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 epsilon 4 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 epsilon 2 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 epsilon 2. Conclusion: Discovery efforts for susceptibility loci for Alzheimer disease could benefit from the use of neuropathologic intermediate phenotypes as a complement to other approaches. Neurology (R) 2009; 72: 1495-1503