The comedian George Burns once quipped, “By the time you’re eighty years old, you’ve learned everything. You only have to remember it.” With the average life expectancy in the United States up from 54 a century ago to 74 today, the damage that can be done by aging and mental decline is more prevalent than ever. We see evidence of it all too often in our world leaders, families, and communities.
My friend Barry is 81 and very active. He runs a small business, loves to finish his deli lunch with a piece of cake, and then rides his bicycle everywhere. This morning he took a wrong turn on his way to work for the first time in over 45 years, and I’m starting to worry that his “senior moments” are turning into something more serious: the dreaded dementia.
When the most common form of dementia was first described over a hundred years ago in a fifty-year-old patient, Dr. Alzheimer noted that it was characterized by nerve tangles and “senile plaques.” By using the word “senile,” he was suggesting that these plaques could be expected in an older patient, almost implying that they may be inevitable with age. However, scientific understanding has grown greatly since his time. We know that physiological changes always have a cause, not merely a calendar.
In recent weeks, the FDA’s full approval of the drug Leqembi made headlines. It is a monoclonal antibody that cleans up plaque proteins associated with Alzheimer’s. The drug helps slow the progress of the disease, but because it performs a powerful cleanup in the central nervous system, it also has serious potential side effects. Even advocates are asking the FDA for additional guidance in making a risk/benefit analysis for specific patients, because it is not benign, and because the physician’s oath still applies: to do no harm.
The problem with Leqembi and other anti-plaque drugs on the approval path is that even when they work, they never cure the patient. And if fixing the plaques does not fix the disease, the clear implication is that these drugs are not treating an underlying cause.
Looking for underlying causes, researchers have focused for over thirty years on neuroinflammation, and many anti-inflammatory agents have been tested as prospective cures for Alzheimer’s, ranging from NSAIDs like ibuprofen to the rheumatoid arthritis drug etanercept (Enbrel). While there have been glimmers of hope in early clinical trials, there are currently no anti-neuroinflammation drugs available for prescription. And of the thousands of drugs being investigated for Alzheimer’s, only seventeen anti-neuroinflammation candidates are in trials.
More recently, a prospective path to find an underlying cause has opened up through advances in DNA and RNA analysis. Over time, our genetic blueprints accumulate changes that are sometimes reversible and change the way our cells work. We become less resilient, more inflamed, and more susceptible to age-related decline and disease. So perhaps diseases can be treated by reversing those genetic changes. In the case of Alzheimer’s, there are specific genetic changes that have been connected to the disease.
This summer, clinical data for one of the anti-neuroinflammation candidate drugs, NE3107, was analyzed to determine the drug’s effect on patient genes. In a controlled Phase 2 clinical trial, patients showed improved cognition. And concurrently, their DNA showed that genetic decline had been reversed at hundreds of sites. While it was already known that patients with the disease show epigenetic interference at those sites, these results connect the restoration of cognition with restored gene health.
These results in a small test are not conclusive, but larger clinical tests are underway for this candidate and several other anti-neuroinflammation drugs. One of these may be the first to truly stop or reverse Alzheimer’s, which will likely relegate anti-plaque treatments to a fading memory.
Ken Blaker is a Los Angeles-based health care and technology consultant focused on medical devices and FDA compliance. As an author, Ken has written on a variety of topics, including treatments for neurodegenerative diseases, cancer research, and the opioid epidemic.