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Cited by 16Peroxisome Proliferator-Activated ReceptorsDementia and Cognitive Impairment ResearchAlzheimer's disease research and treatments

Effects of peroxisome proliferator-activated receptor-gamma agonists on cognitive function: a systematic review and meta-analysis

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Zhong, Hongfei, Geng, Rulin, Zhang, Yu, Ding, Jingwen, Liu, Miao, Deng, Shengfeng, Tu, Qiuyun·2023·Biomedicines
DOI 10.3390/biomedicines11020246PMC PMC9953157
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Abstract

Diabetes mellitus (DM) is known to be a risk factor for dementia, especially in the elderly population, and close associations between diabetes and Alzheimer disease (AD) have been determined. Peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists are insulin-sensitising drugs. In addition to their anti-diabetic properties, their effectiveness in preventing and decreasing cognitive impairment are the most recent characteristics that have been studied. For this study, we conducted a systematic review and meta-analysis to critically analyse and evaluate the existing data on the effects of PPAR-γ agonist therapy on the cognitive status of patients. For this purpose, we first analysed both early intervention and later treatment with PPAR-γ agonists, according to the disease status. The involved studies indicated that early PPAR-γ agonist intervention is beneficial for patients and that high-dose PPAR-γ therapy may have a better clinical effect, especially in reversing the effects of cognitive impairment. Furthermore, the efficacy of pioglitazone (PIO) seems to be promising, particularly for patients with comorbid diabetes. PIO presented a better clinical curative effect and safety, compared with rosiglitazone (RSG). Thus, PPAR-γ agonists play an important role in the inflammatory response of AD or DM patients, and clinical therapeutics should focus more on relevant metabolic indices.

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  • Pharmacological inhibition of the MPC is neuroprotective and stimulates long-term potentiation and cognition.

    “pharmacological inhibition of the MPC is neuroprotective and stimulates long-term potentiation and cognition (Mansour et al., 2021; Zhong et al., 2023)”

    From Inhibition of the mitochondrial pyruvate carrier in astrocytes reduces amyloid and tau accumulation in the 3xTgAD mouse model of Alzheimer's disease (2024) · cites this paper as Zhong et al., 2023

    The Discussion reports some support for a protective effect against dementia, and the Conclusions report improved cognitive function, with PPAR-γ agonists. The paper does not establish that these effects result from pharmacological inhibition of the MPC, or report stimulation of long-term potentiation; searches for MPC inhibition and long-term potentiation found no relevant passage. Page numbers were not available in our copy. (LLM, conf=0.82)

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  1. [1]Huang L. Zhu M. Ji J. Association between hypoglycemia and dementia in patients with diabetes: A systematic review and meta-analysis of 1.4 million patients Diabetol. Metab. Synd. 2022 14 31 10.1186/s13098-022-00799-9 35164844 PMC8842524 · DOI · Paper page
  2. [4]Moheet A. Mangia S. Seaquist E.R. Impact of diabetes on cognitive function and brain structure Ann. N. Y. Acad. Sci. 2015 1353 60 71 10.1111/nyas.12807 26132277 PMC4837888 · DOI
  3. [5]Rawlings A.M. Sharrett A.R. Schneider A.L. Coresh J. Albert M. Couper D. Griswold M. Gottesman R.F. Wagenknecht L.E. Windham B.G. Diabetes in midlife and cognitive change over 20 years: A cohort study Ann. Intern. Med. 2014 161 785 793 10.7326/M14-0737 25437406 PMC4432464 · DOI · Paper page
  4. [6]Zilliox L.A. Chadrasekaran K. Kwan J.Y. Russell J.W. Diabetes and Cognitive Impairment Curr. Diab. Rep. 2016 16 87 10.1007/s11892-016-0775-x 27491830 PMC5528145 · DOI
  5. [7]Pelimanni E. Jehkonen M. Type 2 Diabetes and Cognitive Functions in Middle Age: A Meta-Analysis J. Int. Neuropsychol. Soc. 2019 25 215 229 10.1017/S1355617718001042 30575498 · DOI
  6. [8]Mittal K. Katare D.P. Shared links between type 2 diabetes mellitus and Alzheimer’s disease: A review Diabetes Metab. Syndr. 2016 10 S144 S149 10.1016/j.dsx.2016.01.021 26907971 · DOI
  7. [9]Rizvi S.M. Shaikh S. Waseem S.M. Shakil S. Abuzenadah A.M. Biswas D. Tabrez S. Ashraf G.M. Kamal M.A. Role of anti-diabetic drugs as therapeutic agents in Alzheimer’s disease EXCLI J. 2015 14 684 696 10.17179/excli2015-252 27152105 PMC4849108 · DOI
  8. [10]Cameron B. Landreth G.E. Inflammation, microglia, and Alzheimer’s disease Neurobiol. Dis. 2010 37 503 509 10.1016/j.nbd.2009.10.006 19833208 PMC2823849 · DOI
  9. [12]Silva-Abreu M. Calpena A.C. Andres-Benito P. Aso E. Romero I.A. Roig-Carles D. Gromnicova R. Espina M. Ferrer I. Garcia M.L. PPARgamma agonist-loaded PLGA-PEG nanocarriers as a potential treatment for Alzheimer’s disease: In vitro and in vivo studies Int. J. Nanomed. 2018 13 5577 5590 10.2147/IJN.S171490 PMC6154713 30271148 · DOI
  10. [13]Quan Q. Qian Y. Li X. Li M. pioglitazone Reduces beta Amyloid Levels via Inhibition of PPARgamma Phosphorylation in a Neuronal Model of Alzheimer’s Disease Front. Aging Neurosci. 2019 11 178 10.3389/fnagi.2019.00178 31379559 PMC6650543 · DOI
  11. [14]Wang L. Liu W. Fan Y. Liu T. Yu C. Effect of rosiglitazone on amyloid precursor protein processing and Abeta clearance in streptozotocin-induced rat model of Alzheimer’s disease Iran. J. Basic Med. Sci. 2017 20 474 480 10.22038/IJBMS.2017.8669 28656081 PMC5478774 · DOI
  12. [15]Sarathlal K.C. Kakoty V. Marathe S. Chitkara D. Taliyan R. Exploring the Neuroprotective Potential of Rosiglitazone Embedded Nanocarrier System on Streptozotocin Induced Mice Model of Alzheimer’s Disease Neurotox. Res. 2021 39 240 255 10.1007/s12640-020-00258-1 32683650 · DOI
  13. [16]Burns D.K. Alexander R.C. Welsh-Bohmer K.A. Culp M. Chiang C. O’Neil J. Evans R.M. Harrigan P. Plassman B.L. Burke J.R. Safety and efficacy of pioglitazone for the delay of cognitive impairment in people at risk of Alzheimer’s disease (TOMMORROW): A prognostic biomarker study and a phase 3, randomised, double-blind, placebo-controlled trial Lancet Neurol. 2021 20 537 547 10.1016/S1474-4422(21)00043-0 34146512 · DOI · Paper page
  14. [17]Geldmacher D.S. Fritsch T. McClendon M.J. Landreth G. A randomized pilot clinical trial of the safety of pioglitazone in treatment of patients with Alzheimer disease Arch. Neurol. 2011 68 45 50 10.1001/archneurol.2010.229 20837824 · DOI · Paper page
  15. [19]Hanyu H. Sato T. Kiuchi A. Sakurai H. Iwamoto T. Pioglitazone improved cognition in a pilot study on patients with Alzheimer’s disease and mild cognitive impairment with diabetes mellitus J. Am. Geriatr. Soc. 2009 57 177 179 10.1111/j.1532-5415.2009.02067.x 19170800 · DOI
  16. [20]Hanyu H. Sato T. Sakurai H. Iwamoto T. The role of tumor necrosis factor-alpha in cognitive improvement after peroxisome proliferator-activator receptor gamma agonist pioglitazone treatment in Alzheimer’s disease J. Am. Geriatr. Soc. 2010 58 1000 1001 10.1111/j.1532-5415.2010.02841.x 20722838 · DOI
  17. [21]Harrington C. Sawchak S. Chiang C. Davies J. Donovan C. Saunders A.M. Irizarry M. Jeter B. Zvartau-Hind M. van Dyck C.H. Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer’s disease: Two phase 3 studies Curr. Alzheimer Res. 2011 8 592 606 10.2174/156720511796391935 21592048 · DOI
  18. [22]Hildreth K.L. Van Pelt R.E. Moreau K.L. Grigsby J. Hoth K.F. Pelak V. Anderson C.A. Parnes B. Kittelson J. Wolfe P. Effects of pioglitazone or exercise in older adults with mild cognitive impairment and insulin resistance: A pilot study Dement. Geriatr. Cogn. Disord. Extra 2015 5 51 63 10.1159/000371509 25852732 PMC4361908 · DOI
  19. [23]Risner M.E. Saunders A.M. Altman J.F. Ormandy G.C. Craft S. Foley I.M. Zvartau-Hind M.E. Hosford D.A. Roses A.D. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer’s disease Pharm. J. 2006 6 246 254 10.1038/sj.tpj.6500369 16446752 · DOI · Paper page
  20. [24]Ryan C.M. Freed M.I. Rood J.A. Cobitz A.R. Waterhouse B.R. Strachan M.W. Improving metabolic control leads to better working memory in adults with type 2 diabetes Diabetes Care 2006 29 345 351 10.2337/diacare.29.02.06.dc05-1626 16443885 · DOI
  21. [25]Sato T. Hanyu H. Hirao K. Kanetaka H. Sakurai H. Iwamoto T. Efficacy of PPAR-γ agonist pioglitazone in mild Alzheimer disease Neurobiol. Aging 2011 32 1626 1633 10.1016/j.neurobiolaging.2009.10.009 19923038 · DOI · Paper page
  22. [26]Tzimopoulou S. Cunningham V.J. Nichols T.E. Searle G. Bird N.P. Mistry P. Dixon I.J. Hallett W.A. Whitcher B. Brown A.P. A multi-center randomized proof-of-concept clinical trial applying [¹⁸F]FDG-PET for evaluation of metabolic therapy with rosiglitazone XR in mild to moderate Alzheimer’s disease J. Alzheimers Dis. 2010 22 1241 1256 10.3233/JAD-2010-100939 20930300 · DOI
  23. [27]Watson G.S. Cholerton B.A. Reger M.A. Baker L.D. Plymate S.R. Asthana S. Fishel M.A. Kulstad J.J. Green P.S. Cook D.G. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: A preliminary study Am. J. Geriatr. Psychiatry 2005 13 950 958 10.1176/appi.ajgp.13.11.950 16286438 · DOI
  24. [28]Zvartau-Hind M. Alderton C. Ritchie S. Saunders A. Irizarry M. Craft S. Landreth G. Linnamägi Ü. Sawchak S. Gold M. P1-245: Safety and tolerability of rosiglitazone XR in a randomised, placebo-controlled study in APOE4-stratified subjects with mild-to-moderate Alzheimer’s disease Alzheimer’s Dement. 2009 5 P248 10.1016/j.jalz.2009.04.252 · DOI
  25. [29]Bohlken J. Jacob L. Kostev K. Association Between the Use of Antihyperglycemic Drugs and Dementia Risk: A Case-Control Study J. Alzheimers Dis. 2018 66 725 732 10.3233/JAD-180808 30320593 · DOI
  26. [30]Chou P.S. Ho B.L. Yang Y.H. Effects of pioglitazone on the incidence of dementia in patients with diabetes J. Diabetes Complicat. 2017 31 1053 1057 10.1016/j.jdiacomp.2017.01.006 28254448 · DOI
  27. [31]Fink A. Heneka M. Doblhammer G. P2-295: The Effect of the Prescription of Pioglitazone on the Incidence of Dementia Alzheimer’s Dement. 2014 10 P585 P586 10.1016/j.jalz.2014.05.973 · DOI
  28. [32]Heneka M.T. Fink A. Doblhammer G. Effect of pioglitazone medication on the incidence of dementia Ann. Neurol. 2015 78 284 294 10.1002/ana.24439 25974006 · DOI
  29. [33]Imfeld P. Bodmer M. Jick S.S. Meier C.R. Metformin, other antidiabetic drugs, and risk of Alzheimer’s disease: A population-based case-control study J. Am. Geriatr. Soc. 2012 60 916 921 10.1111/j.1532-5415.2012.03916.x 22458300 · DOI
  30. [34]Kim J.Y. Ku Y.S. Kim H.J. Trinh N.T. Kim W. Jeong B. Heo T.Y. Lee M.K. Lee K.E. Oral diabetes medication and risk of dementia in elderly patients with type 2 diabetes Diabetes Res. Clin. Pract. 2019 154 116 123 10.1016/j.diabres.2019.07.004 31279960 · DOI
  31. [35]Secnik J. Xu H. Schwertner E. Hammar N. Alvarsson M. Winblad B. Eriksdotter M. Garcia-Ptacek S. Religa D. The association of antidiabetic medications and Mini-Mental State Examination scores in patients with diabetes and dementia Alzheimer’s Res. Ther. 2021 13 197 10.1186/s13195-021-00934-0 34857046 PMC8641148 · DOI
  32. [36]Tseng C.H. Pioglitazone Reduces Dementia Risk in Patients with Type 2 Diabetes Mellitus: A Retrospective Cohort Analysis J. Clin. Med. 2018 7 306 10.3390/jcm7100306 30262775 PMC6209987 · DOI
  33. [37]Tseng C.H. Rosiglitazone has a neutral effect on the risk of dementia in type 2 diabetes patients Aging 2019 11 2724 2734 10.18632/aging.101944 31085804 PMC6535054 · DOI
  34. [38]Liu J. Wang L.N. Jia J.P. Peroxisome proliferator-activated receptor-gamma agonists for Alzheimer’s disease and amnestic mild cognitive impairment: A systematic review and meta-analysis Drugs Aging 2015 32 57 65 10.1007/s40266-014-0228-7 25504005 · DOI
  35. [39]Cheng H. Shang Y. Jiang L. Shi T.L. Wang L. The peroxisome proliferators activated receptor-gamma agonists as therapeutics for the treatment of Alzheimer’s disease and mild-to-moderate Alzheimer’s disease: A meta-analysis Int. J. Neurosci. 2016 126 299 307 10.3109/00207454.2015.1015722 26001206 · DOI
  36. [40]Khan M.A. Alam Q. Haque A. Ashafaq M. Khan M.J. Ashraf G.M. Ahmad M. Current Progress on Peroxisome Proliferator-activated Receptor Gamma Agonist as an Emerging Therapeutic Approach for the Treatment of Alzheimer’s Disease: An Update Curr. Neuropharmacol. 2019 17 232 246 10.2174/1570159X16666180828100002 30152284 PMC6425074 · DOI
  37. [41]Jojo G.M. Kuppusamy G. Scope of new formulation approaches in the repurposing of pioglitazone for the management of Alzheimer’s disease J. Clin. Pharm. Ther. 2019 44 337 348 10.1111/jcpt.12808 30738020 · DOI
  38. [42]Yang S. Chen Z. Cao M. Li R. Wang Z. Zhang M. Pioglitazone ameliorates Abeta42 deposition in rats with diet-induced insulin resistance associated with AKT/GSK3beta activation Mol. Med. Rep. 2017 15 2588 2594 10.3892/mmr.2017.6342 28447730 PMC5428924 · DOI
  39. [43]Biessels G.J. Despa F. Cognitive decline and dementia in diabetes mellitus: Mechanisms and clinical implications Nat. Rev. Endocrinol. 2018 14 591 604 10.1038/s41574-018-0048-7 30022099 PMC6397437 · DOI · Paper page
  40. [44]Arnold S.E. Arvanitakis Z. Macauley-Rambach S.L. Koenig A.M. Wang H.Y. Ahima R.S. Craft S. Gandy S. Buettner C. Stoeckel L.E. Brain insulin resistance in type 2 diabetes and Alzheimer disease: Concepts and conundrums Nat. Rev. Neurol. 2018 14 168 181 10.1038/nrneurol.2017.185 29377010 PMC6098968 · DOI · Paper page
  41. [45]Biessels G.J. Staekenborg S. Brunner E. Brayne C. Scheltens P. Risk of dementia in diabetes mellitus: A systematic review Lancet Neurol. 2006 5 64 74 10.1016/S1474-4422(05)70284-2 16361024 · DOI · Paper page
  42. [46]Knight E.M. Ruiz H.H. Kim S.H. Harte J.C. Hsieh W. Glabe C. Klein W.L. Attie A.D. Buettner C. Ehrlich M.E. Unexpected partial correction of metabolic and behavioral phenotypes of Alzheimer’s APP/PSEN1 mice by gene targeting of diabetes/Alzheimer’s-related Sorcs1 Acta Neuropathol. Commun. 2016 4 16 10.1186/s40478-016-0282-y 26916443 PMC4766719 · DOI
  43. [47]Alagiakrishnan K. Sclater A. Psychiatric disorders presenting in the elderly with type 2 diabetes mellitus Am. J. Geriatr. Psychiatry 2012 20 645 652 10.1097/JGP.0b013e31823038db 21989315 · DOI
  44. [48]Prakash A. Kumar A. Role of nuclear receptor on regulation of BDNF and neuroinflammation in hippocampus of amyloid β-protein animal model of Alzheimer’s disease Neurotox. Res. 2014 25 335 347 10.1007/s12640-013-9437-9 24277156 · DOI · Paper page
  45. [49]Papadopoulos P. Rosa-Neto P. Rochford J. Hamel E. pioglitazone improves reversal learning and exerts mixed cerebrovascular effects in a mouse model of Alzheimer’s disease with combined amyloid-beta and cerebrovascular pathology PLoS ONE 2013 8 e68612 10.1371/journal.pone.0068612 23874687 PMC3715495 · DOI
  46. [50]Li H. Wu J. Zhu L. Sha L. Yang S. Wei J. Ji L. Tang X. Mao K. Cao L. Insulin degrading enzyme contributes to the pathology in a mixed model of Type 2 diabetes and Alzheimer’s disease: Possible mechanisms of IDE in T2D and AD Biosci. Rep. 2018 38 BSR20170862 10.1042/BSR20170862 29222348 PMC6435468 · DOI
  47. [51]Yu Y. Li X. Blanchard J. Li Y. Iqbal K. Liu F. Gong C.X. Insulin sensitizers improve learning and attenuate tau hyperphosphorylation and neuroinflammation in 3xTg-AD mice J. Neural Transm. 2015 122 593 606 10.1007/s00702-014-1294-z 25113171 · DOI
  48. [52]Secnik J. Xu H. Schwertner E. Hammar N. Alvarsson M. Winblad B. Eriksdotter M. Garcia-Ptacek S. Religa D. Dementia Diagnosis Is Associated with Changes in Antidiabetic Drug Prescription: An Open-Cohort Study of Approximately 130,000 Swedish Subjects over 14 Years J. Alzheimers Dis. 2020 76 1581 1594 10.3233/JAD-200618 32741836 PMC7504989 · DOI
  49. [53]O’Bryant S.E. Zhang F. Petersen M. Johnson L. Hall J. Rissman R.A. A Precision Medicine Approach to Treating Alzheimer’s Disease Using Rosiglitazone Therapy: A Biomarker Analysis of the REFLECT Trials J. Alzheimers Dis. 2021 81 557 568 10.3233/JAD-201610 33814447 PMC8203239 · DOI
  50. [54]Didsbury J. Gabriel H. Strittmatter W. Chamberlain S. Abstracts of 20th Annual ASENT Meeting Neurotherapeutics 2018 15 819 835 10.1007/s13311-018-0641-4 29987760 PMC6095775 · DOI

Cited by

Sorted by citations

Authors
Zhong, H., Geng, R., Zhang, Y., Ding, J., Liu, M., Deng, S., & Tu, Q.
Affiliations
Fifth Affiliated Hospital of Sun Yat-sen University (CN)
Corresponding author
Tu, Qiuyun
ORCID
Venue
Biomedicines
Publisher
MDPI AG
Published
2023-01-18
Volume
11
Issue
2
Pages
246
ISSN
2227-9059 (ISSN-L)
DOI
10.3390/biomedicines11020246
PMC
PMC9953157
OpenAlex
W4317393282
Cited by
16
References
4
Citations by year
2026: 1 · 2025: 6 · 2024: 7 · 2023: 2
FWCI
0.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Biomedicines (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (81671398)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
PPARγ agonists, cognitive function, diabetes mellitus, Alzheimer's disease, dementia, pioglitazone, rosiglitazone, cognitive impairment, early intervention, drug safety, inflammation

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