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What factors increase someone’s risk for Alzheimer’s disease? A Q&A with Dr. Joseph C. Masdeu

Posted on: January 3, 2023

In Categories: Alzheimer's

Joseph Masdeu PhD

At Houston Methodist Hospital, Dr. Joseph C. Masdeu directs the Nantz National Alzheimer Center, a world-renowned research and referral center that treats thousands of patients each year. 

Dr. Masdeu has been passionate about treating diseases of the brain for many years and is continually inspired by his patients. “The more we collaborate, the better research we produce. It’s easy to collaborate here [in Houston] because I’m close to the University of Texas, Baylor University, and other institutions.”

The Racing to End Alzheimer’s team sat down with Dr. Masdeu to ask him some of your most pressing questions about Alzheimer’s disease and its prospective cure.

Dr. Masdeu and Phil Frengs discuss the recent work being done at Nantz National Alzheimer Center

The number one question we get is, “How close are we to finding a cure for Alzheimer’s?” How would you respond to this inquiry since we know Alzheimer’s thus far isn’t curable?  

I once heard this quote that if someone were to say, “tell us your plan for the next five years,” I’d respond by saying, “if I knew what I was doing in the next five years I’d do it today.” 

[When it comes to Alzheimer’s] it’s impossible to know how far out the cure is. The good part is that the system for research has improved a lot in the last few years … Even the way we approach the research is so different now. They didn’t have these techniques before 2014. We now also have a vast understanding about how the disease develops based on studies. 

For example, in the preclinical stage of the disease, the person is completely healthy without evidence that in the future that they could develop Alzheimer’s disease. If you do imaging, you might see increased amyloid [protein], which means they could have ten to twenty years of increased amyloid in the brain while still being ok. At this stage, if we were to decrease amyloid we could prevent the disease. So how long will it take for us to prevent Alzheimer’s? Right now we are doing clinical trials for certain medications. If the outcome is positive, then we will have “cured” Alzheimer’s, but we are much closer to prevention than to a cure. 

Inflammation in the brain is also important in all stages and might be playing a big role at later stages of the disease. We are currently studying giving patients an anti-inflammatory drug to slow down the disease and this clinical trial should have results in four years. We are probably the center that has the most experience with inflammation imaging.

Right now, all approaches are really making a difference.

Dr. Joseph Masdeu examines the scan of a patient's brain

What about Alzheimer’s makes it such a difficult disease to understand from a treatment perspective?

The process is so complicated: different people in different pathways lead to the same final situation.

The information that we need in order to come up with the cure and prevention of Alzheimer’s is what I like to call personalized medicine because it’s development, progression, and treatment is unique to the individual. 

I am very proud of what we are doing here because we are going back and forth between different departments looking at the same data sets together. We ask ourselves, what is the correlation? What is the difference between people with this disease who are slow progressors and fast progressors? We really look at everything because it’s such a complex disease. We know that diseases that happen older in life are typically multi-factorial (they have multiple causes). So you have to determine those causes to understand it better: it’s important to go back and forth between genomic and clinical data. As the science changes, you have to constantly make new correlations.

For example, it used to be that if you mapped a person’s genes, you’d only be looking at five percent of their DNA because the rest of it used to be called “junk DNA.” We have since learned that it’s not junk. In humans there’s a huge regulatory effect of other sequences up and down the genome. The genome has three billion pairs, so it’s quite a bit of data. In Houston, they have one of two genome centers in the US, so they are studying Alzheimer’s patients with not only imaging but also the entire genome. Then we also measure more than 1,0000 chemicals in their blood. Typically there are many causes of all diseases in older people.

What factors increase someone’s risk for Alzheimer’s disease?

Diet and exercise can have a huge effect on the cardiovascular state of the brain, so this can impact developing dementia. Someone who has Alzheimer’s changes in the brain has to have a lot of those changes in order for there to be an impact. The U.S. POINTER Study is looking at the effect of exercise and other risk factors that impact cognitive decline.

Can Alzheimer’s go into remission?

In some people it does. Is it frequent? No, but some patients plateau. Alzheimer’s disease progresses differently at a different speeds in different people. I’ve seen some people since 2014 that are basically the same, while others in just a few months decline. Everyone evolves differently. Once you hit certain markers, it’s easier to know how the disease is going to go. We need a bit of personal history to predict the progression in individual patients.

For the patient, the progression doesn’t have to be horrible at all because the family is there to compensate for the deficits the person may have. Little things make such a difference.

We’d like to thank Dr. Masdeu and the team at the Nantz National Alzheimer Center for their dedication to making that difference happen. Ten years have gone by since the founding of NNAC, and we have a lot of work ahead of us in the fight against Alzheimer’s. Remember that any contribution you make to Racing to End Alzheimer’s directly supports their work, so we can continue to strengthen this united front against Alzheimer’s. 

Dr. Masdeu, Phil Frengs, Belen Pascual, Jim Nantz and Nick Galante with the Racing to End Alzheimer's tribute car
(L to R) Dr. Masdeu, Phil Frengs, Belen Pascual, Jim Nantz and Nick Galante with the Racing to End Alzheimer’s tribute car at Houston Methodist.

For more information about the Nantz Alzheimer Center, visit the organization’s website 

The Nantz Alzheimer Center is a hub of research that brings better therapeutic approaches for the prevention and treatment of neurodegenerative diseases like Alzheimer’s disease. Its goals: prevent Alzheimer’s disease, slow memory loss progression, and improve the quality of life for every patient. Excelling in the use of clinical and research imaging biomarkers, the NNAC has contributed important scientific information relevant to treatment. Multiple preclinical and clinical studies are proceeding to evaluate various approaches and new medications aimed at delaying the progression of the disease or stopping its course.


Research at the NNAC

The NNAC’s research has resulted in the following contributions in understanding Alzheimer’s disease:

Rather than amyloid, tau deposition in the brain is closely associated with neurodegeneration. Our study clarified the role of excess amyloid and tau in the brains of people with Alzheimer’s disease. These two proteins define two different stages of the disease, and measuring them in the brains of people is critical in selecting the appropriate medication to treat patients at their current disease stage. Previous clinical trials failed to identify the importance of tailoring a patient’s treatment to their specific disease stage. Therefore, they didn’t produce the desired results. Patients at the Nantz National Alzheimer Center can benefit from sophisticated brain imaging to define the stage of their disease, resulting in tailored therapeutic options.

Pathological, toxic tau is passed from diseased neurons to healthy neurons, spreading neuron toxicity and worsening disease. Tau protein is important to healthy neuron function, but having a disease can alter tau structure and make it toxic instead. Pathological tau in diseased neurons is carried through a normal transport system used in healthy brains. Stopping pathological tau could stop the progression of disease. This discovery stimulated the use of antibodies directed against pathological tau as a treatment for Alzheimer’s disease. The subtle structural difference between toxic tau and healthy tau can be detected by antibodies, enabling us to target pathological tau while preserving healthy tau to carry on proper neuron function.

Researchers at the NNAC are characterizing and using imaging biomarkers of brain inflammation. Brain inflammation is being measured at the NNAC by means of positron emission tomography (PET) tracers that bind to a protein called TSPO expressed by microglia, which are the inflammatory cells of the brain. The NNAC is one of only a few centers in the world using this important measurement. We have demonstrated that inflammation behaves like a forest fire in dementia, moving from “burned” tissue to healthy tissue. Researchers in Dr. Appel’s lab have shown that the blood in the patients with Alzheimer’s disease has altered immune cells.

Based on these findings and findings from other Alzheimer’s disease centers, physician-scientists and scientists in the NNAC are currently conducting clinical trials that test potential medications to:

  1. Reduce brain amyloid in the brains of cognitively unimpaired people with amyloid buildup (A4 and A3-A5 studies*)
  2. Reduce brain amyloid in early mild cognitive impairment (Biogen aducanumab study)
  3. Reduce tau in the brains of people with early Alzheimer’s disease
    1. AbbVie study
    2. Biogen Tango study
    3. Lilly Periscope study
  4. Reduce inflammation in the brains of people with early Alzheimer’s disease through the use of immunotherapy (immune-modulating drug study)