Therapeutics

Gemfibrozil

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Overview

Name: Gemfibrozil
Synonyms: Lopid, Jezil, Gen-Fibro
Therapy Type: Small Molecule (timeline)
Target Type: Cholesterol
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Approved for: Hyperlipidemia

Background

Gemfibrozil is an old member of the fibrate class of drugs. These drugs activate peroxisome proliferator-activated receptor-α (PPARα), nuclear receptors involved in lipid metabolism. Fibrates reduce triglyceride levels. They are widely prescribed to control cholesterol and for related indications. Gemfibrozil came into use in the 1980s and is available as a generic.

Some studies have linked the use of fibrates to reduced AD risk (Defouil et al., 2005). More recently, gemfibrozil in particular has been considered to increase expression of microRNA 107 (NIH GrantOme). Expression of miR107 has been reported to be reduced in Alzheimer's, which may contribute to the upregulation of BACE levels in this disease (Feb 2008 news; Nelson and Wang, 2010; Hebert et al., 2013). MiR107 has also been reported to be expressed in cerebrovascular endothelial cells, and proposed as a biomarker for mild cognitive impairment or Alzheimer's disease (Wang et al., 2016; Wang et al., 2015; Liu et al., 2016; Wang et al., 2016). Panels for measuring CSF microRNA in neurodegeneration research are being developed (Wang et al., 2016). 

Gemfibrozil-mediated activation of PPARα has also been reported to stimulate non-amyloidogenic APP processing by ADAM10, thus reducing Aβ production (Corbett et al., 2015).

Two preclinical studies reported that treating AD mouse models with gemfibrozil decreased amyloid plaque accumulation in the cortex and hippocampus, and improved learning and memory in a PPARα-dependent pathway (Chandra and Pahan, 2019; Luo et al., 2019). The latter study also reported activated autophagy in plaque-associated microglia and astrocytes, suggesting gemfibrozil enhanced Aβ clearance.

Findings

In May 2014, an NIA-funded trial at the University of Kentucky started to evaluate whether gemfibrozil can safely modulate microRNA-107 levels for the prevention or early-stage treatment of AD. The study enrolled 48 cognitively normal and 24 mildly impaired (CDR 0.5) participants for a one-year, twice-daily course of 600 mg gemfibrozil or placebo. As primary outcomes, the trial assessed adverse events, blood and CSF gemfibrozil levels, and CSF Aβ40 and 42 levels. Secondary outcomes included two cognitive tests known to be sensitive at early stages, the Free and Cued Selective Reminding Test (FCSRT) and the Paired Associates Learning (PAL) tests. 

Investigators presented results at the 2019 CTAD conference. Gemfibrozil appeared safe, and lowered the concentration of miR-107 in plasma. In CSF, miR-107 was undetectable. Changes over time in CSF Aβ42, p-tau, and p-tau/Aβ42 ratio trended in the right direction with treatment compared to placebo, but the differences were not statistically significant. Likewise, treatment-related trends toward less brain atrophy, reduced plasma TNF-α, and better scores on some memory tests did not reach statistical significance (Dec 2019 conference news).

For all trials on gemfibrozil, see clinicaltrials.gov.

Last Updated: 10 Jan 2020

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References

News Citations

  1. At CTAD, Early Failures and Hints of Success, from Small Trials
  2. Number 107: MicroRNA Gets to First BACE in AD Brain

Paper Citations

  1. Dufouil C, Richard F, Fiévet N, Dartigues JF, Ritchie K, Tzourio C, Amouyel P, Alpérovitch A. APOE genotype, cholesterol level, lipid-lowering treatment, and dementia: the Three-City Study. Neurology. 2005 May 10;64(9):1531-8. PubMed.
  2. Nelson PT, Wang WX. MiR-107 is reduced in Alzheimer's disease brain neocortex: validation study. J Alzheimers Dis. 2010;21(1):75-9. PubMed.
  3. Hébert SS, Wang WX, Zhu Q, Nelson PT. A Study of Small RNAs from Cerebral Neocortex of Pathology-Verified Alzheimer's Disease, Dementia with Lewy Bodies, Hippocampal Sclerosis, Frontotemporal Lobar Dementia, and Non-Demented Human Controls. J Alzheimers Dis. 2013 Jan 1;35(2):335-48. PubMed.
  4. Wang WX, Danaher RJ, Miller CS, Berger JR, Nubia VG, Wilfred BS, Neltner JH, Norris CM, Nelson PT. Expression of miR-15/107 family microRNAs in human tissues and cultured rat brain cells. Genomics Proteomics Bioinformatics. 2014 Feb;12(1):19-30. Epub 2014 Jan 28 PubMed.
  5. Wang T, Chen K, Li H, Dong S, Su N, Liu Y, Cheng Y, Dai J, Yang C, Xiao S. The feasibility of utilizing plasma miRNA107 and BACE1 messenger RNA gene expression for clinical diagnosis of amnestic mild cognitive impairment. J Clin Psychiatry. 2015 Feb;76(2):135-41. PubMed.
  6. Liu W, Cai H, Lin M, Zhu L, Gao L, Zhong R, Bi S, Xue Y, Shang X. MicroRNA-107 prevents amyloid-beta induced blood-brain barrier disruption and endothelial cell dysfunction by targeting Endophilin-1. Exp Cell Res. 2016 May 1;343(2):248-57. Epub 2016 Mar 30 PubMed.
  7. Wang T, Shi F, Jin Y, Jiang W, Shen D, Xiao S. Abnormal Changes of Brain Cortical Anatomy and the Association with Plasma MicroRNA107 Level in Amnestic Mild Cognitive Impairment. Front Aging Neurosci. 2016;8:112. Epub 2016 May 18 PubMed.
  8. Wang WX, Fardo DW, Jicha GA, Nelson PT. A Customized Quantitative PCR MicroRNA Panel Provides a Technically Robust Context for Studying Neurodegenerative Disease Biomarkers and Indicates a High Correlation Between Cerebrospinal Fluid and Choroid Plexus MicroRNA Expression. Mol Neurobiol. 2016 Nov 29; PubMed.
  9. Corbett GT, Gonzalez FJ, Pahan K. Activation of peroxisome proliferator-activated receptor α stimulates ADAM10-mediated proteolysis of APP. Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):8445-50. Epub 2015 Jun 15 PubMed.
  10. Chandra S, Pahan K. Gemfibrozil, a Lipid-Lowering Drug, Lowers Amyloid Plaque Pathology and Enhances Memory in a Mouse Model of Alzheimer's Disease via Peroxisome Proliferator-Activated Receptor α. J Alzheimers Dis Rep. 2019 May 18;3(1):149-168. PubMed.
  11. Luo R, Su LY, Li G, Yang J, Liu Q, Yang LX, Zhang DF, Zhou H, Xu M, Fan Y, Li J, Yao YG. Activation of PPARA-mediated autophagy reduces Alzheimer disease-like pathology and cognitive decline in a murine model. Autophagy. 2019 Mar 22;:1-18. PubMed.

External Citations

  1. clinicaltrials.gov
  2. Gemfibrozil
  3. GrantOme

Further Reading

No Available Further Reading