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A\u03b2 peptides are the main constituent of amyloid plaques in Alzheimer\u2019s Disease (AD). The physiological functions of APP in the human adult brain are very diverse including intracellular signaling, synaptic and neuronal plasticity, and cell adhesion, among others. There is growing evidence that APP becomes dysfunctional in AD and that this dyshomeostasis may impact several APP functions beyond A\u03b2 generation. The vast majority of current anti-amyloid approaches in AD have focused on reducing the synthesis of A\u03b2 or increasing the clearance of brain A\u03b2 aggregates following a paradigm in which A\u03b2 plays a solo in APP dyshomeostasis. A wider view places APP at the center stage in which A\u03b2 is an important, but not the only, factor involved in APP dyshomeostasis. Under this paradigm, APP dysfunction is universal in AD, but with some differences across different subtypes. Little is known about how to approach APP dysfunction therapeutically beyond anti-A\u03b2 strategies. In this review, we will describe the role of APP dyshomeostasis in AD beyond A\u03b2 and the potential therapeutic strategies targeting APP.<\/jats:p>","DOI":"10.1186\/s13195-024-01504-w","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T02:02:11Z","timestamp":1719885731000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["APP dyshomeostasis in the pathogenesis of Alzheimer\u2019s disease: implications for current drug targets"],"prefix":"10.1186","volume":"16","author":[{"given":"S\u00f2nia","family":"Sirisi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c9rika","family":"S\u00e1nchez-Aced","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Belbin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Lle\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,29]]},"reference":[{"issue":"Pt 12","key":"1504_CR1","doi-asserted-by":"publisher","first-page":"3738","DOI":"10.1093\/brain\/awt273","volume":"136","author":"CH Andrade-Moraes","year":"2013","unstructured":"Andrade-Moraes CH, Oliveira-Pinto AV, Castro-Fonseca E, da Silva CG, Guimar\u00e3es DM, Szczupak D, et al. 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