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

ABSTRACT INTRODUCTION This study examined the impact of apolipoprotein ɛ4 ( APOEɛ4 ) allele frequency and sex on the phenotype of Alzheimer’s disease (AD). METHODS The baseline characteristics, CSF, and neuroimaging biomarkers, and cognition scores collected from 45 patients aged 50-74 years with confirmed early AD from clinical trial NCT03186989 were evaluated in a post-hoc study. RESULTS A phenotypic spectrum was observed from a predominant amyloid and limbic-amnestic phenotype in male APOEɛ4 homozygotes to a predominantly tau, limbic-sparing, and multidomain cognitive impairment phenotype in female APOEɛ4 noncarriers. Amyloid pathology inversely correlated with tau pathophysiology, glial activation, and synaptic injury, with the strongest correlations observed in male APOEɛ4 carriers. Tau pathophysiology was correlated with glial activation, synaptic injury, and neuroaxonal damage, with the strongest correlation observed in female APOEɛ4 noncarriers. DISCUSSION Glial activation is influenced by apoE isoform and sex, which explains much of the phenotypic heterogeneity in early AD below age 75 years. HIGHLIGHTS APOEɛ4 homozygotes displayed a predominantly amyloid and limbic-amnestic phenotype. Female APOEɛ4 noncarriers displayed a predominantly tau, limbic-sparing, and multidomain cognitive impairment phenotype. In male APOEɛ4 carriers, amyloid pathology was inversely correlated with tau pathophysiology, synaptic injury, and glial activation Females displayed a non- APOEɛ4 allele frequency-dependent increase in glial activation and synaptic injury In female APOEɛ4 noncarriers, tau pathophysiology was strongly correlated with glial activation, synaptic injury, and neuroaxonal damage RESEARCH IN CONTEXT Systematic review The impact of APOEɛ4 alleles and sex on phenotypic features was examined in 45 patients, aged 50-74 years, with early AD. Interpretation Findings: 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 in APOEɛ4 homozygotes 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 female APOEɛ4 noncarriers was associated with the highest tau pathology and synaptic injury, the lowest amyloid pathology, greater ventricular expansion, and multi-domain cognitive deficits. Future directions This 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.