The Role Of High-Density Lipoprotein Cholesterol In The Risk Of Late-Onset Alzheimer's

Association of HIgher Levels of HDL-C in Elderly Individuals and Lower Risk of Late-Onset AD

Dyslipidemia, or high blood pressure and triglyceride levels, is an established vascular risk factor, and vascular disease seems to play an important role in the risk for Alzheimer’s. While the specific relationship between the two remains unclear, there is evidence that cholesterol alters the degradation of the amyloid precursor protein and shows an effect on amyloid fibril formation. In a study conducted from 1999-2001, the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, sought to elucidate this relationship by examining the association of lipid profiles in 1130 Medicare recipients 65 and older with no signs of cognitive impairment at baseline. During the 4469 person-years of follow up, a total of 89 patients were diagnosed with probable AD, and 12 patients with possible AD. Overall, higher levels of HDL cholesterol, defined as greater than 55 mg/dL, were associated with a reduced risk of AD. These findings remained after adjusting for possible confounding factors such as age, sex, education, ethnic group, APOE e4 genotype, vascular risk factors and the use of lipid-lowering treatment. Individuals in the highest HDL-C quartile (greater than 56 mg/dL) were least likely to develop AD. As would be predicted, it was found that these same individuals were also at a reduced risk for vascular dementia.

Some of the possible explanations for these findings include that HDL-C may play a role in the removal of cholesterol from the brain by interaction with APOE and heparin sulfate proteoglycans in the subendothelian space of cerebromicrovessels. Therefore, low HDL-C levels could contribute to AD through a cerebrovascular pathway. Non-cerebrovascular mechanisms are possible as well in that levels of total-cholesterol and low HDL-C levels, which likely accompany hyperinsulinemia, may influence amyloid clearance in the brain and the formation of neurofibrillary tangles through altering the degradation of APP. Related to this hypothesis, it is possible that low total cholesterol levels are part of a pre-clinical stage of AD. In fact, the Honolulu-Asia Study supports this idea, reporting that total cholesterol levels in men who later developed dementia declined at least 15 years before a diagnosis was made, and that their cholesterol levels remained lower than the total cholesterol levels in men who did not develop dementia.

While these findings are certainly important, it deserves mention that a similar study conducted by the Taub Institute in 1992-1994 reported failed to report a significant association between HDL-C levels and AD. Nevertheless, it is possible that these contrasting findings are indicative of an improvement in cardiovascular health of the US adult population. Specifically, a significant increase in the number of individuals using statins has occurred since 1994 and the 1999-2001 cohort had higher mean HDL-C levels at 48.3 mg/dL compared to the 1992-1994 cohort at 47.2 mg/dL.