This narrative review focuses on the role of
cholesteryl ester transfer protein (CETP) and peripheral
lipoproteins in the vascular contributions to
cognitive impairment and
dementia (VCID). Humans have a peripheral
lipoprotein profile where
low-density lipoproteins (
LDL) represent the dominant
lipoprotein fraction and
high-density lipoproteins (HDL) represent a minor
lipoprotein fraction. Elevated
LDL-cholesterol (
LDL-C) levels are well-established to cause
cardiovascular disease and several
LDL-C-lowering
therapies are clinically available to manage this vascular risk factor. The efficacy of
LDL-C-lowering
therapies to reduce risk of all-cause
dementia and AD is now important to address as recent studies demonstrate a role for
LDL in Alzheimer's Disease (AD) as well as in all-cause
dementia. The
LDL:HDL ratio in humans is set mainly by CETP activity, which exchanges
cholesteryl esters for
triglycerides across
lipoprotein fractions to raise
LDL and lower HDL as CETP activity increases. Genetic and pharmacological studies support the hypothesis that CETP inhibition reduces cardiovascular risk by lowering
LDL, which, by extension, may also lower VCID. Unlike humans, wild-type mice do not express catalytically active CETP and have HDL as their major
lipoprotein fraction. As HDL has potent beneficial effects on endothelial cells, the naturally high HDL levels in mice protect them from vascular disorders, likely including VCID. Genetic restoration of CETP expression in mice to generate a more human-like
lipid profile may increase the relevance of murine models for VCID studies. The therapeutic potential of existing and emerging
LDL-lowering
therapies for VCID will be discussed. Figure Legend.
Cholesteryl Ester Transfer Protein in
Alzheimer's Disease. CETP is mainly produced by the liver, and exchanges
cholesteryl esters for
triglycerides across
lipoprotein fractions to raise circulating
LDL and lower HDL as CETP activity increases. Low CETP activity is associated with better cardiovascular health, due to decreased
LDL and increased HDL, which may also improve brain health. Although most peripheral
lipoproteins cannot enter the brain parenchyma due to the BBB, it is increasingly appreciated that direct access to the vascular endothelium may enable peripheral
lipoproteins to have indirect effects on brain health. Thus,
lipoproteins may affect the cerebrovasculature from both sides of the BBB. Recent studies show an association between elevated plasma
LDL, a well-known cardiovascular risk factor, and a higher risk of AD, and considerable evidence suggests that high HDL levels are associated with reduced CAA and lower
neuroinflammation. Considering the potential detrimental role of
LDL in AD and the importance of HDL's beneficial effects on endothelial cells, high CETP activity may lead to compromised BBB integrity, increased CAA deposits and greater
neuroinflammation. Abbreviations: CETP - cholesteryl transfer
ester protein;
LDL -
low-density lipoproteins; HDL -
high-density lipoproteins; BBB - blood-brain barrier; CAA -
cerebral amyloid angiopathy, SMC - smooth muscle cells, PVM - perivascular macrophages, RBC - red blood cells.