LONDON — Experimental studies suggest the potential of treating and preventing Alzheimer disease with cholesterol-lowering agents. The studies, discussed here at the World Congress of Neurology in June, examine the link between the physiological function of the amyloid precursor protein, its beta-amyloid domain, the free beta-amyloid peptide, and neuronal cholesterol.
“Studies have shown that people aged 50 and older who are treated with cholesterol-lowering agents have a three-fold lower risk of developing dementia,” said Konrad Beyreuther, MD, of the University of Heidelberg in Germany, in a seminar on the molecular biology of Alzheimer disease. “It is now understood that hypertension and hypercholesterolemia are risk factors for Alzheimer disease, and that high serum cholesterol in midlife is a significant risk factor for AD.”
Dr. Beyreuther continued:“Statins are promising compounds for Alzheimer. Our experimental studies suggest new approaches for prevention and possibly intervention with statins.”
Dr. Beyreuther said it has been previously shown that synaptic loss occurs early in the course of dementia, but that neurons die much later. Hardly any synapses are detected under beta amyloid plaques in autopsied brains of Alzheimer patients, but neurons are still there, he explained.
“This suggests that the plaque itself is probably not toxic,” Dr. Beyreuther told listeners.
Studies of post-mortem Alzheimer disease brains demonstrated a correlation between beta amyloid levels and neuritic plaques as well as between beta amyloid levels and neurofibrillary tangles. However, no correlation was found between insoluble beta amyloid and neurofibrillary tangles. These studies suggest that the damage associated with the disease is related to soluble beta amyloid, said Dr. Beyreuther.
Subsequent experiments have suggested that the beta amyloid domain is essential for the axonal transport of amyloid precursor protein, Dr. Beyreuther said. The beta amyloid sequence of that protein appears to function as an axonal sorting signal that mediates its recruitment into axonally transported vesicles. In Alzheimer disease, the neuronal sorting receptor may be blocked by excess beta amyloid produced within neurons, “causing a traffic jam” in axonal transport, he said.
THE CHOLESTEROL LINK
Dr. Beyreuther and others have studied the influence of neuronal cholesterol on beta amyloid generation in vitro and in vivo. These studies were prompted by the observation that the lipid transport gene overloads neurons with cholesterol and that axonal transport of membrane proteins is cholesterol-dependent.
Experiments in rats showed that cholesterol depletion with lovastatin led to a 50 percent reduction in production of beta amyloid. A similar reduction in beta amyloid production was seen when guinea pigs had simvastatin added to their food.
“These studies suggested that both the physiological and pathogenic regulation of axonal transport by beta amyloid appears to be controlled by cholesterol, “Dr. Beyreuther said. “This implies a link between brain cholesterol, amyloid precursor protein transport, beta amyloid production, and the risk of developing AD. This intriguing relationship opens new and immediately accessible vistas for the treatment and prevention of AD,” he concluded.