Abstract

Variants in ABCA7 are among the most consistently replicated genetic risk factors for late-onse Alzheimer's disease (AD), yet the cellular mechanisms remain poorly defined. Here, we characterise the impact of the common ABCA7 rs3752231 risk variant on amyloid-{beta} (A{beta}) pathology and glial responses in human post-mortem brain, combining quantitative neuropathology of 4G8-immunostained mid-temporal gyrus from 99 donors (Braak 0-VI) with glial-enriched single-nucleus RNA sequencing from 54 of them. ABCA7 rs3752231 carriers exhibited an increased A{beta} burden and larger plaques with late AD explained by a selective expansion of diffuse plaques and relative reduction in compact plaques, consistent with impaired microglial-mediated plaque maturation. Transcriptional responses to increasing A{beta} burden were largely genotype-specific: non-carriers showed canonical disease-associated microglial activation, including upregulation of complement, phagocytic, and inflammatory pathways,alongside astrocyte responses consistent with preserved synaptic support, while carriers exhibited a distinguishable activation state. Exploratory ligand-receptor analysis identified carrier-specific intercellular signals suggesting non-cell autonomous suppression of microglial phagocytosis. Together, these findings position ABCA7 rs3752231 as a regulator of glial responses to AD pathology, linking a common coding variant to impaired microglial plaque containment and maladaptive astrocyte responses and nominate microglial TREM2 activation and CD33 inhibition and astrocytic EAAT2 induction as candidate therapeutic strategies.