Incremental Attempts At Solving Alzheimer’s Puzzle

Alzheimer’s disease continues to be a relatively common cause of mental decline in the United States. Its cause is unknown and its clinical course is relatively unpredictable. It inexorably diminishes the mental abilities of the affected individual, but the rate of that deterioration varies from case to case.

Dozens of drugs have been put forth by dozens of pharmaceutical companies claiming that their concoctions will slow the decline caused by the disease. A handful of these candidate drugs have been approved by the Food and Drug Administration (FDA) as safe and effective, but physicians managing people with Alzheimer’s disease have yet to observe a dramatic effect with any of these “treatments.”

The most recently approved drug, Aduhelm, did not even meet the minimum standards for a claim of efficacy but was nonetheless approved for the treatment of Alzheimer’s disease. The public demand for something to treat this scourge is so strong that even an allegedly objective and independent federal agency felt the need to approve a safe but ineffective drug for sale. The warning label on this drug might well have included the old Latin saying, “Caveat emptor” (Buyer beware).

What has emerged from the decades of work on and study of this disease is a clearer picture of what it is, what may cause it, and what may benefit affected individuals. We are no closer to knowing how to prevent this disease than we were a century ago, but that can change overnight.  When discussing inevitably progressive and fatal diseases, physicians routinely point to pernicious anemia and general paresis.

Pernicious anemia was called “pernicious” (really bad) because it was a fatal blood condition. Affected individuals could not make enough healthy red blood cells to survive and often developed spinal cord disease before they died. Some clever investigators discovered that injecting vitamin B12 halted the disease in many of the affected people, and the diagnosis was no longer a death sentence.

Similarly, many people infected with syphilis developed a brain rot from the germ and exhibited a progressive and invariably fatal mental deterioration (thus the origin of the name “general paresis,” which means a diffuse intellectual weakness). American mental hospitals were overflowing with victims of general paresis until researchers discovered penicillin and found it killed the responsible germ. Syphilis became curable, and general paresis became rare.

And so it might be with Alzheimer’s disease. A medical student working in a cold-water flat in Kenya may some day call the editor of a prestigious medical journal to report that he or she had found the cause or the cure for Alzheimer’s disease. The editor will, of course, dismiss the claim and reject the report (as was the case for the first paper demonstrating the usefulness of L-DOPA in people with Parkinson disease), but when a more established, establishment physician hears rumors of the claim and duplicates the unknown student’s work, the cure for Alzheimer’s disease will be in hand, and the established physician will win the Nobel Prize.

There are at least two recent developments that warrant optimism in the search for an effective treatment for Alzheimer’s disease. One is the unexpected failure of Aduhelm to benefit patients.  The other is the unexpected genealogical findings in an obscure religious sect in Montana.

Aside from the obvious wasting of the brain evident on imaging studies, the brains of affected individuals demonstrate consistent changes at a microscopic level. These include the development of tangles of fine tubules inside nerve cells (neurofibrillary tangles), widespread loss of nerve cells (neuronal loss), and collections of materials with a waxy appearance where nerve cells would normally be evident (amyloid plaques). One widely supported theory was that the elimination or the prevention of amyloid plaque development would reverse or at least halt the ravages of Alzheimer’s disease. 

This was the rationale behind the development of Aduhelm. This drug accomplished its intended goal of inhibiting the formation of amyloid plaques, but it failed to halt the progression of dementia, the loss of mental abilities characteristic of Alzheimer’s disease. Amyloid plaques are apparently a consequence of Alzheimer’s disease, rather the cause of it. Enormous time and resources were spent on developing agents like Aduhelm. Those efforts will now be directed elsewhere.

The other major insight into Alzheimer’s disease that emerged in recent months was courtesy of genetic studies in Hutterite communities in Montana. The Hutterites are fundamentalist Christians living in effectively closed, agrarian communities in north central United States and south central Canada. Hutterites marry Hutterites. They have little if any genetic contributions from individuals outside their communities, and they maintain extensive and detailed genealogical (family tree) records. 

By studying the prevalence of specific genes in individuals developing Alzheimer’s disease in these communities, researchers discovered a gene highly associated with the development of the disease in women. Although this gene was not linked to chromosomes determining the sex of the individual, men carrying the gene were not affected by Alzheimer’s disease to the extent women were. This indicated that in some populations Alzheimer’s disease is linked to a genetic defect that causes problems only in the setting of other factors, including the sex of the individual carrying the gene.  

Alzheimer’s disease may be the end result of numerous conditions that devastate the same areas of the brain and leave the same debris in their wake. This would be similar to the situation found in a variety of lethal infections of the brain.  Whether an individual with a brain infection (encephalitis) has been killed by a staph or strep or other bacterial disease may not be evident on examination of the brain and may require efforts to grow the responsible germ to obtain an answer.

None of these recent insights are dramatic advances, but incremental progress should lead to a cure for Alzheimer’s disease. There were numerous failures and dead ends in the development of antibiotics and anticancer drugs, but the time and effort that went into these investigations ultimately paid off. Perhaps that medical student in Kenya or Sweden or Mexico already has the answers to the Alzheimer puzzle and is just waiting for his or her discovery to be published.

Dr. Lechtenberg is an Easton resident who graduated from Tufts University and Tufts Medical School in Massachusetts and subsequently trained at The Mount Sinai Hospital and Columbia-Presbyterian Medical Center in Manhattan.  He worked as a neurologist at several New York Hospitals, including Kings County and The Long Island College Hospital, while maintaining a private practice, teaching at SUNY Downstate Medical School, and publishing 15 books on a variety of medical topics. He worked in drug development in the USA, as well as in England, Germany, and France.

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