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
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.
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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