Low HDL-C, Triglyceride Levels in Late Life Independently Associated With Alzheimer Disease and Related Dementias

Low high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels are independently associated with an increased risk of Alzheimer disease and related dementias (ADRD), suggesting that the development of interventions targeting low HDL-C and TG levels should integrate considerations for mitigating dementia risk, according to the results of a data analysis and review published in Alzheimer’s & Dementia.¹

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The interplay between cholesterol levels and cognitive decline has been investigated in prior literature. Study results from the ASPREE trial indicated that cholesterol variability over time in adults could be associated with a heightened risk of dementia compared with those who have stable cholesterol levels. However, the association has remained inconclusive, though the current investigators note that there is a “plausible biological mechanism” for how lipid levels may increase dementia risk. Meanwhile, recent studies have found that high TG levels are also associated with increased cognitive decline and dementia risk, an important finding given the strong inverse relationship between HDL-C and TG.^1-3

Factoring in this inverse correlation between HDL-C and TG levels is critical when attempting to describe how these lipids may be linked to dementia risk. Investigations that have sought to examine these lipids in relation to dementia have been burdened by inadequate adjustments of covariates and small sample sizes. Given that clinical treatment recommendations for dementia may differ depending on the type and level of lipids in older adults, the current authors aimed to extend their ongoing research efforts into the associations of TG and HDL-C levels with ADRD in late life.^1,4

The investigators analyzed a dataset from a large and diverse survey cohort of older Kaiser Permanente Northern California (KPMC) members with repeated lipid measurements and longitudinal follow-up in electronic health records, featuring up to 17 years of follow-up. Improving on limitations of prior work of their own and those of other authors, comprehensive laboratory measurements as well as exhaustive demographic and health behavior data provided the opportunity to more thoroughly elucidate the possible association.¹

After sorting the data, the final analytic sample included 177,680 KPMC members; over an average of 8.80 years, 24,105 incident ADRD cases occurred, the authors wrote. Notably, the investigators residualized continuous lipid values against strong study confounders and used residualized lipids in their primary model to predict the onset of ADRD. In their discussion, the authors noted that negative residuals indicate a lower level of lipid than what is expected from an individual's body mass index, sex, and age, whereas positive residuals indicate higher than expected levels of lipid.¹

There was a nonlinear relationship between residual HDL-C (HDL.r) and hazard of dementia, both with and without adjustment for residual TG (TG.r). Without adjusting for TG, enrollees with HDL.r in the lowest quintile had a 6% elevation in hazard of dementia (HR: 1.06; 95% CI, 1.02–1.10) compared with the middle quintile, whereas the highest quintile of HDL.r was associated with a 7% elevation in risk (HR: 1.07; 95% CI, 1.03–1.12) compared to the middle quintile, the authors found. These results were consistent when using unresidualized HDL-C instead of HDL.r. Additionally, there was a linear relationship between TG.r and dementia, as lower TG.r residuals corresponded to a higher risk of dementia, again remaining consistent when using unresidualized TG.¹

Ultimately, these results indicate independent associations between low HDL-C and low TG levels and dementia incidence. Concerningly, they also suggest a further hazard of dementia for patients with both low HDL-C and low TG levels, the investigators wrote. Pharmacists and treatment providers should take HDL-C and TG levels into account when monitoring older adults for ADRD risk.¹

“If future studies find these associations to be causal, our findings suggest that the development of clinical interventions targeting low HDL-C and TG levels warrants investigation for mitigating dementia risk,” the study authors wrote in their conclusion.¹

REFERENCES

1. Ferugson EL, Zimmerman SC, Jiang C, et al. Independent associations of high-density lipoprotein cholesterol and triglyceride levels with Alzheimer's disease and related dementias. Alzheimer’s & Dementia. 2025;21(2):e14575. doi:10.1002/alz.14575

2. Antrim A. AHA 2024: Unexplained changes in cholesterol could help identify adults at risk of dementia. Pharmacy Times. Published November 16, 2024. Accessed April 3, 2025. https://www.pharmacytimes.com/view/aha-2024-unexplained-changes-in-cholesterol-could-help-identify-adults-at-risk-of-dementia

3. Gong J, Harris K, Peters SAE, Woodward M. Serum lipid traits and the risk of dementia: A cohort study of 254,575 women and 214,891 men in the UK Biobank. eClinicalMedicine. 2022;54:101695. doi:10.1016/j.eclinm.2022.101695

4. Ferguson EL, Zimmerman SC, Jiang C, et al. Low- and high-density lipoprotein cholesterol and dementia risk over 17 years of follow-up among members of a large health care plan. Neurology. 2023;101(21):e2172-e2184. doi:10.1212/WNL.0000000000207876