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

Abstract

ABSTRACTINTRODUCTIONThis study examined the impact ofapolipoprotein ɛ4(APOEɛ4) allele frequency and sex on the phenotype of Alzheimer’s disease (AD).METHODSThe baseline characteristics, CSF, and neuroimaging biomarkers, and cognition scores collected from 45 patients aged 50-74 years with confirmed early AD from clinical trialNCT03186989were evaluated in a post-hoc study.RESULTSA phenotypic spectrum was observed from a predominant amyloid and limbic-amnestic phenotype in maleAPOEɛ4homozygotes to a predominantly tau, limbic-sparing, and multidomain cognitive impairment phenotype in femaleAPOEɛ4noncarriers. Amyloid pathology inversely correlated with tau pathophysiology, glial activation, and synaptic injury, with the strongest correlations observed in maleAPOEɛ4carriers. Tau pathophysiology was correlated with glial activation, synaptic injury, and neuroaxonal damage, with the strongest correlation observed in femaleAPOEɛ4noncarriers.DISCUSSIONGlial activation is influenced by apoE isoform and sex, which explains much of the phenotypic heterogeneity in early AD below age 75 years.HIGHLIGHTSAPOEɛ4homozygotes displayed a predominantly amyloid and limbic-amnestic phenotype.FemaleAPOEɛ4noncarriers displayed a predominantly tau, limbic-sparing, and multidomain cognitive impairment phenotype.In maleAPOEɛ4carriers, amyloid pathology was inversely correlated with tau pathophysiology, synaptic injury, and glial activationFemales displayed a non-APOEɛ4allele frequency-dependent increase in glial activation and synaptic injuryIn femaleAPOEɛ4noncarriers, tau pathophysiology was strongly correlated with glial activation, synaptic injury, and neuroaxonal damageRESEARCH IN CONTEXTSystematic reviewThe impact ofAPOEɛ4alleles and sex on phenotypic features was examined in 45 patients, aged 50-74 years, with early AD.InterpretationFindings were consistent with prior reports and suggest that glial activation, influenced by apoE isoform and sex, explains much of the phenotypic heterogeneity in early AD below age 75 years. Lower glial activation inAPOEɛ4homozygotes associated with the highest levels of amyloid and the lowest levels of tau pathology, and a limbic-amnestic phenotype, suggesting degeneration of basal forebrain cholinergic neurons. Higher glial activation in femaleAPOEɛ4noncarriers was associated with the highest tau pathology and synaptic injury, the lowest amyloid pathology, greater ventricular expansion, and multi-domain cognitive deficits.Future directionsThis work defined a combined sex, genotype, and age framework that delineates multiple pathways to end-stage AD. Confirmation is required, followed by optimization of therapeutic approaches to amyloid, tau, and glial activation pathologies along the disease stage continuum.