SAN DIEGO—A low level of HDL cholesterol and a high level of LDL cholesterol may be associated with elevated cerebral amyloid-beta in elderly persons with high vascular risk, according to a study presented at the 65th Annual Meeting of the American Academy of Neurology. The study is one of the most recent efforts to determine the relationship between cholesterol and susceptibility to the brain amyloidosis seen in Alzheimer’s disease.
“Epidemiologic literature has suggested that higher cholesterol values, particularly at midlife, are associated with an increased risk of Alzheimer’s disease,” said Bruce R. Reed, PhD, Associate Director of the Alzheimer’s Disease Research Center at the University of California, Davis. “This is a complicated literature; it’s not entirely consistent. But there are fairly strong findings.”
In addition, several large observational studies have found a substantial reduction in Alzheimer’s disease risk associated with statin use, “though randomized controlled trials have been negative,” said Dr. Reed. “The epidemiologic work has taken on additional interest because of basic science work that has shown that cholesterol plays an important role in the processing of amyloid.”
The Aging Brain Study
To investigate the relationship between cholesterol levels and contemporaneous cerebral amyloid-beta, Dr. Reed and his associates studied 66 men and women in the Aging Brain Study, a longitudinal project that examines vascular contributions to dementia. The mean age of the 66 study participants was 78, and 44 (67%) had a history of stroke or transient ischemic attack (TIA), myocardial infarction, or coronary artery bypass grafting. Nearly half (31) had a Clinical Dementia Rating Scale score of 0 (normal). Of the remaining 35 individuals, 32 had a score of 0.5 (mild cognitive impairment) and three had a score of 1 (demented).
The researchers assayed fasting HDL and LDL cholesterol and triglycerides and used 11-C labeled Pittsburgh compound B (PIB) PET to measure cerebral amyloid-beta. The primary predictors were total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides. Secondary measures included VLDL cholesterol, apolipoprotein A-I, and apolipoprotein B. “Apolipoprotein A-I is the primary protein of HDL cholesterol; it’s involved in reverse cholesterol transport,” said Dr. Reed. “Apolipoprotein B is thought to be the atherogenic constituent of LDL cholesterol.”
Regional distribution volume ratio (DVR) values were calculated using a cerebellar reference region. “The level of amyloid-beta was quantified with global PIB index, which was the mean DVR in regions susceptible to amyloidosis,” explained Dr. Reed.
Most Participants Used Cholesterol-Lowering Drugs
In a multiple regression model that adjusted for age and sex, HDL and LDL cholesterol had significant, independent effects on the PIB index. Specifically, lower HDL and higher LDL were associated with a higher PIB index. Adding APOE ε4 status to the model left the association essentially unchanged. APOE ε4 had an independent effect on PIB in the expected direction. Using identical modeling, the researchers found that higher Apo A-1 and lower Apo B were associated with a higher PIB index that remained significant after the investigators adjusted for APOE ε4 status.
Nearly three-quarters of study participants (71%) were on cholesterol-lowering drugs, and 65% were taking a statin. When the researchers adjusted the model for cholesterol treatment, it did not modify the results. “We modeled this in a number of ways, and the treatment effects were not significant,” said Dr. Reed. “The apolipoprotein A-1 and apolipoprotein B effects mirrored the effects of HDL and LDL.”
Serum Cholesterol Has a Complex Relationship With Amyloid-Beta
The precise mechanism of action behind the findings remains unclear, Dr. Reed said, but it is believed that cholesterol levels—primary HDL—modulate the synthesis, transport, toxicity, and clearance of amyloid-beta.
“In vitro and animal work supports the idea that higher cholesterol appears to promote gamma- and beta-secretase activity,” he said. “It seems to shift amyloid precursor protein processing away from the alpha-secretase pathway, and it promotes amyloid-beta aggregation.”
Dr. Reed emphasized that the relationship between serum cholesterol and brain cholesterol is complex. “Serum cholesterol and brain cholesterol are separate pools; cholesterol in the brain is locally synthesized and doesn’t correlate with cholesterol in the periphery,” he commented. “Also, cholesterol metabolism and levels change throughout adulthood, and the deposition of amyloid-beta occurs over 10 to 20 years. This is much more than a short-term, single, direct relationship.”
The study findings “need replication, but replication may require a cohort with high vascular risk burden,” Dr. Reed said. “The role of serum lipids in amyloid-beta regulation is of great interest because of the potential to modify amyloid-beta deposition through the modification of vascular risk.”
IMNG Medical News