A new era in Alzheimer’s and Parkinson's treatment

By Dr. Malù Gámez Tansey 
Real Clear Wire

The human and financial toll of Alzheimer's, Parkinson's, and other neurodegenerative diseases is growing by the day. Over 7 million Americans currently battle Alzheimer's and another 1 million fight Parkinson's.  

Both conditions are becoming more common. By 2050, Alzheimer's is expected to afflict 13 million Americans and cost the nation about $1 trillion annually, unless better treatments or cures are developed. 

To forestall this looming catastrophe, both public and private institutions have invested tens of billions of dollars into studying these conditions. And that research keeps revealing that these diseases all share a common trigger: systemic inflammation within the body as a whole, and within the brain specifically. 

That's why one recent clinical trial, conducted by a small Florida-based biotech company, is so exciting for researchers like me. The trial provided compelling evidence that it's possible to halt cognitive decline in certain Alzheimer's patients by targeting a protein that causes brain inflammation without simultaneously targeting a related protein that helps protect the brain. 

Researchers have known for some time that inflammation is more than just a byproduct or biomarker of neurodegeneration. In many cases, it's a contributing cause -- perhaps even the root cause.  

In Alzheimer's disease, for instance, inflammation disrupts the healthy functioning of the immune cells of the central nervous system. In Parkinson's disease, inflammatory proteins can lead to the degradation of certain neurons.  

Much of my own research into these diseases has focused on one particular inflammatory protein: tumor necrosis factor, or TNF.  

There are two forms of this protein. The good type, transmembrane TNF, remains within the protective membrane surrounding neurons and plays important roles in immune regulation and tissue repair. The bad type, soluble TNF, circulates freely in the bloodstream and cerebrospinal fluid and is a potent driver of chronic inflammation.  

That distinction matters because the TNF-inhibiting drugs on the market today, such as adalimumab, etanercept, and infliximab, target both forms of the protein — the good and the bad. 

These drugs were designed, and are currently used, to treat autoimmune diseases like rheumatoid arthritis. But past research has revealed that they also inadvertently decrease autoimmune patients' risk of developing Alzheimer's.  

Patients with untreated rheumatoid arthritis are roughly seven times more likely to develop Alzheimer's than people who don't have rheumatoid arthritis -- which strongly suggests that the inflammation that causes rheumatoid arthritis also plays a role in causing, or at least accelerating, the development and progression of Alzheimer's. When rheumatoid arthritis patients go on TNF-inhibiting drugs, their odds of later developing Alzheimer's drops by roughly half or more. 

However, because these drugs target both the good and bad types of TNF, they interfere with important immune processes and raise the risk of infection. That's why they're not prescribed preventively to patients merely at risk of Alzheimer's and Parkinson's -- the harm to the immune system outweighs the potential benefits of reducing the heightened, but still relatively low, risk of developing one of those neurodegenerative conditions. 

That's why the recent clinical trial results are so exciting. The experimental drug in question -- which I co-invented in 2003 and had previously studied in animal models -- targets soluble TNF in early-stage Alzheimer's patients without affecting transmembrane TNF.  

I'd been watching this trial closely, since it was the first human test of my hypothesis that exclusively targeting soluble TNF could reduce the inflammation I believe drives Alzheimer's.  

The Phase 2 trial, which enrolled over 200 participants with early Alzheimer's and at least one of four biomarkers for inflammation, didn't meet its primary endpoint – a benefit in participants' scores on a number of cognitive tests compared to a placebo group -- for the entire study population.   

But the trial wasn't a failure -- just the opposite. The results for a large subpopulation of participants with amyloid-beta pathology (Aβ+), and at least two of those biomarkers of inflammation, were mostly beneficial. In just six months, this group of patients experienced protection of their cognitive scores, compared to a decline in the placebo group. By comparison, donanemab and lecanemab -- the two Alzheimer's drug treatments most recently approved by the FDA, were associated only with slowing of cognitive decline over the course of 18 months.  

Participants in this subpopulation also showed a beneficial effect on behavioral symptoms and biological markers of Alzheimer's pathology -- without suffering any of the brain swelling or bleeding events that are potential side effects of those two existing treatments.   

These results validate decades of basic science. My lab and others have shown in animal models that soluble TNF sits at the apex of a cascade of inflammatory signals that fuel neurodegeneration. But the recent clinical trial is, to my knowledge, the first direct test in a large group of humans of what happens when we target that specific driver of inflammation.  

It also reinforces the need to look beyond the brain. Inflammation isn't localized. Many of the immune cells that end up in the brain originate elsewhere: in the gut, liver, and lungs. Chronic conditions like diabetes, obesity, fatty liver disease, and even sleep apnea all contribute to inflammation throughout the body, which in turn fuels inflammation in the brain.  

When explaining the problem to friends without extensive scientific backgrounds, I've often used an analogy. Imagine firefighters are trying to suppress a blaze in a building with an open gas line. Unless we shut off that gas line -- the inflammation that triggers a host of other health problems -- we'll never fully extinguish the fire.

Of course, there's a long road ahead. Larger trials will be needed to confirm the findings. But the biological rationale is sound. If we can target neuroinflammation in a precise and safe way, we could transform how we treat -- and think about -- Alzheimer's, Parkinson's, and similar neurodegenerative diseases. This could be delivered as a standalone treatment, or potentially, in combination with the already existing treatments targeting different pathways in these diseases. 

We're entering an era where treating neurodegeneration may increasingly resemble treating cancer: by personalizing therapy based on biomarkers, by intervening early in the inflammatory cascade, and by combining treatments. Simply put, selectively targeting the source of this inflammation could help us beat diseases that steal our memories, mobility, and independence. 

The views expressed are of Dr. Malù Gámez Tansey and do not necessarily represent the views of Indiana University.