Glial activation mediates phenotypic effects ofAPOEε4and sex in Alzheimer’s disease

Abstract

INTRODUCTION: This study examined the impact of apolipoprotein e4 (APOEe4) allele frequency and sex on the phenotype of Alzheimer disease (AD). METHODS: The baseline characteristics, CSF, and neuroimaging biomarkers, and cognition scores collected from 45 patients aged 50-74 years with confirmed mild AD from clinical trialNCT03186989were evaluated in a post-hoc study. RESULTS: A phenotypic spectrum was observed from a predominant amyloid and limbic-amnestic phenotype in male APOEe4 homozygotes to a predominantly tau, limbic-sparing, and multidomain cognitive impairment phenotype in female APOEe4 noncarriers. Amyloid pathology inversely correlated with tau pathophysiology, glial activation, and synaptic injury, with the strongest correlations observed in male APOEe4 carriers. Tau pathophysiology was correlated with glial activation, synaptic injury, and neuroaxonal damage, with the strongest correlation observed in female APOEe4 noncarriers. DISCUSSION: Glial activation is influenced by apoE isoform and sex, which explains much of the phenotypic heterogeneity in mild AD below age 75 years.