Harvard-Amgen Scholars Program An Alzheimer's Disease Risk Variant ofTREM2 Confers Sex-Specific Changes in Adult Hippocampal Neurogenesis Sophia Kouznetsov, Ryan W. Castro, Se Hoon Choi Worcester Polytechnic Institute | Neuroscience | 2026 Alzheimer's disease (AD) is a progressive neurodegenerative disorder, affecting over 55 million people globally. The hippocampus, a central structure in learning and memory, is severely affected in AD, where impaired adult hippocampal neurogenesis (AHN) contributes to the marked cognitive decline. AHN occurs in the dentate gyrus, where neural stem cells can self-renew or differentiate into neural progenitor cells (NPCs), eventually giving rise to mature granule neurons or glia. This process declines with age and is further disrupted in AD due to mechanisms that are yet to be fully understood. Variants in the immune-modulatory gene TREM2 — Triggering Receptor Expressed on Myeloid Cells 2 — which is expressed primarily by microglia in the central nervous system, confer up to a four- fold risk of developing AD. Due to the emerging role of microglia as regulators of AHN, understanding the role of this microglia- specific AD risk factor in AHN regulation is imperative. Thus, we quantified facets of neurogenesis, namely the proliferation, differentiation, and survival of NPCs, in 4-month-old male and female mice (N = 5 per group) harboring wild-type TREM2, full TREM2 gene knockout, or the TREM2-R47H mutation, which is the most prevalent and widely studied TREM2-mutation that confers increased AD risk. While no genotype-specific effects were observed in proliferation or differentiation, female R47H mice exhibited increased NPC survival, suggesting a sex- specific vulnerability. Premature differentiation and subsequent depletion of the stem cell reserve are common hallmarks of AD, and the higher prevalence of AD in females is well described. Thus, the current findings highlight a possible link between microglial dysfunction driven by TREM2 mutations and impaired neurogenesis in AD. Targeting TREM2 may offer a dual therapeutic approach, modulating inflammation and supporting neurogenesis, improving cognitive outcomes beyond current plaque-targeting strategies. Investigating the Role of TMED Cargo Receptors in Brain Health and Disease Dora Michaelides, Giulia Monti, Anna Greka

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