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