Associations between serum cholesterol levels and cerebral amyloidosis

Abstract

Importance: Because deposition of cerebral β-amyloid (Aβ) seems to be a key initiating event in Alzheimer disease (AD), factors associated with increased deposition are of great interest. Whether elevated serum cholesterol levels act as such a factor is unknown.

Objective: To investigate the association between serum cholesterol levels and cerebral Aβ during life early in the AD process.

Design, setting, and participants: A multisite, university medical center-based, cross-sectional analysis of potential associations between contemporaneously assayed total serum cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and cerebral Aβ, measured with carbon C11-labeled Pittsburgh Compound B (PIB) positron emission tomography. Seventy-four persons (mean age, 78 years) were recruited via direct outreach in stroke clinics and community senior facilities following a protocol designed to obtain a cohort enriched for cerebrovascular disease and elevated vascular risk. Three patients had mild dementia. All others were clinically normal (n = 33) or had mild cognitive impairment (n = 38).

Results: Cerebral Aβ was quantified using a Global PIB Index, which averages PIB retention in cortical areas prone to amyloidosis. Statistical models that controlled for age and the apolipoprotein E ε4 allele revealed independent associations among the levels of LDL-C, HDL-C, and PIB index. Higher LDL-C and lower HDL-C levels were both associated with a higher PIB index. No association was found between the total cholesterol level and PIB index. No association was found between statin use and PIB index, and controlling for cholesterol treatment in the statistical models did not alter the basic findings.

Conclusions and relevance: Elevated cerebral Aβ level was associated with cholesterol fractions in a pattern analogous to that found in coronary artery disease. This finding, in living humans, is consistent with prior autopsy reports, epidemiologic findings, and animal and in vitro work, suggesting an important role for cholesterol in Aβ processing. Because cholesterol levels are modifiable, understanding their link to Aβ deposition could potentially and eventually have an effect on retarding the pathologic cascade of AD. These findings suggest that understanding the mechanisms through which serum lipids modulate Aβ could offer new approaches to slowing Aβ deposition and thus to reducing the incidence of AD.

Figure 1

Distributions of cholesterol values. Light gray indicates total sample and dark gray indicates subset of cases that were PIB positive. Dashed vertical lines mark the target guideline values given by the American Heart Association.

Figure 2

Independent effects of LDL and HDL cholesterol on cerebral Aβ. Individual data points and the slope of the regression of Aβ on LDL cholesterol (left) and HDL cholesterol (right). PIB index values are residual values from the model that evaluated HDL and LDL simultaneously while covarying age, sex and apoE ε4 status.