Too much of the good cholesterol can be bad for the brain

Very high levels of high-density lipoprotein cholesterol (HDL-C) appear to contribute to increased risk of developing dementia among healthy older adults, as reported in a study.

Post hoc analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial showed that participants with HDL-C levels of >80 mg/dL had a 27 percent higher risk of dementia (hazard ratio [HR], 1.27; 95 percent CI, 1.03–1.58) compared with those who had HDL-C levels of 40–60 mg/dL. [Lancet Reg Health West Pac 2023;doi:10.1016/j.lanwpc.2023.100963]

Of note, the association between very high HDL-C levels and dementia risk was stronger among participants at least 75 years of age (HR, 1.42; 95 percent CI, 1.10–1.83) than among those younger than 75 years (HR, 1.02; 95 percent CI, 0.68–1.51).

The increased risk of dementia linked to very high HDL-C persisted despite adjustments for covariates such as age, sex, country of enrolment, daily exercise, education, alcohol consumption, weight change over time, non-HDL-C, HDL-C-polygenic risk score, and APOE genotype.

“This is the most comprehensive study to report high HDL-C and the risk of dementia in older people,” according to the investigators led by Dr Monira Hussain of Monash University School of Public Health and Preventive Medicine.

“Although ASPREE is a randomized controlled trial of 100 mg enteric coated aspirin, these results are not due to the effect of aspirin on dementia, as our previous analyses showed that aspirin did not affect the incidence of dementia,” Hussain added. [Neurology 2020;95:e320-e331]

The present analysis included 18,668 cognitively intact ASPREE participants who were free of evident cardiovascular disease, physical disability, or a chronic illness expected to limit survival to less than 5 years. A total of 850 (4.6 percent) cases of incident dementia were documented over 6.3 years.

Participants diagnosed with dementia tended to be older, female, less physically active, less likely to be a current or former smoker or to report alcohol use, but with a higher prevalence of prefrailty/frailty at baseline compared with dementia-free participants. The prevalence of hypertension, diabetes, and chronic kidney disease did not differ between the two groups, although participants with dementia had a higher prevalence of APOE e3/e4 and APOE e4/e4 genotype groups.

In contrast to the present study, a recent meta-analysis of 100 studies found no link between HDL-C and dementia. This meta-analysis analysis grouped HDL-C levels into tertiles or quartiles and potentially was not able to capture individuals with exceptionally high HDL-C levels. Meanwhile, published data from the Copenhagen General Population Study and the Copenhagen City Heart Study suggested a link between very high HDL-C and dementia in a relatively younger population with prevalent comorbidities. [Brain Sci 2020;10:386; Cardiovasc Res 2022;118:1330-1343]

“Our results extend the Copenhagen studies by including older participants who were initially healthy and cognitively intact,” Hussain said.

As to why high HDL-C might be associated with an increased risk of dementia, Hussain acknowledged that it was unclear but pointed to earlier studies suggesting that moderately high HDL levels were associated with better cognitive function and that low HDL-C levels were associated with an increased severity of Alzheimer's disease.

“However, HDLs are complex particles with various physiological functions likely determined by proteins and other compounds carried in their phospholipid coating. Plasma HDL-C levels do not necessarily reflect functional aspects of lipid transport and at very high levels this may be dysfunctional. The possibility also exists that increased dementia and very high HDL are both consequences of a separate and unrelated pathology,” Hussain noted. [Circulation 2021;143:2293-2309; Eur Heart J 2022;44:1394-1407]

“While we know HDL cholesterol is important for cardiovascular health, [the present] study suggests that we need further research to understand the role of very high HDL cholesterol in the context of brain health,” she stated.

Hussain also highlighted the potential value of considering very high HDL-C levels in prediction algorithms for dementia risk.

“Currently, there is a lack of proven noninvasive biomarkers of early dementia risk and no well-established interventions to slow cognitive decline. Circulating HDL-C levels are easily measurable, potentially modifiable, and therefore may become a useful dementia biomarker, albeit relevant to only a small fraction of individuals,” she said.