Cholesterol is often viewed as something that is bad for us, but it actually plays essential roles in the structure and function of our cells, especially in the brain [1]. Changes to cholesterol levels can alter the way cells communicate with each other. Major disturbances in cellular cholesterol levels can result in dysfunction and inflammation, and, in turn, increase the risk of cognitive impairment.
Cholesterol is transported throughout the body in association with carrier molecules, called lipoproteins [2]. The two major cholesterol carriers are low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Cholesterol is made in the liver and transported out to cells via LDL, while excess cellular cholesterol is transported back to the liver via HDL. As a result, the levels of cholesterol bound to LDL and HDL (referred to as LDL-C and HDL-C), can be used as markers of these processes, and provide information about whether cellular cholesterol levels are being properly maintained.
When LDL-C levels are higher than HDL-C levels, it means there is an excess of cholesterol in the cells and blood [3]. This imbalance can drive inflammatory processes, and has been associated with poor cardiovascular outcomes. Because of this relationship between high LDL-C with risk for adverse cardiovascular events, LDL-C is often labelled as ‘bad cholesterol’. The biology is slightly more complex, because LDL-C particles can vary by size and composition, which impacts their potential to drive damaging vascular inflammation, but in general, there is a correlation between elevated LDL-C and poor vascular health [4].
Evidence indicates that high LDL-C may also increase the risk for dementia, such that it was added to the Lancet Commission on dementia’s list of modifiable risk factors in 2024 [5]. The mechanistic link is not fully understood, but is thought to be related to its associations with vascular damage and systemic inflammation.
While relatively higher levels of HDL-C are generally considered to be a sign of good cardiovascular health and a more anti-inflammatory profile, HDL-C levels have not been as reliable an indicator of health outcomes [6]. HDL-C particles can be modified in a large number of ways, and each of these modifications impacts their function. As a result, the subtype of HDL-C particles present may be more relevant to health outcomes than the total number of HDL-C particles.
One key modification that affects the functionality of the lipoproteins is their association with accessory molecules. LDL-C particles associate with an accessory protein called apoB [2]. ApoB attaches to a variety of lipoproteins that have been implicated in vascular pathology. Correspondingly, elevations in apoB levels are also correlated with increased risk for cardiovascular disease and dementia [7; 8].
An elevation in LDL-C generally means the body is making too much cholesterol relative to its needs. While we can obtain cholesterol through food, most of our cholesterol is produced by the body, primarily in the liver [9]. Therefore, high LDL-C is not simply a sign of eating too much cholesterol, but rather is a sign of problematic metabolic changes, typically linked with excessive inflammation.
Since LDL-C can serve as a useful marker regarding risk for cardiovascular disease and dementia, it is a good idea to have blood cholesterol levels checked as part of an annual physical exam. If LDL-C levels are flagged as high, it is important to work with your healthcare provider to take steps to reverse these metabolic changes and get your cholesterol levels in check. This will likely include efforts aimed at reducing systemic inflammation, such as through exercise and a whole foods-based diet. It may also include taking medications that lower cholesterol production, such as statins.
The risk associated with dysregulated cholesterol builds up over time, so it is important to be proactive and act early to help maintain long-term brain health.
Betsy Mills, PhD, is a member of the ADDF's Aging and Alzheimer's Prevention program. She critically evaluates the scientific evidence regarding prospective therapies to promote brain health and/or prevent Alzheimer's disease, and contributes to CognitiveVitality.org. Dr. Mills came to the ADDF from the University of Michigan, where she served as the grant writing manager for a clinical laboratory specializing in neuroautoimmune diseases. She also completed a Postdoctoral fellowship at the University of Michigan, where she worked to uncover genes that could promote retina regeneration. She earned her doctorate in neuroscience at Johns Hopkins University School of Medicine, where she studied the role of glial cells in the optic nerve, and their contribution to neurodegeneration in glaucoma. She obtained her bachelor's degree in biology from the College of the Holy Cross. Dr. Mills has a strong passion for community outreach, and has served as program presenter with the Michigan Great Lakes Chapter of the Alzheimer's Association to promote dementia awareness.
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