Sex Differences in APOE ԑ4-Associated Risk for Primary Progressive Aphasia

Abstract

Primary progressive aphasia (PPA), a language neurodegenerative disorder caused by atrophy of the frontal and temporal lobes, has three variants: The nonfluent/agrammatic variant (naPPA) is marked by slowed speech and difficulty with complex grammar; the semantic variant (svPPA), by impaired naming and single-word comprehension; and the logopenic variant (lvPPA), by difficulty with sentence repetition. Alzheimer’s disease pathology (AD-P), found in approximately one-third of PPA cases, is left- lateralized in PPA compared to a more symmetric distribution in Alzheimer’s disease (AD). Because the APOE ε4 allele is a major risk factor for AD, I hypothesized that ε4 carriers were at increased risk for lvPPA, which is often associated with AD-P. Odds ratios analyses on genetic data from the National Alzheimer’s Coordinating Cen- ter and the University of Pennsylvania Frontotemporal Degeneration Center showed that the ε4 allele increased risk for svPPA and lvPPA, but not naPPA. Additionally, this research extends previous work indicating an increased risk of PPA for women with the ε2/ε4 genotype. Analyses stratified by sex revealed that female, but not male, ε4 carriers had a statistically significant increase in risk for all PPA variants. These findings suggest a sex difference in risk that may be related to estrogen-APOE interactions in women.