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The amyloid-cascade hypothesis took hold very early, supported by discoveries that dominant mutations in APP, PSEN1, and PSEN2 cause the very rare, early-onset, familial forms of the disease. However, in the past decade, a stunning series of failed Phase-3 clinical trials, testing anti-amyloid antibodies or processing-enzyme inhibitors, prompts the question, What went wrong? The FDA\u2019s recent controversial approval of aducanumab, despite widespread concerns about efficacy and safety, only amplifies the question. The assumption that common, late-onset Alzheimer\u2019s is a milder form of familial disease was not adequately questioned. The differential timing of discoveries, including blood\u2013brain\u2013barrier-penetrant tracers for imaging of plaques and tangles, made it easy to focus on amyloid. Furthermore, the neuropathology community initially implemented Alzheimer\u2019s diagnostic criteria based on plaques only. The discovery that MAPT mutations cause frontotemporal dementia with tauopathy made it even easier to overlook the tangles in Alzheimer\u2019s. Many important findings were simply ignored. The accepted mouse models did not predict the human clinical trials data. Given this lack of pharmacological validity, input from geneticists in collaboration with neuroscientists is needed to establish criteria for valid models of Alzheimer\u2019s disease. More generally, scientists using genetic model organisms as whole-animal bioassays can contribute to building the pathogenesis network map of Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.1093\/genetics\/iyab185","type":"journal-article","created":{"date-parts":[[2021,10,31]],"date-time":"2021-10-31T13:26:05Z","timestamp":1635686765000},"source":"Crossref","is-referenced-by-count":4,"title":["Unraveling the Gordian knot: genetics and the troubled road to effective therapeutics for Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"220","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0052-3285","authenticated-orcid":false,"given":"Linda L","family":"Restifo","sequence":"first","affiliation":[{"name":"Department of Neurology, University of Arizona Health Sciences, Tucson, AZ 85724, USA"},{"name":"Department of Cellular and Molecular Medicine, University of Arizona Health Sciences, Tucson, AZ 85724, USA"},{"name":"Department of Neuroscience and Graduate Interdisciplinary Program in Neuroscience, University of Arizona, Tucson, AZ 85721, USA"},{"name":"Graduate Interdisciplinary Program in Genetics, University of Arizona, Tucson, AZ 85719, USA"},{"name":"Evelyn F. 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