CHARACTERISING THE EFFECT OF APOE4 GENOTYPE IN ALZHEIMER’S DISEASE PATHOPHYSIOLOGY AT THE LEVEL OF NEUROINFLAMMATION AND COGNITIVE DECLINE

APOE4 is the strongest genetic risk factor for Alzheimer’s disease (AD) and has been proposed as a distinct dementia subtype. AD is characterised by progressive cognitive decline, synaptic dysfunction, and chronic neuroinflammation, with microglia playing a central role in immune regulation and synaptic homeostasis. While APOE isoforms differentially influence neuroinflammatory signalling and microglial function, how these effects contribute to early behavioural changes and microglia–synapse interactions before disease onset remains unclear. This study aimed to characterise early AD-related
cognitive and behavioural changes across APOE genotypes in mice and to examine microglial phagocytic function.
Six cohorts (5xFAD, WT, E4FAD, APOE4, E3FAD, APOE3) were studied at 4 and 6 months, representing pre- and post-onset stages of amyloid pathology. Each cohort included n = 20 mice with a 1:1 sex ratio. Behavioural assessment at 6 months included the Object Location Task (OLT), Y-maze, and Open Field (OF). At both timepoints, primary microglia and synaptosomes were isolated and combined in a crossed design to dissociate microglial-intrinsic effects from synaptic dysfunction, exposing microglia to WT, genotype-matched, or disease-associated synaptosomes.
E4FAD mice showed worse working memory than E3FAD mice, with female APOE4 carriers displaying greater deficits, highlighting sex- and genotype-specific vulnerability. E4FAD and APOE4 mice exhibited hyperactivity in the OF. In vitro analyses revealed impaired microglial phagocytosis, more strongly associated with synaptosome dysfunction than intrinsic microglial deficits.
These results characterise APOE4 as a driver of early behavioural and cellular changes in AD models and open avenues to explore interventions targeting microglial function or synaptic resilience.