Efforts to modify the relentless course of Alzheimer disease have until now been based on altering the production or clearance of beta-amyloid, the protein found in plaques in the brains of patients with the disease. Results have been disappointing, possibly because our models of the disease—mostly based on the rare, inherited form—may not be applicable to the much more common sporadic form.
Ely Lilly’s recent announcement that it is halting research into semagacestat, a drug designed to reduce amyloid production, only cast further doubt on viability of the amyloid hypothesis as a framework for effective treatments for Alzheimer disease.
Because of the close association of sporadic Alzheimer disease with vascular disease and type 2 diabetes mellitus, increased efforts to treat and prevent these conditions may be the best approach to reducing the incidence of Alzheimer disease.
This article will discuss current thinking of the pathophysiology of Alzheimer disease, with special attention to potential prevention and treatment strategies.
THE CANONICAL VIEW: AMYLOID IS THE CAUSE
The canonical view is that the toxic effects of beta-amyloid are the cause of neuronal dysfunction and loss in Alzheimer disease.
Beta-amyloid is a small peptide, 38 to 42 amino acids long, that accumulates in the extracellular plaque that characterizes Alzheimer pathology. Small amounts of extracellular beta-amyloid can be detected in the brains of elderly people who die of other causes, but the brains of people who die with severe Alzheimer disease show extensive accumulation of plaques.
The amyloid precursor protein is cleaved by normal constitutive enzymes, leaving beta-amyloid as a fragment. The beta-amyloid forms into fibrillar aggregations, which further clump into the extracellular plaque. Plaques can occur in the normal aging process in relatively low amounts. However, in Alzheimer disease, through some unknown trigger, the immune system appears to become activated in reference to the plaque. Microglial cells—the brain’s macrophages—invade the plaque and trigger a cycle of inflammation. The inflammation and its by-products cause local neuronal damage, which seems to propagate the inflammatory cycle to an even greater extent through a feed-forward loop. The damage leads to metabolic stress in the neuron and collapse of the cytoskeleton into a neurofibrillary tangle. Once the neurofibrillary tangle is forming, the neuron is probably on the path to certain death.
This pathway might be interrupted at several points, and in fact, much of the drug development world is working on possible ways to do so.
GENETIC VS SPORADIC DISEASE: WHAT ARE THE KEY DIFFERENCES?
Although the autosomal dominant form of the disease accounts for probably only 1% or 2% of all cases of Alzheimer disease, most animal models and hence much of the basic research and drug testing in Alzheimer disease are based on those dominant mutations. The pathology—the plaques and tangles—in Alzheimer disease in older adults is identical to that in younger adults, but the origins of the disease may not be the same. Therefore, the experimental model for one may not be relevant to the other.