Low- and High-Density Lipoprotein Cholesterol and Dementia Risk Over 17 Years of Follow-up Among Members of a Large Health Care Plan

Background and Objectives:

The associations of high- and low-density lipoprotein cholesterol (HDL-C and LDL-C) with dementia risk in later life may be complex, and few studies have sufficient data to model non-linearities or adequately adjust for statin use. We evaluated the observational associations of HDL-C and LDL-C with incident dementia in a large and well-characterized cohort with linked survey and electronic health record (EHR) data.

Methods:

Kaiser Permanente Northern California health plan members aged 55 years and older who completed a health behavior survey between 2002 and 2007, had no history of dementia prior to the survey, and had laboratory measurements of cholesterol within two years after survey completion were followed through December 2020 for incident dementia (Alzheimer's Disease Related Dementia [ADRD]; Alzheimer's, vascular, and/or non-specific dementia) based on ICD9 or ICD10 codes in EHRs. We used Cox models for incident dementia with follow-up time beginning 2 years post-survey (after cholesterol measurement) and censoring at end of membership, death, or end of study period. We evaluated non-linearities using b-splines, adjusted for demographic, clinical, and survey confounders, and tested for effect modification by baseline age or prior statin use.

Results:

184,367 participants [mean age at survey of 69.5 years, mean HDL-C=53.7 mg/dL (SD = 15.0), LDL-C=108 mg/dL (SD = 30.6)] were included. Higher and lower HDL-C values were associated with elevated ADRD risk compared to the middle quantile: HDL-C in the lowest quintile was associated with an HR of 1.07 (95% CI: 1.03-1.11) and HDL-C in the highest quintile was associated with an HR of 1.15 (95% CI: 1.11-1.20). LDL-C was not associated with dementia risk overall, but statin use qualitatively modified the association. Higher LDL-C was associated with slightly greater risk of ADRD for statin users (53% of the sample, HR per 10 mg/dL increase=1.01, 95% CI: 1.01-1.02) and lower risk for non-users (HR per 10 mg/dL increase=0.98; 95% CI: 0.97-0.99). There was evidence for effect modification by age with linear HDL-C (p=0.003) but not LDL-C (p=0.59).

Discussion:

Both low and high levels of HDL-C were associated with elevated dementia risk. The association between LDL-C and dementia risk was modest.