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. 2023 Nov 21;101(21):e2172-e2184.
doi: 10.1212/WNL.0000000000207876. Epub 2023 Oct 4.

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

Erin L Ferguson  1 , Scott C Zimmerman  2 , Chen Jiang  2 , Minhyuk Choi  2 , Kaitlin Swinnerton  2 , Vidhu Choudhary  2 , Travis J Meyers  2 , Thomas J Hoffmann  2 , Paola Gilsanz  2 , Akinyemi Oni-Orisan  2 , Rachel A Whitmer  2 , Neil Risch  2 , Ronald M Krauss  2 , Catherine A Schaefer  2 , M Maria Glymour  2
Affiliations

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

Erin L Ferguson et al. Neurology. .

Abstract

Background and objectives: The associations of high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) with dementia risk in later life may be complex, and few studies have sufficient data to model nonlinearities 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 before the survey, and had laboratory measurements of cholesterol within 2 years after survey completion were followed up through December 2020 for incident dementia (Alzheimer disease-related dementia [ADRD]; Alzheimer disease, vascular dementia, and/or nonspecific dementia) based on ICD-9 or ICD-10 codes in EHRs. We used Cox models for incident dementia with follow-up time beginning 2 years postsurvey (after cholesterol measurement) and censoring at end of membership, death, or end of study period. We evaluated nonlinearities using B-splines, adjusted for demographic, clinical, and survey confounders, and tested for effect modification by baseline age or prior statin use.

Results: A total of 184,367 participants [mean age at survey = 69.5 years, mean HDL-C = 53.7 mg/dL (SD = 15.0), mean LDL-C = 108 mg/dL (SD = 30.6)] were included. Higher and lower HDL-C values were associated with elevated ADRD risk compared with 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 a 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 a lower risk for nonusers (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.

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Conflict of interest statement

The authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.

Figures

Figure 1
Figure 1. Hazard Ratios for ADRD With B-Splines for Each Average Cholesterol Measure
Knots at the 25th, 50th, and 75th percentiles of: (A) average HDL-C (unscaled), (B) average LDL-C (unscaled). Range of predicted HRs shown for the 2nd to the 98th percentile of LDL-C (52.7–175 mg/dL) and HDL-C (30.7–91 mg/dL) observed in the analytic data. ADRD = Alzheimer disease–related dementia.
Figure 2
Figure 2. Hazard Ratios for ADRD for First Cholesterol Measure vs 2-Year Average of Cholesterol Measures in Most Adjusted Model
All models include B-splines for cholesterol with knots at the 25th, 50th, and 75th percentiles. (A) HDL-C (unscaled). (B) LDL-C (unscaled). Range of predicted HRs shown for the 2nd to the 98th percentile of LDL-C (52.7–175 mg/dL) and HDL-C (30.7–91 mg/dL) observed in the analytic data. ADRD = Alzheimer disease–related dementia.
Figure 3
Figure 3. Hazard Ratios for ADRD for Linear Average Cholesterol Measure in Most Adjusted Covariate Set, Stratified by History of Statin Use at Survey Completion
All models include B-splines for cholesterol with knots at the 25th, 50th, and 75th percentiles. (A) HDL-C (unscaled). (B) LDL-C (unscaled). Range of predicted HRs shown for the 2nd to the 98th percentile of LDL-C (52.7–175 mg/dL) and HDL-C (30.7–91 mg/dL) observed in the analytic data. ADRD = Alzheimer disease–related dementia.
Figure 4
Figure 4. Hazard Ratios for ADRD for Linear Average Cholesterol Measure in Most Adjusted Covariate Set, Stratified by a Dichotomous Indicator of Age (Younger and Older than 65 Years) at Survey Completion
All models include B-splines for cholesterol with knots at the 25th, 50th, and 75th percentiles. (A) HDL-C (unscaled). (B) LDL-C (unscaled). Range of predicted HRs shown for the 2nd to the 98th percentile of LDL-C (52.7–175 mg/dL) and HDL-C (30.7–91 mg/dL) observed in the analytic data. ADRD = Alzheimer disease–related dementia.
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