsy, representing those accumulated up to July, 1998.

Section snippets

Respondents

The study and the methods for necropsy approach were approved in each centre by the local research ethics committee, and more recently by the Multicentre Research Ethics Committee.

MRC CFAS has been fully described elsewhere.11 At each of five centres in England and Wales (Cambridgeshire, Gwynedd, Newcastle upon Tyne, Nottingham, and Oxford), random samples of about 2500 people aged 64 years and over (with an 82% response rate), agreed to a structured initial interview, which included the

Results

Age at death in this sample ranged from 70 years to 103 years. There were more women than men in the sample (table 1). The median age at death was 86 for women and 85 years for men. The median time from last interview until death was 1·2 years (range 3 days to 4·2 years; 81% within the 2 years before death). The proportion with dementia diagnosis before death was similar in all the centres (overall, 48%). Dementia was more common in women than in men, and in both sexes it was more common at

Discussion

Although there have been many epidemiological studies based on clinical methods of detection of dementia that have reported on prevalence and incidence, there have been no large community-based neuropathological studies of the relation between dementia and ageing. We present data from the first 209 individuals who came to necropsy in this large multicentre study. The striking findings are the high frequency of the neuropathological features usually associated with dementia in this older

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