Exploring the Complex Relationship Between High HDL-C Levels and Dementia Risk: Insights from the ASPREE Trial


The association between high levels of high-density lipoprotein cholesterol (HDL-C) and a reduced risk of cardiovascular disease (CVD) has been a well-established paradigm in medical literature. However, recent reports have brought attention to a potential flip side of this relationship, indicating that very high HDL-C levels might be linked to various adverse health conditions.

This article delves into the findings of recent studies, particularly focusing on a report from large community-based cohorts in Denmark and the implications of the Aspirin in Reducing Events in the Elderly (ASPREE) trial.

Denmark Cohorts and the Link to Dementia

A recent report from two large community-based cohorts in Denmark has added a new layer to the understanding of HDL-C levels and health risks. The study revealed an association between very high HDL-C levels and an increased future risk of all-cause dementia and Alzheimer’s disease. The cohorts comprised middle-aged men and women, aged between 47 and 68 years, shedding light on the potential impact of HDL-C on cognitive function in aging populations.

Structural Components and Actions of HDL-C

HDL-C particles, composed of lipids and apolipoproteins, serve crucial roles in both systemic circulation and the central nervous system. Within the central nervous system, HDL-C plays a vital role in delivering lipids to neurons, supporting membrane synthesis, and potentially contributing to the restoration of synaptic connections in neurodegenerative conditions. However, at extremely high plasma levels, the structural components and actions of HDL-C undergo changes that may prove detrimental to health.

Associations with Adverse Health Conditions

Beyond the link to dementia, recent studies have identified associations between very high HDL-C levels and a spectrum of adverse health conditions. These include an increased risk of all-cause mortality, age-related macular degeneration, sepsis, and fractures. These findings underscore the importance of scrutinizing the potential downsides of excessively elevated HDL-C levels.

The ASPREE Trial: Unraveling the HDL-C and Dementia Connection

The Aspirin in Reducing Events in the Elderly (ASPREE) trial emerges as a pivotal investigation into the relationship between plasma HDL-C levels and incident dementia risk. This randomized controlled trial involved healthy Australian and U.S. participants aged 70 and above (or >65 for U.S. minorities). As part of the trial, plasma HDL-C levels were measured at the time of enrollment, and participants underwent longitudinal follow-up with detailed measures of cognitive function, allowing for the assessment of dementia according to DSM-IV criteria.

Discussion: Unraveling the Complex Link Between Very High HDL-C Levels and Incident Dementia

Association with Incident Dementia: The primary revelation of our study is the association between very high levels of plasma HDL-C (>80 mg/dL) and an increased risk of incident dementia in initially healthy older individuals. Intriguingly, this association reached statistical significance in individuals aged 75 years and older. This elevated dementia risk was found to be independent of established dementia risk factors, including physical activity, alcohol intake, education, diabetes, and smoking.

Genetic Influences and Lifestyle Factors: Notably, our findings persisted even after adjusting for genetic influences on HDL-C levels through both APOE genotype and an HDL-C-PRS. The little difference observed in HDL-C levels among those with high dementia risk APOE genotypes further strengthens the notion that the increased dementia risk associated with very high HDL-C is not confounded by genetic factors.

While both genetic and lifestyle factors significantly influence HDL-C levels, a purely genetic explanation is not entirely satisfactory. Previous Mendelian randomization studies have not conclusively supported a causal role for HDL-C genetic variability in dementia development. Additionally, studies involving the artificial elevation of HDL-C levels through cholesteryl ester transfer protein (CETP) inhibition did not indicate an influence on dementia risk. The results of the ASPREE trial, a randomized controlled trial involving low-dose aspirin, further confirmed that the observed dementia risk was not attributable to aspirin.

Contrasting Findings and Study Validity: Our findings present a stark contrast to a recent meta-analysis of 100 studies suggesting no clear association between HDL-C levels and dementia. However, it’s crucial to note that most studies in this meta-analysis categorized HDL-C in tertiles or quartiles, potentially missing the nuanced impact of very high HDL-C levels.

In contrast, our study aligns with recent data from the Copenhagen General Population Study and the Copenhagen City Heart Study, indicating a link between very high HDL-C and dementia, particularly in a relatively younger population with prevalent comorbidities. The extension of these findings to older participants who were initially healthy and cognitively intact adds a unique dimension to our understanding of this relationship.

Mechanistic Uncertainties: The exact mechanisms underlying the association between high HDL-C and increased dementia risk remain elusive. Previous studies had suggested a positive correlation between moderately high HDL levels and better cognitive function, posing a paradox against our findings.

The complexity of HDL particles, with diverse physiological functions influenced by proteins and other compounds, raises questions about the functional aspects of lipid transport, especially at very high levels. Further investigations are warranted to explore whether the observed correlation is a result of dysfunctional HDL particles or stems from a separate, unrelated pathology shared by both very high HDL and dementia.

Implications and Future Directions: Considering the burgeoning challenge of aging populations and the escalating societal and economic impact of dementia, our findings propose a potential avenue for early identification of high-risk individuals. With circulating HDL-C levels easily measurable and potentially modifiable, they may emerge as a practical biomarker for dementia, albeit relevant to a specific fraction of individuals. Further exploration of the role of high HDL-C could provide insights not only into the pathogenesis of dementia but also into other adverse outcomes associated with elevated HDL-C, such as higher mortality rates, adverse cardiovascular outcomes, and fractures.

Study Strengths and Limitations: The strengths of our study lie in its focus on healthy community-dwelling individuals aged ≥70 years, rigorous data collection, and expert adjudication of dementia as a primary trial endpoint. Despite being an observational study, the internal consistency of findings across key subgroups enhances their validity. However, generalizability may be limited to healthy Caucasian adults, and potential unadjusted confounding from heavy alcohol intake must be considered.

The HDL-C-PRS, based on common variants, may not fully capture all genetic contributions to HDL-C levels. The possibility that dysfunctional HDL particles, rather than HDL-C levels per se, explain our results warrants further investigation.

Conclusions: In conclusion, our study provides compelling evidence linking very high HDL-C levels with incident dementia risk in older individuals, independent of established risk factors and genetic influences. While these findings open up new avenues for early identification strategies, a comprehensive understanding of the underlying pathophysiology remains elusive, necessitating further research to unravel this intricate relationship. As the pursuit of non-invasive biomarkers for early dementia risk gains urgency, circulating HDL-C levels stand out as a potential marker, offering hope for future interventions and targeted therapies.

reference link: https://www.thelancet.com/journals/lanwpc/article/PIIS2666-6065(23)00281-X/fulltext


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