{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T05:06:34Z","timestamp":1784091994612,"version":"3.55.0"},"reference-count":664,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>It is hypothesized that in most cases of sporadic late-onset Alzheimer\u2019s disease (LOAD), the abnormally elevated cholesterol level in brain neurons represents a critical causative factor that drives the pathogenic processes of LOAD. Specifically, it is hypothesized that the abnormally elevated neuronal cholesterol will disrupt mitochondrial structure and metabolic activity, resulting in ATP deficiency as well as reduced formation of neuroactive metabolic intermediates (such as mevalonate and geranylgeraniol) along the cholesterol synthesis pathway in brain neurons. In addition, the abnormally elevated neuronal cholesterol will cause direct neuronal damage as well as other pathogenic changes in the brain, including increased formation and deposition of amyloid \u03b2 (A\u03b2) plaques. It is speculated that A\u03b2 accumulation and plaque formation in most LOAD cases only represent characteristic secondary pathological changes and are usually not the main force driving the pathogenesis of LOAD. As discussed in detail in this paper, abnormally elevated neuronal cholesterol in conjunction with ATP deficiency and lack of neuroactive metabolic intermediates will not only cause learning and memory impairment, but will also induce tauopathy and reduce the formation of cholinergic vesicles. It is expected that these pathogenic changes are more readily seen initially in ischemia-sensitive neurons in hippocampus and posterior parietal cortex, which are then followed by neurodegenerative and atrophic changes in other brain regions along with progressive cognitive decline. As explained in this paper, ApoE4 is a major risk factor in LOAD because it has a drastically reduced ability than ApoE2 and ApoE3 to efflux excess cholesterol out of neurons. Overall, there is a large body of direct, indirect and circumstantial clinical and experimental evidence which jointly offers strong support for the cholesterol-centered hypothesis on the etiology and pathogenesis of LOAD. Considerable efforts are made to apply the proposed hypothesis to offer a better mechanistic explanation for many of the poorly understood experimental and\/or clinical observations related to AD (mostly LOAD).<\/jats:p>","DOI":"10.3390\/molecules31142418","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T14:17:51Z","timestamp":1783606671000},"page":"2418","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cholesterol at the Center of Alzheimer\u2019s Disease: A Unifying Hypothesis on the Pathogenic Mechanism"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8791-8460","authenticated-orcid":false,"given":"Bao Ting","family":"Zhu","sequence":"first","affiliation":[{"name":"Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"ref_1","first-page":"146","article-title":"\u00dcber eine eigenartige Erkrankung der Hirnrinde [About a peculiar disease of the cerebral cortex]","volume":"64","author":"Alzheimer","year":"1907","journal-title":"Allg. 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