Reassessment of Pioglitazone for Alzheimer's Disease

Overview

Journal Front Neurosci

Date 2021 Jul 5

PMID 34220427

Citations 30

Authors

Ann M Saunders

Daniel K Burns

William Kirby Gottschalk

Affiliations

Soon will be listed here.

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.

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References

Xu W, Qiu C, Gatz M, Pedersen N, Johansson B, Fratiglioni L . Mid- and late-life diabetes in relation to the risk of dementia: a population-based twin study. Diabetes. 2008; 58(1):71-7. PMC: 2606895. DOI: 10.2337/db08-0586. View

Han S, Einstein G, Weisgraber K, Strittmatter W, Saunders A, Pericak-Vance M . Apolipoprotein E is localized to the cytoplasm of human cortical neurons: a light and electron microscopic study. J Neuropathol Exp Neurol. 1994; 53(5):535-44. DOI: 10.1097/00005072-199409000-00013. View

Badhwar A, Lerch J, Hamel E, Sled J . Impaired structural correlates of memory in Alzheimer's disease mice. Neuroimage Clin. 2013; 3:290-300. PMC: 3814975. DOI: 10.1016/j.nicl.2013.08.017. View

Weissman L, Jo D, Sorensen M, de Souza-Pinto N, Markesbery W, Mattson M . Defective DNA base excision repair in brain from individuals with Alzheimer's disease and amnestic mild cognitive impairment. Nucleic Acids Res. 2007; 35(16):5545-55. PMC: 2018628. DOI: 10.1093/nar/gkm605. View

Fakhfouri G, Ahmadiani A, Rahimian R, Grolla A, Moradi F, Haeri A . WIN55212-2 attenuates amyloid-beta-induced neuroinflammation in rats through activation of cannabinoid receptors and PPAR-γ pathway. Neuropharmacology. 2012; 63(4):653-66. DOI: 10.1016/j.neuropharm.2012.05.013. View

Valla J, Schneider L, Niedzielko T, Coon K, Caselli R, Sabbagh M . Impaired platelet mitochondrial activity in Alzheimer's disease and mild cognitive impairment. Mitochondrion. 2006; 6(6):323-30. PMC: 1864936. DOI: 10.1016/j.mito.2006.10.004. View

Toba J, Nikkuni M, Ishizeki M, Yoshii A, Watamura N, Inoue T . PPARγ agonist pioglitazone improves cerebellar dysfunction at pre-Aβ deposition stage in APPswe/PS1dE9 Alzheimer's disease model mice. Biochem Biophys Res Commun. 2016; 473(4):1039-1044. DOI: 10.1016/j.bbrc.2016.04.012. View

Terry R, Masliah E, Salmon D, Butters N, DeTeresa R, Hill R . Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991; 30(4):572-80. DOI: 10.1002/ana.410300410. View

Cutler N . Cerebral metabolism as measured with positron emission tomography (PET) and [18F] 2-deoxy-D-glucose: healthy aging, Alzheimer's disease and Down syndrome. Prog Neuropsychopharmacol Biol Psychiatry. 1986; 10(3-5):309-21. DOI: 10.1016/0278-5846(86)90010-2. View

10.

Bouhrara M, Reiter D, Bergeron C, Zukley L, Ferrucci L, Resnick S . Evidence of demyelination in mild cognitive impairment and dementia using a direct and specific magnetic resonance imaging measure of myelin content. Alzheimers Dement. 2018; 14(8):998-1004. PMC: 6097903. DOI: 10.1016/j.jalz.2018.03.007. View

11.

Jack Jr C, Bennett D, Blennow K, Carrillo M, Dunn B, Budd Haeberlein S . NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018; 14(4):535-562. PMC: 5958625. DOI: 10.1016/j.jalz.2018.02.018. View

12.

Vossel K, Zhang K, Brodbeck J, Daub A, Sharma P, Finkbeiner S . Tau reduction prevents Abeta-induced defects in axonal transport. Science. 2010; 330(6001):198. PMC: 3024010. DOI: 10.1126/science.1194653. View

13.

Mouchard A, Boutonnet M, Mazzocco C, Biendon N, Macrez N . ApoE-fragment/Aβ heteromers in the brain of patients with Alzheimer's disease. Sci Rep. 2019; 9(1):3989. PMC: 6408522. DOI: 10.1038/s41598-019-40438-4. View

14.

Boucher J, Kleinridders A, Kahn C . Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol. 2014; 6(1). PMC: 3941218. DOI: 10.1101/cshperspect.a009191. View

15.

Mattson M, Cheng B, Davis D, Bryant K, Lieberburg I, Rydel R . beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci. 1992; 12(2):376-89. PMC: 6575616. View

16.

Matsuzaki T, Sasaki K, Tanizaki Y, Hata J, Fujimi K, Matsui Y . Insulin resistance is associated with the pathology of Alzheimer disease: the Hisayama study. Neurology. 2010; 75(9):764-70. DOI: 10.1212/WNL.0b013e3181eee25f. View

17.

Baura G, Foster D, Kaiyala K, Porte Jr D, Kahn S, Schwartz M . Insulin transport from plasma into the central nervous system is inhibited by dexamethasone in dogs. Diabetes. 1996; 45(1):86-90. DOI: 10.2337/diab.45.1.86. View

18.

. 2020 Alzheimer's disease facts and figures. Alzheimers Dement. 2020; . DOI: 10.1002/alz.12068. View

19.

Subbaramaiah K, Howe L, Zhou X, Yang P, Hudis C, Kopelovich L . Pioglitazone, a PPARγ agonist, suppresses CYP19 transcription: evidence for involvement of 15-hydroxyprostaglandin dehydrogenase and BRCA1. Cancer Prev Res (Phila). 2012; 5(10):1183-94. PMC: 3694442. DOI: 10.1158/1940-6207.CAPR-12-0201. View

20.

Takeda S, Sato N, Uchio-Yamada K, Sawada K, Kunieda T, Takeuchi D . Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Abeta deposition in an Alzheimer mouse model with diabetes. Proc Natl Acad Sci U S A. 2010; 107(15):7036-41. PMC: 2872449. DOI: 10.1073/pnas.1000645107. View