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  • Writer's pictureEric Goulder, MD, FACC

Heart Talk - January 2024

Navigating the Complexity of High-Density Lipoprotein (HDL)

 A correlation between high-density lipoprotein (HDL) cholesterol levels and the risk of dementia has become a focal point for research and a topic of casual conversation due to widespread interest and recent publications in mainstream media. A study titled: Association of plasma high-density lipoprotein cholesterol level with risk of incident dementia: a cohort study of healthy older adults has garnered public attention. This prompts a deeper exploration into the multifaceted nature of HDL and its intricate and complicated relationship with long-term cognitive health. 


While HDL is often heralded as the “good cholesterol” and LDL the “bad,” we are the first to recognize that this over-simplification misrepresents the nuanced and complex nature of what we know about HDL. 


REVISITING THE ASPREE TRIAL 

The ASPREE (Aspirin in Reducing Events in the Elderly) trial focused primarily on healthy older adults with no known cardiovascular disease, dementia, or other significant comorbidities. The researchers observed an association with baseline HDL levels above 80mg/dL and a 27% increased risk of dementia in participants over age 75 years of age followed for 6.3 years. Similarly, those with low levels of HDL (<40) also show an associated risk of dementia. This effect was significant after adjusting for age, sex, daily exercise, education, alcohol consumption, weight change over time, non- HDL-C and APOE genotype.


It is vital to note that findings of this study are not universally applicable, as the dynamics of HDL and its implications differ across diverse populations (ie: people with plaque in their arteries may have high HDL cholesterol as the result of excellent treatment). It is essential to consider additional evidence and viewpoints for a more comprehensive perspective. 


SUPPORTING STUDIES: COPENHAGEN INSIGHTS 

The Copenhagen General Population Study and the Copenhagen City Heart Study, as elucidated by Kjeldsen et al. (2022), lends support to the notion of an association between very high baseline levels of plasma HDL cholesterol and dementia risk. However, a genetic randomization showed that genetically elevated HDL is not associated with Alzheimer’s disease. The takeaway from this data is that HDL cholesterol can and should be considered as one of many biomarkers to further personalize an individual’s risk for all forms of dementia. 


CONTRADICTORY NARRATIVES: EXAMINING THE DISSENT 

Studies by Sáiz-Vazquez et al. (2020), Zhong et al. (2020), Wan et al. (2019), Button et al. (2019), and W. et al. (2015) introduce a layer of complexity by challenging the presumed straightforward relationship between HDL cholesterol and dementia risk. These meta-analyses and retrospective cohort studies present alternative viewpoints, prompting a reassessment of our understanding and emphasizing the need for cautious interpretation of results. 


In these studies, results showed no difference in HDL-C serum levels between patients with Alzheimer’s Disease and those without; additionally, Button et al. suggests high HDL-C levels are associated with reduced dementia risk and is instead protective against cerebrovascular dysfunction. 

Iwagami et al. (2021) examined the relationship between HDL cholesterol and risk of dementia over two decades, utilizing a retrospective cohort study. The study aimed to examine the association between baseline total cholesterol, LDL, HDL and triglycerides and incident dementia diagnosis. Results showed no consistent associations for HDL and triglycerides in relationship to incident dementia. 


THE COMPLEXITY OF HDL: UNANSWERED QUESTIONS 

Biomarkers utilized within the BaleDoneen Method such as haptoglobin lend complexity to this issue, as we know that haptoglobin 2-2 individuals often have elevated HDL due to oxidation of free hemoglobin. In this case, HDL elevation is a byproduct of oxidative stress, which we recognize as the root cause of disease. We also know that the studies linking elevated HDL to dementia risk did not explore the effects of sleep apnea or dental pathogens, which have both demonstrated a strong relationship with dementia. 


BOTTOM LINE: High-density lipoproteins are complex, and we are far from having the clinical tools to understand their functionality. HDL is known to be protective in many ways, but we also know that HDL particles can lose their protective functions and even gain adverse functions in the presence of chronic disease or infections, such autoimmune conditions, diabetes and chronic kidney disease. When HDL dysfunction is present, HDL has the potential to do more harm than good. 


A NUANCED CONCLUSION 

The recent publication linking WZHDL levels to an increased risk for dementia serves as a catalyst for a more nuanced examination of this complicated relationship. HDL has emerged as an extremely complex player with multifaceted functions, demanding a more comprehensive understanding of its implications for cognitive health. 


The existence of contradictory evidence calls for continued work to understand HDL’s many complexities and functions. The ongoing evolution of research in this field will certainly shed more light on this nuanced issue, hopefully guiding us toward a more holistic comprehension of HDL’s role in both health and disease. For now, a conversation with your provider about your HDL level in the context of your overall health, duration of treatment, genetics and potential for risk is an excellent place to start. 


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