Elevated HDL-C Efflux Capacity Could Protect Cognitive Function in Adults

John Giacona, PhD, PA-C

Credit: UT Southwestern

Elevated high-density lipoprotein cholesterol (HDL-C) efflux capacity was positively linked to greater brain gray matter volume (GMV) in middle-aged adults, suggesting a potential neuroprotective function against cognitive decline, according to new research.¹

Examination of more than 1800 participants from the multi-ethnic, population-based Dallas Heart Study revealed small HDL particle (HDL-P) concentration was correlated with higher GMV normalized to total cranial volume (TCV), which remained after adjustment for relevant risk factors. 

“Our study has identified a novel role of HDL-C in maintaining gray matter volume in the brain, which is important for cognitive function in middle-aged adults,” lead investigator John Giacona, PhD, PA-C, assistant professor of applied clinical research and internal medicine in the school of health professions at UT Southwestern Medical Center, said in a statement.² “Our study was the first to investigate for a potential link between HDL function and brain volume.”

Epidemiological research has tied low levels of HDL-C to impaired cognitive function, with the presence of amyloid beta deposits in the brain linked to dementia.³ Higher HDL-C efflux capacity, a measure of HDL reverse cholesterol transport functionality, has demonstrated a linear association with reduced cardiovascular disease risk.

However, the link between plasma HDL-C efflux capacity or HDL composition, and brain structure, requires further investigation. In this analysis, Giacona and colleagues sought to evaluate the correlation between HDL measures and brain function among 1826 adults (47%) Black who participated in the Dallas Heart Study.¹

The team measured TCV, white matter hyperintensities (WMH), and whole-brain GMV using brain MRI, followed by neurocognitive function using the Montreal Cognitive Assessment (MoCA). HDL-C efflux capacity was evaluated using fluorescence-labeled cholesterol efflux from J774 macrophages and HDL particle size by nuclear magnetic resonance (NMR) spectroscopy.

A multivariable linear regression analysis measured the association of HDL-C efflux capacity and cognitive phenotypes, adjusted for classic risk factors including age, smoking status, education level, race and ethnicity, and daily physical activity.

Upon analysis, Giacona and colleagues identified a positive correlation between both a higher HDL-C efflux capacity and small HDL-P concentration to a higher GMV normalized to TCV, after adjustment for relevant risk factors (β, 0.078 [95% CI, 0.029 to 0.126], P = 0.002, and β, 0.063 [95% CI, 0.014 to 0.111], P = 0.012, respectively).

On the other hand, the investigative team identified no link between HDL measures, WMH, or MoCA (all P >.05). Notably, the team found the association of HDL-C efflux capacity and small HDL-P with GMV/TCV were unmodified by ApoE-ε4 status or race and ethnicity.

Overall, investigators suggested the function of HDL-C or levels of small HDL particles could provide biomarkers for a population at risk of developing cognitive decline. However, they noted further research is needed to confirm the connection.

“HDL particles exist in many sizes, which may be linked to their function,” senior investigator Wanpen Vongpatanasin, MD, professor of internal medicine and director of the hypertension section in the division of cardiology at UT Southwestern, said in a statement.² “We now need to understand exactly how the small HDL particle, which can cross the blood-brain barrier, may have a beneficial role in maintaining brain health.”

References

1. _{Giacona JM, Wang J, Zhang R, et al. Associations Between High-Density Lipoprotein Cholesterol Efflux and Brain Grey Matter Volume. J Clin Med. 2024;13(20):6218. Published 2024 Oct 18. doi:10.3390/jcm13206218}
2. _{Center USM. ‘Good’ Cholesterol May Protect Against Brain Atrophy, Dementia. Newswise. January 2, 2025. Accessed January 3, 2025. https://www.newswise.com/articles/good-cholesterol-may-protect-against-brain-atrophy-dementia.}
3. _{Gottesman RF, Schneider AL, Zhou Y, et al. Association Between Midlife Vascular Risk Factors and Estimated Brain Amyloid Deposition. JAMA. 2017;317(14):1443-1450. doi:10.1001/jama.2017.3090}