A large-scale genetic analysis of about 1.09 million people suggests that lifelong, genetically lower cholesterol—specifically non‑HDL cholesterol—is associated with substantially reduced dementia risk. Using Mendelian randomization to emulate the effects of cholesterol‑lowering drug targets such as those for statins (HMGCR) and ezetimibe (NPC1L1), the study found up to an approximately 80% lower risk per 1 mmol/L reduction for some targets. ([research-information.bris.ac.uk](https://research-information.bris.ac.uk/en/publications/cholesterollowering-drug-targets-reduce-risk-of-dementia-mendelia?utm_source=openai))
Led by Dr. Liv Tybjærg Nordestgaard during her time at the University of Bristol and the Department of Clinical Biochemistry at Copenhagen University Hospital – Herlev and Gentofte, the research pooled data from the UK Biobank, the Copenhagen General Population Study, the Copenhagen City Heart Study, the FinnGen study, and the Global Lipids Genetics Consortium. The peer‑reviewed paper was published in Alzheimer’s & Dementia on October 8, 2025. (sciencedaily.com)
The team applied Mendelian randomization, examining variants in drug targets that lower non‑HDL cholesterol (including HMGCR, NPC1L1 and CETP) to minimize confounding from lifestyle factors. In meta‑analyses, a genetically proxied 1 mmol/L (≈39 mg/dL) reduction in non‑HDL cholesterol corresponded to markedly lower odds of dementia for these targets—roughly 70% to 82%—while evidence for PCSK9, ANGPTL4 and LPL was inconclusive. “If you have variants that lower your cholesterol, you have a significantly lower risk of developing dementia,” Dr. Nordestgaard said. (pmc.ncbi.nlm.nih.gov)
Researchers noted a plausible mechanism: high cholesterol can drive atherosclerosis, the buildup of fatty deposits in blood vessels in the body and brain, which may promote small blood clots linked to some dementias. (sciencedaily.com)
The findings support the idea that keeping cholesterol low—genetically or with medicines—could help lower dementia risk, but they do not prove that drugs themselves prevent dementia. Because dementia typically develops late in life, the authors argue that only very long randomized trials could determine whether cholesterol‑lowering therapies reduce risk; they suggest studies spanning roughly 10 to 30 years. (sciencedaily.com)
Funding for the work came from the UK Medical Research Council, the Independent Research Fund Denmark, and the Research Council at the Capital Region of Denmark. (sciencedaily.com)
