Longevity Briefs: Lower ‘Bad Cholesterol’ May Significantly Reduce Dementia Risk

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Dementia is a collection of debilitating, incurable conditions for which the risk increases significantly in old age. The good news is that while dementia may not be curable, research suggests that nearly 50% of cases can be prevented through a healthy lifestyle. Understanding which lifestyle factors contribute most to dementia is therefore crucial for prevention, but also challenging due to the complex interactions between genetic and environmental factors.

One of the largest and more recently established risk factors for dementia is high levels of cholesterol carried by low-density lipoprotein (LDL-C), sometimes referred to simply as ‘bad cholesterol’. LDL particles are membrane packages that deliver cholesterol and triglycerides to tissues. While high LDL-C appears to promote dementia, the relationship may not be so straightforward, with some studies suggesting that low LDL-C also increased dementia risk, while others found no association or even a protective effect. In this study, researchers set out to clarify the issue.

The discovery:

Researchers collected a large amount of data from 11 university hospitals in Korea, including information on 12,233,274 individuals. They focused on two groups: those with an LDL-C score of less than 1.8 mmol/L (70mg/dL), which is considered low (a score of under 2.6 mmol/L is considered optimal), and those with a score of over 3.4 mmol/L (130mg/dL), which is considered borderline high.

They then compared the incidence of dementia in the two groups over a variable follow-up period. In an attempt to control for confounding factors (people with higher cholesterol are likely to be unhealthy in other ways), researchers used a matched pair technique. This means that each person in the low LDL-C group was paired to someone in the high LDL-C group with similar characteristics such as age, sex, smoking status and use of statins (cholesterol-lowering drugs).

This left the study with 108,980 matched pairs. The study ultimately found that LDL-C levels below 1.8 mmol/L was associated with a 26% reduction in the risk of all-cause dementia and a 28% reduction in Alzheimer’s disease-related dementia (ADRD) risk compared to levels above 3.4 mmol/L. When looking specifically at even lower LDL-C levels (less than 1.4 mmol/L), there was a slightly smaller protective effect (an 18% risk reduction for both all-cause dementia and ADRD), while LDL-C levels below 0.8 mmol/L did not show any significant risk reduction compared to levels above 3.4 mmol/L. The study also compared statin users to non-users within each LDL-C level group. They found that statin use was associated with additional protection against dementia, particularly in individuals with LDL-C levels below 1.8 mmol/L.

The implications:

This research suggests that low LDL-C may significantly lower dementia and Alzheimer’s risk, but that very low LDL-C levels (less than 0.8 mmol/L) are equivalent to borderline high levels in terms of risk. It also suggests that statins, aside from lowering LDL-C themselves, also have additional benefits for dementia risk reduction at low LDL-C, as shown by the fact that people in the low LDL-C group taking statins were less at risk than those who achieved low LDL-C without the aid of statins. This could suggest that people taking statins benefit from additional dementia risk reductions in addition to cardiovascular benefits when they reach specific LDL-C levels, and that people with an already low LDL-C might still benefit from statins when it comes to dementia prevention. This will all need to be demonstrated by clinical trials, as given this study’s observational nature, it cannot prove a causal relationship between low LDL-C, statin use and disease risk.

As for why low LDL-C lowers dementia risk, it is likely to be through a combination of improving cardiovascular health (which is a major factor in preventing dementia) as well as direct effects on the brain (cholesterol is involved in oxidative stress and inflammation in the brain). However, cholesterol is also essential for the brain, as it is needed to maintain cellular membranes, synapses and myelin (the structures that wrap around nerve fibres to speed up the transmission of electrical impulses), and so the very lowest levels of cholesterol may start to counteract some of the other beneficial effects.