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Significantly, there are prominent sex differences in the risk, onset, progression, and severity of AD, as well as response to therapies, with disease burden disproportionately affecting women. Although menopause onset (i.e., perimenopause) may be a critical transition stage for AD susceptibility in women, the role of early ovarian decline in initial disease pathology, particularly key neuroinflammatory processes, is not well understood. To study this, we developed a unique mouse model of perimenopausal AD by combining an accelerated ovarian failure (AOF) model of menopause induced by 4-vinylcyclohexene diepoxide (VCD) with the 5xFAD transgenic AD mouse model. To target early stages of disease progression, 5xFAD females were studied at a young age (\u223c4 months) and at the beginning stage of ovarian failure analogous to human perimenopause (termed \u201cperi-AOF\u201d), and compared to age-matched males. Assessment of neuropathology was performed by immunohistochemical labeling of A\u03b2 as well as markers of astrocyte and microglia activity in the hippocampus, a brain region involved in learning and memory that is deleteriously impacted during AD. Our results show that genotype, AOF, and sex contributed to AD-like pathology. Aggregation of A\u03b2 was heightened in female 5xFAD mice and further increased at peri-AOF, with hippocampal subregion specificity. Further, select increases in glial activation also paralleled A\u03b2 pathology in distinct hippocampal subregions. However, cognitive function was not affected by peri-AOF. These findings align with the hypothesis that perimenopause constitutes a period of susceptibility for AD pathogenesis in women.<\/jats:p>","DOI":"10.1101\/2025.03.14.643317","type":"posted-content","created":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T15:16:06Z","timestamp":1742397366000},"source":"Crossref","is-referenced-by-count":1,"title":["Perimenopause promotes neuroinflammation in select hippocampal regions in a mouse model of Alzheimer\u2019s disease"],"prefix":"10.64898","author":[{"given":"Roberta","family":"Marongiu","sequence":"first","affiliation":[{"name":"Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, 407 East 61st St, New York, NY 10065 USA"},{"name":"Neurological Surgery Department, Weill Cornell Medicine, 1300 York Ave, New York, NY 10065 USA"},{"name":"Genetic Medicine Department, Weill Cornell Medicine, 1300 York Ave, New York, NY 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