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In the present study, we investigated bone loss in mouse models of familial Alzheimer's disease harboring the Presenilin 1 (L166P) knock\u2010in mutation (PSEN1 KI), with or without the human amyloid precursor protein transgene (hAPP Tg+) known to induce brain amyloid pathology by 6 months. Female and not male 12\u2010month PSEN1\/hAPP Tg+ mice exhibited reduced whole\u2010body bone mineral density and bone mineral content, compared to sex\u2010matched controls. Consistent with PSEN1 L166P driving the phenotype, female PSEN1 KI mice lacking the hAPP transgene also displayed low bone mass with a reduction in bone microarchitecture observed as early as 1 month of age. Correspondingly, PSEN1 KI mice exhibit reduced cortical and trabecular bone mass compared to age\u2010 and sex\u2010matched control mice. The loss of bone microarchitecture was largely attributed to a reduction in bone formation as indicated by decreases in serum P1NP levels and osteoblast ALP activity and mRNA expression in\u00a0vitro. At the ages examined, PSEN1 KI mice exhibited increased follicle stimulating hormone (FSH) levels, which is known to cause a decrease in bone mass. Western blotting also identified both PSEN1 and amyloid\u2010beta protein expression in bone and brain tissue. Taken together, the data indicate that female\u2010specific bone loss in familial AD is potentially due to the direct actions of mutant PSEN1 in bone cells combined with systemic crosstalk caused by brain\u2010expressed PSEN1 L116P.<\/jats:p>","DOI":"10.1002\/cph4.70097","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T07:56:38Z","timestamp":1767772598000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Presenilin\n                    <scp>L166P<\/scp>\n                    Mutation, a Model of Familial Alzheimer's Disease, Leads to Early Onset Bone Loss"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4081-2989","authenticated-orcid":false,"given":"Vidyani","family":"Suryadevara","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, School of Medicine Indiana University  Indianapolis Indiana 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Endocrine, Neoplasia and Hormonal Disorders University of Texas\u2010 MD Anderson Cancer Center  Houston Texas USA"},{"name":"Indiana Center for Musculoskeletal Health, School of Medicine Indiana University  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre P.","family":"Eleniste","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Applied Sciences, School of Dentistry Indiana University  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumana","family":"Posritong","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Applied Sciences, School of Dentistry Indiana University  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung Min","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Applied Sciences, School of Dentistry Indiana University  Indianapolis Indiana 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