<i>APOE</i> is a correlate of phenotypic heterogeneity in Alzheimer disease in a national cohort.

Abstract

To compare the proportion of <i>APOE</i> ε4 genotype carriers in aphasic vs amnestic variants of Alzheimer disease (AD). The proportion of <i>APOE</i> ε4 carriers was compared among the following 3 groups: (1) 42 patients with primary progressive aphasia (PPA) and AD pathology (PPA/AD) enrolled in the Northwestern Alzheimer Disease Center Clinical Core; (2) 1,418 patients with autopsy-confirmed AD and amnestic dementia of the Alzheimer type (DAT/AD); and (3) 2,608 cognitively normal controls (NC). The latter 2 groups were compiled from the National Alzheimer Coordinating Center database. Logistic regression models analyzed the relationship between groups and <i>APOE</i> ε4 carrier status, adjusting for age at onset and sex as needed. Using NC as the reference and adjusting for sex and age, the DAT/AD group was 3.97 times more likely to be <i>APOE</i> ε4 carriers. Adjusting for sex and age at symptom onset, the DAT/AD group was 2.46 times as likely to be carriers compared to PPA/AD. There was no significant difference in the proportion of <i>APOE</i> ε4 carriers for PPA/AD compared to NC. PPA subtypes included 24 logopenic, 10 agrammatic nonfluent, and 8 either mixed (n = 5) or too severe (n = 3) to subtype. The proportion of carriers and noncarriers was similar for logopenic and agrammatic subtypes, both having fewer carriers. The proportion of <i>APOE</i> ε4 carriers was elevated in amnestic but not aphasic manifestations of AD. These results suggest that <i>APOE</i> ε4 is an anatomically selective risk factor that preferentially increases the vulnerability to AD pathology of memory-related medial temporal areas rather than language-related neocortices.