Researchers have uncovered fresh evidence indicating that maintaining low cholesterol levels throughout one’s lifespan, whether due to genetic factors or pharmaceutical interventions, may reduce the risk of dementia by as much as 80% for specific drug targets. This conclusion stems from an extensive study monitoring over one million individuals across Denmark, England, and Finland.
The investigation, spearheaded by Dr. Liv Tybjærg Nordestgaard at the Universities of Bristol and Copenhagen, employed a clever strategy: they analyzed individuals born with genetic variants that inherently resemble cholesterol-reducing medications. This can be likened to nature conducting its own lengthy clinical trial spanning decades, focusing on cholesterol’s impact on brain health.
By contrasting approximately 1.1 million people with these variants against those without, scientists assessed how various drug targets influence dementia risk. The research concentrated on genes responsible for the same biological processes that are targeted by statins, ezetimibe, and other cholesterol-lowering drugs.
“Our findings suggest that individuals with these variants that reduce cholesterol levels appear to have a notably diminished risk of developing dementia.”
The outcomes fluctuated significantly based on the biological pathway that was impacted. A minor reduction in non-HDL cholesterol by merely one millimole per liter linked to risk reductions ranging from 18% to 82% for specific genetic targets. The most pronounced effects were observed for variants in HMGCR (the target for statins), NPC1L1 (the target of ezetimibe), and CETP.
A Lifelong Study Encoded in DNA
The research utilized a method known as Mendelian Randomization, which leverages the random assortment of genes that happens during reproduction. Since genetic variants are determined at conception and remain unchanged throughout life, they avoid the numerous confounding variables that affect traditional studies. Factors like dietary changes, exercising habits, and smoking status do not complicate the genetic signal.
The researchers evaluated dementia diagnoses compiled over several decades. Within the Danish groups, the median follow-up duration reached 12 years, with some individuals monitored for as long as 46 years. The UK Biobank contributed 13 years of follow-up information. Throughout this period, over 29,000 individuals were diagnosed with some type of dementia.
Interestingly, the protective effects were most pronounced for vascular dementia and unspecified dementia, and somewhat less for Alzheimer’s disease. This trend aligns with current theories regarding how cholesterol harms the brain: mainly through atherosclerosis, which involves the accumulation of fatty deposits within blood vessels.
“Atherosclerosis results from cholesterol build-up in your blood vessels. This occurs both in the body and the brain and raises the likelihood of forming small blood clots, which are a contributing factor to dementia.”
From Genetics to Pharmaceuticals: The Translational Challenge
This is where complications arise. The study assessed lifelong exposure to lower cholesterol levels, beginning at birth. This fundamentally differs from taking a medication starting at age 60. Dr. Nordestgaard recognized this disparity, suggesting that the next logical phase would involve randomized clinical trials lasting between 10 to 30 years.
The timing issue is significant because dementia generally manifests later in life, although its underlying mechanisms may commence decades sooner. Some data indicate that elevated cholesterol levels during midlife heighten the risk of dementia, whereas high cholesterol in older age may actually confer protection, possibly due to the early stages of dementia leading to weight loss and reductions in cholesterol levels.
The study also could not entirely account for the potential ancillary benefits of cholesterol-lowering medications. For example, statins possess anti-inflammatory characteristics that may safeguard the brain through channels not related to cholesterol reduction.
Despite these qualifications, the genetic data reinforces the ascending consensus that cardiovascular health and cognitive health are interlinked. High blood pressure, diabetes, and increased LDL cholesterol during midlife all seem to elevate dementia risk in subsequent years. The vessels nourishing the heart are, in essence, composed of the same material as those serving the brain.
The research utilized information from the UK Biobank, Copenhagen General Population Study, Copenhagen City Heart Study, FinnGen study, and Global Lipids Genetics Consortium. The research was solely focused on individuals of European descent, which may restrict the breadth of the findings’ applicability.
For the time being, the study provides yet another motivation to take cardiovascular risk factors seriously, particularly in midlife. Whether cholesterol-reducing medications prescribed in later life can avert dementia remains an unresolved issue, but the genetic evidence suggests that managing cholesterol levels throughout adulthood may be a means to safeguard brain health in the long run.
Alzheimer’s & Dementia: 10.1002/alz.70638
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