NEW cholesterol and dementia research reveals promising reductions in dementia risk through specific cholesterol-lowering drug targets. A large-scale genetic analysis suggests certain pathways may offer long-term protection against cognitive decline.
Linking Cholesterol and Dementia
Growing evidence shows an association between cholesterol and dementia, particularly through non-high-density lipoprotein cholesterol (non-HDL-C). Dementia affects 50 million people globally, and shared pathways with cardiovascular disease have prompted investigation into lipid-modifying treatments as potential preventive strategies for neurodegenerative conditions.
Methods and Key Findings from Genetic Analyses
Researchers examined data from 1,091,775 individuals across three prospective cohorts and two large consortia using Mendelian randomization and Cox regression. Genetic variants within HMGCR, NPC1L1, PCSK9, ANGPTL4, LPL, and CETP, all linked to non-HDL-C reduction, served as proxies for drug targets. Meta-analysis showed odds ratios per 1 mmol/L (39 mg/dL) lower non-HDL-C of 0.24 (0.18–0.31) for HMGCR, 0.18 (0.12–0.25) for NPC1L1, 0.97 (0.70–1.35) for PCSK9, 1.66 (0.52–5.36) for ANGPTL4, 1.41 (0.63–3.16) for LPL, and 0.30 (0.26–0.34) for CETP. These findings indicate that genetic lowering of non-HDL cholesterol via HMGCR, NPC1L1, and CETP reduces dementia risk, suggesting lifelong lipid regulation is key. Effects from PCSK9, ANGPTL4, and LPL variants remain inconclusive but cannot be ruled out.
Implications for Future Practice
Findings underscore the potential of targeting lipid pathways to reduce dementia incidence. Understanding the link between cholesterol and dementia supports exploration of existing cardiovascular therapies for cognitive protection. Future clinical trials with extended follow-up could establish whether early lipid control prevents dementia onset. Clinicians may soon consider lipid-lowering strategies not only for heart health but also for safeguarding brain function, integrating dementia prevention into cardiovascular care.
Reference
Nordestgaard LT et al. Cholesterol‐lowering drug targets reduce risk of dementia: Mendelian randomization and meta‐analyses of 1 million individuals. Alzheimer’s & Dementia. 2025;21(10):e70638.
