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Our analyses have revealed that (1) persistent mitochondrial alkalization is due to chronic inflammation coupled with elevated iron and copper metabolisms; (2) the affected cells activate multiple acid-producing metabolisms to keep the mitochondrial pH stable for survival; (3) the most significant one is the continuous import and hydrolysis of glutamine to glutamate, NH3, and H+, resulting in persistent release of glutamate, an excitatory neurotransmitter, into the extracellular space; (4) this leads to persistent hyperexcitability of the nearby neurons, resulting in their continuous firing and release of H+-rich synaptic vesicles; (5) the H+ is neutralized by bicarbonates released by the neighboring astrocytes in normal tissues, which could not keep up with the increased release of H+ in their discharge rates of bicarbonates in AD tissues, leading to progressively increased extracellular acidosis and ultimately cell death; and (6) multiple extensively studied AD-associated phenotypes, including A\u03b2 aggregates and tau fibers, are induced to help to alleviate the pH imbalances and beneficial to cell survival in the early phase of AD, which gradually become contributors to the AD development. Each step in this model is largely supported by published studies. Overall, we have developed a fundamentally novel and systems-level view of how AD may have evolved.<\/jats:p>","DOI":"10.1093\/gpbjnl\/qzaf087","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T13:01:12Z","timestamp":1758632472000},"source":"Crossref","is-referenced-by-count":1,"title":["A Model for the Development of Alzheimer\u2019s Disease"],"prefix":"10.1093","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-0029-1729","authenticated-orcid":false,"given":"Zhenyu","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1006-2830","authenticated-orcid":false,"given":"Xuechen","family":"Mu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8752-571X","authenticated-orcid":false,"given":"Qiufen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0536-411X","authenticated-orcid":false,"given":"Lingli","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4940-0174","authenticated-orcid":false,"given":"Jun","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5681-0887","authenticated-orcid":false,"given":"Chunman","family":"Zuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7238-6964","authenticated-orcid":false,"given":"Ye","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4362-2615","authenticated-orcid":false,"given":"Bocheng","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5232-5284","authenticated-orcid":false,"given":"Yingwei","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4446-1610","authenticated-orcid":false,"given":"Renbo","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4790-0466","authenticated-orcid":false,"given":"Long","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7162-7826","authenticated-orcid":false,"given":"Renchu","family":"Guan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7856-3343","authenticated-orcid":false,"given":"Ying","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,9,23]]},"reference":[{"key":"2026071401563610300_qzaf087-B1","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s13024-019-0333-5","article-title":"The 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