Glial activation mediates phenotypic effects of APOEe4 and sex in Alzheimer disease

INTRODUCTIONThis study examined the impact of apolipoprotein {varepsilon}4 (APOE{varepsilon}4) allele frequency and sex on the phenotype of Alzheimers 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 trial NCT03186989 were evaluated in a post-hoc study. RESULTSA phenotypic spectrum was observed from a predominant amyloid and limbic-amnestic phenotype in male APOE{varepsilon}4 homozygotes to a predominantly tau, limbic-sparing, and multidomain cognitive impairment phenotype in female APOE{varepsilon}4 noncarriers. Amyloid pathology inversely correlated with tau pathophysiology, glial activation, and synaptic injury, with the strongest correlations observed in male APOE{varepsilon}4 carriers. Tau pathophysiology was correlated with glial activation, synaptic injury, and neuroaxonal damage, with the strongest correlation observed in female APOE{varepsilon}4 noncarriers. DISCUSSIONGlial activation is influenced by apoE isoform and sex, which explains much of the phenotypic heterogeneity in early AD below age 75 years. HIGHLIGHTSO_LIAPOE{varepsilon}4 homozygotes displayed a predominantly amyloid and limbic-amnestic phenotype. C_LIO_LIFemale APOE{varepsilon}4 noncarriers displayed a predominantly tau, limbic-sparing, and multidomain cognitive impairment phenotype. C_LIO_LIIn male APOE{varepsilon}4 carriers, amyloid pathology was inversely correlated with tau pathophysiology, synaptic injury, and glial activation C_LIO_LIFemales displayed a non-APOE{varepsilon}4 allele frequency-dependent increase in glial activation and synaptic injury C_LIO_LIIn female APOE{varepsilon}4 noncarriers, tau pathophysiology was strongly correlated with glial activation, synaptic injury, and neuroaxonal damage C_LI RESEARCH IN CONTEXTO_ST_ABSSystematic reviewC_ST_ABSThe impact of APOE{varepsilon}4 alleles 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 in APOE{varepsilon}4 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 APOE{varepsilon}4 noncarriers 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.