Reassessment of Pioglitazone for Alzheimer's Disease.

Alzheimer's disease is a quintessential 'unmet medical need', accounting for ∼65% of progressive cognitive impairment among the elderly, and 700,000 deaths in the United States in 2020. In 2019, the cost of caring for Alzheimer's 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's 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.