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Whether mitochondrial deficiency in brain aging and AD is mechanistically linked, however, remains controversial. We report a correlation between intrasynaptosomal amyloid \u03b2 42 (A\u03b242) and synaptic mitochondrial bioenergetics inefficiency in both aging and amnestic mild cognitive impairment, a transitional stage between normal aging and AD. Experiments using a mouse model expressing nonmutant humanized A\u03b2 (humanized A\u03b2-knockin [hA\u03b2-KI] mice) confirmed the association of increased intramitochondrial sequestration of A\u03b242 with exacerbated synaptic mitochondrial dysfunction in an aging factor- and AD risk\u2013bearing context. Also, in comparison with global cerebral A\u03b2, intramitochondrial A\u03b2 was relatively preserved from activated microglial phagocytosis in aged hA\u03b2-KI mice. The most parsimonious interpretation of our results is that aging-related mitochondrial A\u03b2 sequestration renders synaptic mitochondrial dysfunction in the transitional stage between normal aging and AD. Mitochondrial dysfunction in both brain aging and the prodromal stage of AD may follow a continuous transition in response to escalated intraneuronal, especially intramitochondrial A\u03b2, accumulation. Moreover, our findings further implicate a pivotal role of mitochondria in harboring early amyloidosis during the conversion from normal to pathological aging.<\/jats:p>","DOI":"10.1172\/jci.insight.174290","type":"journal-article","created":{"date-parts":[[2023,11,21]],"date-time":"2023-11-21T14:00:56Z","timestamp":1700575256000},"source":"Crossref","is-referenced-by-count":20,"title":["Mitochondria-sequestered A\u03b2 renders synaptic mitochondria vulnerable in the elderly with a risk of Alzheimer disease"],"prefix":"10.1172","volume":"8","author":[{"given":"Kun","family":"Jia","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Kansas, Lawrence, Kansas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Kansas, Lawrence, Kansas, 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