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The relative changes accompanying aging, high cholesterol, and\/or treatment of calcitriol, active vitamin D receptor (VDR) ligand, under normal physiology are unknown. We examined these relative changes in C57BL\/6 mice of ages 2, 4\u20138, and more than 10 months old, which were fed a normal or high fat \/ high cholesterol diet and treated with calcitriol, active ligand of the vitamin D receptor (0 or 2.5\u00a0\u03bcg\/kg \u00d74, intraperitoneally, every other day to elicit cholesterol lowering in liver). A\u03b2<jats:sub>40<\/jats:sub> but not A\u03b2<jats:sub>42<\/jats:sub> accumulation in brain and lower P\u2010glycoprotein (P\u2010gp) and neprilysin protein expressions for A\u03b2 efflux and degradation, respectively, were found to be associated with aging. But there was no trend for BACE1 (\u03b2\u2010secretase 1, a cholesterol\u2010sensitive enzyme) toward A\u03b2 synthesis with age. In response to calcitriol treatment, P\u2010gp was elevated, mitigating partially the age\u2010related changes. Although age\u2010dependent decreasing trends in mRNA expression levels existed for Cyp46a1, the brain cholesterol processing enzyme, whose inhibition increases BACE1 and ApoE to facilitate microglia A\u03b2 degradation, mRNA changes for other cholesterol transporters: Acat1 and Abca1, and brain cholesterol levels remained unchanged. There was no observable change in the mRNA expression of amyloid precursor protein (APP) and the influx (RAGE) and efflux (LRP1) transporters with respect to age, diet, or calcitriol treatment. Overall, aging poses as a risk factor contributing to A\u03b2 accumulation in brain, and VDR\u2010mediated P\u2010gp activation partially alleviates the outcome.<\/jats:p>","DOI":"10.1002\/bdd.2297","type":"journal-article","created":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T08:25:21Z","timestamp":1625473521000},"page":"372-388","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Impact of age, hypercholesterolemia, and the vitamin D receptor on brain endogenous \u03b2\u2010amyloid peptide accumulation in mice"],"prefix":"10.1002","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5725-9361","authenticated-orcid":false,"given":"H. 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