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In 2019, the cost of caring for Alzheimer\u2019s sufferers was $244B, not including the emotional and physical toll on caregivers. In spite of this dismal reality, no treatments are available that reduce the risk of developing AD or that offer prolonged mitiagation of its most devestating symptoms. This review summarizes key aspects of the biology and genetics of Alzheimer\u2019s disease, and we describe how pioglitazone improves many of the patholophysiological determinants of AD. We also summarize the results of pre-clinical experiments, longitudinal observational studies, and clinical trials. The results of animal testing suggest that pioglitazone can be corrective as well as protective, and that its efficacy is enhanced in a time- and dose-dependent manner, but the dose-effect relations are not monotonic or sigmoid. Longitudinal cohort studies suggests that it delays the onset of dementia in individuals with pre-existing type 2 diabetes mellitus, which small scale, unblinded pilot studies seem to confirm. However, the results of placebo-controlled, blinded clinical trials have not borne this out, and we discuss possible explanations for these discrepancies.<\/jats:p>","DOI":"10.3389\/fnins.2021.666958","type":"journal-article","created":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T10:41:53Z","timestamp":1623840113000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":60,"title":["Reassessment of Pioglitazone for Alzheimer\u2019s Disease"],"prefix":"10.3389","volume":"15","author":[{"given":"Ann M.","family":"Saunders","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel K.","family":"Burns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William Kirby","family":"Gottschalk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1706","DOI":"10.2337\/dc09-2030","article-title":"Rosiglitazone and cognitive stability in older individuals with type 2 diabetes and mild cognitive impairment.","volume":"33","author":"Abbatecola","year":"2010","journal-title":"Diabetes Care"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1553","DOI":"10.1515\/hsz-2013-0215","article-title":"Role of the peroxisome proliferator-activated receptors (PPAR)-\u03b1, \u03b2\/\u03b4 and \u03b3 triad in regulation of reactive oxygen species signaling in brain.","volume":"394","author":"Aleshin","year":"2013","journal-title":"Biol. 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