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The phospho-tau cascade hypothesis presented here attempts to answer that question by unifying three hallmark features of AD into a specific sequence of events. It is proposed that the hyperphosphorylation of tau protein leads to the AD-associated deficit of nerve growth factor (NGF), then to atrophy of the cholinergic basal forebrain and dementia. Because the release of pro-nerve growth factor (pro-NGF) is activity-dependent and is controlled by basal forebrain projections to the hippocampus and cortex, our hypothesis is that AChE inhibitors act by increasing acetylcholine-dependent pro-NGF release and, thus, augmenting the availability of mature NGF and improving basal forebrain survival. If correct, improved central nervous system-selective AChE inhibitor therapy started prophylactically, before AD-associated basal forebrain atrophy and cognitive impairment onset, has the potential to delay not only the onset of dementia but also its rate of advancement. The phospho-tau hypothesis thus suggests that preventing hyperphosphorylation of tau protein, early should be a high priority as a strategy to help reduce dementia and its associated widespread social and economic suffering.<\/jats:p>","DOI":"10.1177\/13872877241289602","type":"journal-article","created":{"date-parts":[[2024,11,25]],"date-time":"2024-11-25T01:55:01Z","timestamp":1732499701000},"page":"617-626","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":12,"title":["The phospho-tau cascade, basal forebrain neurodegeneration, and dementia in Alzheimer's disease: Anti-neurodegenerative benefits of acetylcholinesterase inhibitors"],"prefix":"10.1177","volume":"102","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2626-2511","authenticated-orcid":false,"given":"Donald E","family":"Moss","sequence":"first","affiliation":[{"name":"Professor Emeritus, University of Texas at El Paso, El Paso, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth G","family":"Perez","sequence":"additional","affiliation":[{"name":"CEO, R&amp;R Perez LLC, El Paso, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2024,11,12]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1566067"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-021-00533-w"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2018.02.018"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201700359"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000009058"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep46263"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01309-6"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(13)70044-9"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abc0655"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-14159-1"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-160488"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2017.00068"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-006-9270-0"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2014.04.010"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awy132"},{"key":"e_1_3_4_17_2","first-page":"33","volume-title":"IABS Forum 2023","author":"Moss DE","year":"2023","unstructured":"Moss DE, Perez RG. 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