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Vacuolar H+-ATPase (V-ATPase), a proton-pumping enzyme, is essential for synaptic vesicle acidification and neurotransmitter loading. However, whether SV-associated V-ATPase is vulnerable to AD remains unclear. Here, using SV-rich fractions from postmortem brain tissues, we identified SV-associated V-ATPase deficits, including decreased enzymatic activity, impaired complex assembly, and altered expression of its key subunits in AD. SV-associated V-ATPase dysfunction was further associated with pathological and clinical characteristics of AD. Genetic downregulation of the V-ATPase V1D subunit, a component reduced in AD brains, disrupted V-ATPase proton transport and impaired SV acidification. Further experiments using 5\u00d7FAD mice, which exhibited AD-like SV-associated V-ATPase deficits, demonstrated the deleterious impact of V-ATPase dysfunction on SV acidification and synaptic transmission including presynaptic neurotransmitter release. In addition, ex vivo studies identified amyloid \u03b2\u2013induced oxidative stress as a driver of V1D loss and V-ATPase disassembly, linking AD pathology to SV-associated V-ATPase dysfunction. These findings indicate that SV-associated V-ATPase dysfunction contributes to synaptic failure and cognitive deficits in AD. Therapeutic avenues to mitigate V-ATPase dysfunction have the potential to attenuate synaptic failure for the management of AD.<\/jats:p>","DOI":"10.1172\/jci.insight.202983","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T18:00:57Z","timestamp":1791396057000},"source":"Crossref","is-referenced-by-count":0,"title":["Disrupted synaptic vacuolar H+-ATPase renders synaptic vulnerability to Alzheimer\u2019s disease"],"prefix":"10.1172","volume":"11","author":[{"given":"Yanting","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA."},{"name":"Department of Pharmacology and Toxicology, University of Kansas, Lawrence, Kansas, USA."},{"name":"Alzheimer\u2019s Disease Research Center and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khloud Ashraf Farouk","family":"Emam","sequence":"additional","affiliation":[{"name":"Department of 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