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Review
. 2021 Jun 16:15:666958.
doi: 10.3389/fnins.2021.666958. eCollection 2021.

Reassessment of Pioglitazone for Alzheimer's Disease

Ann M Saunders  1 , Daniel K Burns  1 , William Kirby Gottschalk  2
Affiliations
Review

Reassessment of Pioglitazone for Alzheimer's Disease

Ann M Saunders et al. Front Neurosci. .

Abstract

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.

Keywords: Alzheimer’s disease; clinical trials; observational studies; pioglitazone; preclinical models.

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Conflict of interest statement

AS is President and CEO of Zinfandel Pharmaceuticals, Inc. DB is Senior Vice President and COO of Zinfandel Pharmaceuticals, Inc. WG has received consulting fees from Zinfandel Pharmaceuticals, Inc.

Figures

FIGURE 1
FIGURE 1
PPARγ regulates many pathways that contribute to AD risk.
FIGURE 2
FIGURE 2
PPARγ covalent modifications.
FIGURE 3
FIGURE 3
PIO-elicited TOM40 expression in SKNMC neuroblastoma cells. *P < 0.05; **P < 0.01; ***P < 0.001.
See this image and copyright information in PMC

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