Neuropathologic intermediate phenotypes enhance association to Alzheimer susceptibility alleles.
OBJECTIVE
The identification of susceptibility alleles to risk of Alzheimer disease (AD) is a major public health priority. Using apolipoprotein E genotype (APOE), we examined whether neuropathologic intermediate phenotypes, the pathology underlying clinical AD that presumably lies intermediate in the causal chain, would increase power for genetic associations.


METHODS
More than 700 older persons underwent annual evaluation and organ donation as part of the Religious Orders Study or Rush Memory and Aging Project. A total of 536 autopsied persons with clinical AD or without dementia with APOE genotyping and a quantitative measure of AD pathology were analyzed. Regression analyses were used to examine the relation of APOE to clinical AD, to the level of cognitive function proximate to death, and to measures of AD neuropathology.


RESULTS
APOE epsilon4 was associated with increased odds of clinical AD (p = 3 x 10(-7)), and its association with level of cognition was stronger (p = 8 x 10(-12)). However, the use of quantitative measures of AD pathology markedly enhanced the association (p = 9 x 10(-24)). The APOE epsilon2 was not associated with either AD (p = 0.69) or level of cognition (p = 0.82). However, its association with AD pathology (p = 1 x 10(-5)) was sufficiently strong that it would have warranted follow-up if discovered in a genome-wide association study. Power calculations demonstrate that a sample size of 625 subjects with our measure of AD pathology would be required to meet genome-wide significance of p = 5 x 10(-8) for epsilon2.


CONCLUSIONS
Discovery efforts for susceptibility loci for Alzheimer disease could benefit from the use of neuropathologic intermediate phenotypes as a complement to other approaches.
Bennett
David A
DA
Rush Alzheimer's Disease Center, 600 S. Paulina, Suite 1028, Chicago, IL 60062, USA. dbennett@rush.edu
De Jager
Philip L
PL
Leurgans
Sue E
SE
Schneider
Julie A
JA
D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D053327:Apolipoprotein E4 / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics*; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D003072:Cognition Disorders / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008967:Molecular Biology / Q000379:methods; D009483:Neuropsychological Tests; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D011237:Predictive Value of Tests
D053327:Apolipoprotein E4; D001057:Apolipoproteins E