Association between APOE genotype, neuropathology and dementia in the older population of England and Wales.
OBJECTIVE
Apolipoprotein E (APOE) genotype is the major genetic risk factor for sporadic Alzheimer's disease (AD) but it is unclear how this is mediated. Most studies of APOE genotype have used case-control design to compare groups differing by two variables: i.e. dementia and AD pathology, so it is unclear to which of these variables APOE genotype is more strongly related. The prospective Medical Research Council Cognitive Function and Ageing Study neuropathology cohort is population-based sample in which donations are unbiased by dementia status.


METHODS
We investigated the association between APOE genotypes and neuropathological and cognitive data in this cohort (n = 310).


RESULTS
APOEε4 was associated with an increased risk of diffuse plaques, neuritic plaques, tangles and cerebral amyloid angiopathy. APOEε4 was not associated with infarcts, lacunes, haemorrhages or small vessel disease. APOEε2 appeared to have a protective effect on AD pathology and also on the risk of cortical atrophy. APOE genotype had a non-significant effect on the presence of dementia after adjusting for AD pathology.


CONCLUSIONS
APOE genotype is associated with each of the key features of AD pathology but not with cerebrovascular disease other than cerebral amyloid angiopathy. The excess risk of dementia in those with an APOEε4 allele is explained by the pathological features of AD. However, it remains unclear to what extent cognitive dysfunction is caused by these specific pathological features or more directly by closely related APOE-associated mechanisms.
Nicoll
J A R
JA
Division of Clinical Neurosciences, University of Southampton, Southampton, UK. j.nicoll@soton.ac.uk
Savva
G M
GM
Stewart
J
J
Matthews
F E
FE
Brayne
C
C
Ince
P
P
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics*; D001921:Brain / Q000473:pathology*; D015331:Cohort Studies; D003704:Dementia / Q000235:genetics*; D004739:England; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D014852:Wales
D001057:Apolipoproteins E