New Directions for Alzheimer’s Disease

by Guy McKhann, M.D.

April 26, 2011

There are many reports in the media about Alzheimer’s disease, reflecting not only the common occurrence of this disease, but also peoples’ increasing concern as they age. In choosing articles for Brain in the News, we have to dodge many of these articles that are either repetitive or speculative. However, it is worthwhile to step back every so often and ask, Where are we?

The Alzheimer’s Association, in conjunction with the National Institute of Aging (NIA), will soon be publishing an update of the clinical and research criteria for various stages of the disease process. We will cover that aspect next month.

We start with the basic observation that in Alzheimer’s disease, two proteins that are normally present in brain accumulate: A-beta, a component of amyloid, accumulates in plaques, and another protein, tau, accumulates in tangles. These accumulations are the hallmarks of the pathology, resulting, over time, in loss of nerve cells and the clinical symptoms of dementia. Much of the attention of pharmaceutical companies in recent years has been to alter the accumulation of A-beta. To date these therapeutic attempts have not been successful.

In a thoughtful article, “Connecting the Pieces of the Alzheimer’s Puzzle,” Matt Ridley turns attention to other aspects of the disease which have received less attention.  These include: inflammation, protein misfolding, and the role of cholesterol in Alzheimer’s disease.

Inflammation occurs in two forms. One is an acute form such as when you get a local reaction with a splinter in your finger, with symptoms including redness, swelling, and accumulation of pus. The other is chronic form, in which inflammatory cells (lymphocytes, macrophages, and others) accumulate in tissue. This latter form occurs in chronic infections, allergic reactions, and inflammatory processes such as arthritis or multiple sclerosis. Inflammation can be part of the response to an insult, part of the healing process. Alternatively it can be part of the disease process.

Inflammation is present in the brain with Alzheimer’s disease. For a long time this was thought to be a bystander effect, the response of the brain to accumulation of proteins and loss of nerve cells. However, as pointed out in the Wall Street Journal article, inflammation may be an integral part of the disease process.

Protein misfolding is not a new idea. Proteins are made from strings of amino acids, like beads on a string. The conformation of the protein is determined by the sequence of these amino acids. The concept that a naturally occurring protein could fold in an abnormal way and result in disease was promulgated by Stan Prusiner, as the basis for a disease like “mad cow disease,” a so-called “prion disease” (Prusiner won the Nobel prize for his studies in 1997).  Prusiner also suggested from early on that a similar mechanism might be working in other diseases in which proteins accumulate. That is, normally occurring proteins fold in unusual ways and interrupt normal functioning of nerve cells.

We usually associate cholesterol with vascular disease—disease of the blood vessels of the heart or of the brain. Both of these forms of vascular disease become much more frequent as we age. Thus in older people there is a double whammy: Alzheimer’s disease and vascular disease. When people spoke of cholesterol in diseases of the brain, which process were they referring to? Recent evidence suggests that cholesterol, and other lipids, play a role in protein folding. This role is enhanced in the presence of inflammation. Thus our thinking about the role of cholesterol in Alzheimer’s disease is changing—it may play a primary role in the disease mechanism.

It was logical to focus therapeutic attempts at altering the accumulation of A-beta. While A-beta plays some role in the disease process, it is not the final answer. Some of these newer leads provide alternative approaches to therapy.