November 29, 2023

expert reaction to study claiming an association between very high levels of ‘good cholesterol’ and dementia risk

A study published in The Lancet Regional Health – Western Pacific looks at cholesterol levels and the risk of dementia. 

Prof Tara Spires-Jones, President of the British Neuroscience Association, Group Leader at the UK Dementia Research Institute at Edinburgh, and Deputy Director of the Centre for Discovery Brain Sciences at the University of Edinburgh, said:

“Hussain and colleagues report an association between high levels of high-density lipoprotein cholesterol in blood and risk of developing dementia.  Although this type of cholesterol has been associated with lower levels of heart disease, recent data suggests that high levels of this “good” cholesterol are associated with some poor health outcomes and this new study shows an association with increased dementia risk. The study is well conducted, but does have several limitations. This type of study cannot determine conclusively that the high cholesterol levels caused dementia, and the population was predominantly white so the results may not be the same in a wider population.”

Gordon Wilcock, Emeritus Professor of Geratology, University of Oxford, said:

“This is an important study but there are conflicting reports about the potential role of this type of cholesterol in relation to dementia and I think it might turn out to be a marker for something else, or not relevant at all.

“I would not consider altering my lifestyle to adjust my HDL-C level until the evidence is more conclusive. Even if the relationship is confirmed it is likely to be of relevance to only a small number of people.”

Professor Andrew Doig, Professor of Biochemistry, University of Manchester, said:

Does the press release accurately reflect the science?

“Yes, it does.

Is this good quality research?  Are the conclusions backed up by solid data?

“Having a large sample of nearly 20,000 people has allows meaningful conclusions to be determined on links between high-density lipoprotein cholesterol (HDL-C ) levels and the onset of dementia in the elderly. In the over 75 age group, people with the highest levels of HDL-C were more likely to get dementia. The effect but was not large (a 27% increase in risk), but it was real. Careful analysis and consideration of many other factors that could affect the results, such as genetics, weight and smoking, mean that their conclusions are sound.

How does this work fit with the existing evidence?

“We have known for a long time that high levels of HDL-C are beneficial for reducing the risk of heart disease and stroke. This work shows that high HDL-C may not be all good, however, if it makes dementia more likely. An earlier study found the opposite conclusion, but this was in younger patients, where the effects of HDL-C may be quite different.

Have the authors accounted for confounders?

“The authors have accounted for numerous confounders that might be affecting their results. These include sex, country, frailty, physical activity, alcohol use, smoking, level of education, other types of cholesterol, intelligence, hypertension, diabetes, chronic kidney disease and some genetic links to dementia. Their conclusions hold up.

Are there important limitations to be aware of?

“A finding that elderly people with high HDL-C are more likely to have dementia does not prove that high HDL-C is a direct cause of dementia. There might be additional factors that affect both these things, such as a genetic link that we are currently unaware of. The study also only looked at healthy Caucasians from Australia and the USA, so might not generalise to other groups of people.

What are the implications in the real world?

“We need to be able to diagnose dementia earlier and more accurately. Including HDL-C levels might improve a diagnostic, though HDL-C levels on their own would not work.

“More research is needed to try to understand why HDL-C levels and dementia seem to be linked. Perhaps there is a disease pathway between the two that we currently don’t know about. If so, this might point to new ways to develop drugs against dementia. This is all very speculative, but worth looking at, as we desperately need better treatments for dementia.

Is there any overspeculation?

“No, I think the authors are cautious and reasonable in their interpretation.”

Professor David Curtis, Honorary Professor at UCL Genetics Institute, University College London, said:

“It’s quite doubtful that this study is demonstrating a real effect. The main claim is that very high HDL-C is associated with increased risk of dementia but the confidence interval for the hazard ratio very nearly includes 1, implying that the results could quite easily have occurred by chance. In fact, when they take account of APOE genotype, a known risk factor for dementia, the confidence interval actually does include 1, and hence the results are not formally statistically significant. This is a post hoc analysis and if one looks for associations then one is sure to find some by chance. In fact, they suggest that they are testing for this association because a previous study found an association between high HDL-C and dementia. But in the previous study the increased risk was in younger people and the present study in fact shows no increased risk at all in younger people. This kind of association study, incorporating multiple variables as covariates, is always difficult to interpret as different kinds of confounding can arise. Even if the results do reflect some real biological effect, it is not clear that there are any important implications.”

‘Association of plasma high-density lipoprotein cholesterol level with risk of incident dementia: a cohort study of healthy older adults’ by S M Hussain et al. was published in The Lancet Regional Health – Western Pacific at 23:30 UK time on Wednesday 29^th November.

DOI: https://doi.org/10. 1016/j.lanwpc.2023. 100963

Declared interests

Prof Curtis: No conflicts of interest to declare.

Prof Doig: I am a founder and consultant for PharmaKure, which is working on developing new drugs and diagnostics for Alzheimer’s Disease.

Prof Wilcock: I am a retired but still research active academic and don’t have anything relevant to declare.