HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Figures Only Full Text Full Text (PDF) Correspondence: Submit a response Alert me when this article is cited Alert me when Correspondence are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bennett, D. A. Articles by Schneider, J. A. Search for Related Content PubMed PubMed Citation Articles by Bennett, D. A. Articles by Schneider, J. A. Related Collections Alzheimer's disease Cognitive aging Risk factors in epidemiology Association studies in genetics

Neuropathologic intermediate phenotypes enhance association to Alzheimer susceptibility alleles

From Rush Alzheimer's Disease Center and the Department of Neurological Sciences (D.A.B., S.E.L., J.A.S.) and Department of Pathology (Neuropathology) (J.A.S.), Rush University Medical Center, Chicago, IL; Center for Neurologic Diseases (P.L.D.), Department of Neurology, Brigham & Women's Hospital and Harvard Medical School, Boston; Partners Center for Personalized Genetic Medicine Boston (P.L.D.); and Program in Medical & Population Genetics (P.L.D.), Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA.

Address correspondence and reprint requests to Dr. David A. Bennett, Rush Alzheimer's Disease Center, 600 S. Paulina, Suite 1028, Chicago, IL 60062 dbennett{at}rush.edu

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 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 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 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.

Abbreviations: AD = Alzheimer disease; CERAD = Consortium to Establish a Registry for Alzheimer's Disease; CI = confidence interval; MCI = mild cognitive impairment; NIA = National Institute on Aging; OR = odds ratio.

Supported by NIH grants P30AG10161, R01AG15819, R01AG17917, and K08NS46341.

Disclosure: The authors report no disclosures.

Received October 9, 2008. Accepted in final form February 2, 2009.