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Although animal models and conventional cell systems have provided fundamental insights into pathomechanisms, they only partially reproduce the human-specific and multifactorial nature of AD. Human induced pluripotent stem cell (hiPSC)-based models have emerged as a powerful platform to investigate disease-relevant processes within a patient-specific genetic background while enabling the generation of multiple neural cell types and multicellular systems. In this review, we present the evolution of hiPSC-based AD modeling, from reductionist paradigms based on exogenous amyloid-\u03b2 exposure to CRISPR-engineered isogenic models addressing causal mutations and genetic risk variants associated with either familial or sporadic forms. We examine the contribution of three-dimensional brain organoids and neuroglial co-culture systems in recapitulating cell\u2013cell interactions, neuroinflammatory responses, and tissue-level pathological processes. We focus on current challenges, including the limited representation of neuronal aging, variability among organoids, and the need for standardized protocols. Finally, we discuss the translational potential of hiPSC-derived systems for target identification, drug discovery, and regenerative medicine. Collectively, these advances position hiPSC-based platforms as essential complementary models for elucidating AD pathogenesis and accelerating the development of precision therapeutic strategies.<\/jats:p>","DOI":"10.3390\/cells15191793","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T08:19:08Z","timestamp":1790842748000},"page":"1793","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From Amyloid Exposure to Genetic Causality: Converging hiPSC-Based Models of Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4894-5084","authenticated-orcid":false,"given":"Fiorella","family":"Colasuonno","sequence":"first","affiliation":[{"name":"Department of Experimental Medicine, University of Rome \u201cTor Vergata\u201d, 00133 Rome, Italy"},{"name":"Department of Biology, University of Rome \u201cTor Vergata\u201d, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessio","family":"Valenza","sequence":"additional","affiliation":[{"name":"Department of Science, University Roma Tre, 00146 Rome, Italy"},{"name":"LIFE Institute for Research and Health Care\u2014Santa Lucia IRCCS, 00179 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Rossin","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome \u201cTor Vergata\u201d, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1079-3222","authenticated-orcid":false,"given":"Sandra","family":"Moreno","sequence":"additional","affiliation":[{"name":"Department of Science, University Roma Tre, 00146 Rome, Italy"},{"name":"LIFE Institute for Research and Health Care\u2014Santa Lucia IRCCS, 00179 Rome, Italy"},{"name":"Graduate School of Biomedical Sciences, University of Texas Medical Branch, Galveston, TX 77550, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/s41380-019-0468-3","article-title":"Modeling Alzheimer\u2019s Disease with iPSC-Derived Brain Cells","volume":"25","author":"Penney","year":"2020","journal-title":"Mol. 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