High-Density Lipoprotein Over Midlife and Future Cognition in Women

Meiyuzhen Qi, Jeffrey Billheimer, Chung-Chou H Chang, Imke Janssen, Maria M Brooks, Trevor Orchard, Arun S Karlamangla, Emma Barinas-Mitchell, Carol A Derby, Dan McConnell, Sybil Crawford, Samar R El Khoudary
The Journal of Clinical Endocrinology & Metabolism, Volume 110, Issue 7, July 2025, Pages 1980–1988
https://doi.org/10.1210/clinem/dgae697

Abstract

Context

Limited data provides evidence-based insights on the association between the comprehensive metrics of high-density lipoproteins (HDL) and cognitive performance, especially in midlife women for whom the benefit might be the greatest.

Objective

To assess the associations of serum HDL metrics including HDL lipid content [HDL cholesterol, phospholipid (HDL-PL), triglyceride], proteins/subclasses [apolipoprotein A-1 (apoA-1); small, medium, large, total HDL particle (HDL-P); and HDL size], and cholesterol efflux capacity with cognitive performance in midlife women.

Methods

This prospective cohort study was conducted among 503 midlife women (1234 observations) from the Study of Women’s Health Across the Nation HDL ancillary study. Joint models were applied to examine associations of HDL metrics assessed at midlife (50.2 ± 2.9 years, baseline of the current study) and their changes over midlife (6.1 ± 3.9 years of duration) with subsequent cognitive performance [working memory (Digit Span Backward Test), processing speed (Symbol Digit Modalities Test), and episodic memory immediate and delayed recall (East Boston Memory Test)] assessed repeatedly (maximum 5 times) 1.5 ± 1 years later over 7.72 ± 4.10 years of follow-up.

Results

Higher total HDL-P and smaller HDL size at midlife were associated with a better subsequent immediate recall, delayed recall, and/or processing speed. Greater increase in HDL-PL, apoA-1, medium HDL-P, and total HDL-P and less increase in HDL size over midlife were associated with a better subsequent immediate and/or delayed recall.

Conclusion

Enhancing specific serum HDL metrics during midlife could be promising in cognitive restoration, particularly memory, the initial and predominant symptom of Alzheimer’s disease.

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