The ANA Q&A: Alzheimer’s Disease: Where Hope Lies

"Trials to delay or prevent the onset of Alzheimer dementia, and the development of blood-based biomarkers to screen for Alzheimer disease, are among the cutting-edge research initiatives that will be discussed at the ANA Annual Meeting.”

- John C. Morris, MD, the Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology and Director of the Charles F. and Joanne Knight Alzheimer’s Disease Research Center at Washington University School of Medicine in St. Louis

According to the National Institute on Aging, Alzheimer’s disease (AD) is ranked as the sixth leading cause of death in the United States, affecting more than 5.5 million Americans. Furthermore, the disease may rank third—behind only heart disease and cancer—as the leading cause of death among older adults. As we mark Alzheimer’s and Brain Awareness Month in June, we take a sober look at both the setbacks and the promise of research to deliver new treatments to reduce the burden of this progressive disease, which accounts for 60–80% of all dementia cases and destroys memory and cognition in an irreversible, devastating manner.

Alzheimer’s disease will be the topic of the Presidential Symposium at the ANA 2019 Annual Meeting in October. We asked session co-chair John C. Morris, MD, for an update on the state of AD research, both at their program at Washington University in St. Louis and in the field generally.

Dr. Morris is the Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology and Director of the Charles F. and Joanne Knight Alzheimer’s Disease Research Center at Washington University School of Medicine in St. Louis. The ANA Presidential Symposium will address Dominantly Inherited and Late-Onset Alzheimer’s Disease: Genetics, Biomarkers, Timecourse and Treatments.

Q. Where does the field stand in progress to treat Alzheimer’s disease? What will the session address?

The results from clinical trials of anti-Alzheimer investigational drugs continues to be extremely disappointing, as no agent has demonstrated therapeutic benefit for AD dementia. Whereas there had been cautious optimism in recent years that some drugs would be efficacious, that optimism was erased this year when two clinical trials were discontinued after futility analyses predicted no benefit. These failed trials continue a two-decade long record of inability to develop truly effective therapies for AD dementia. This disappointing track record has led some major pharmaceutical companies to reconsider or even discontinue their Alzheimer therapy programs. It also is very discouraging for the individuals with Alzheimer dementia (and their families) who participated in these trials in hopes of contributing to the advancement of Alzheimer therapies.

“On the other hand, there remains the possibility that the drugs that failed to benefit people with symptoms of AD still may be beneficial if they can be administered prior to the onset of AD dementia.”

 

The ANA Presidential Symposium will feature four international experts who are laying the foundation for the advent of prevention studies in AD. Such studies depend on identifying the Alzheimer process in the brain many years, perhaps as much as 2–3 decades, before any signs of dementia appear.  Individuals from rare families in which there is a pathogenic mutation which, if inherited, inevitably causes AD dementia represent an ideal group in which to initiate secondary, and possibly even primary, prevention trials where the goal is to delay or even prevent the onset of AD dementia. Alison Goate, DPhil, led the studies that in 1991 identified the first such mutation that causes autosomal dominant AD (ADAD), and continues to explore the genetic influences that result in AD, both in its asymptomatic (preclinical AD) and symptomatic (AD dementia) stages. Randall Bateman, MD, launched in 2012 the first ever prevention trial with anti-Alzheimer investigational agents in asymptomatic mutation carriers from ADAD families. Although ADAD is extremely rare, the asymptomatic mutation carriers are ideal prevention trial participants because they are destined to develop AD dementia, and the age at which they will do so is generally predictable (on average, around age 45). Yakeel Quiroz, PhD, has studied brain abnormalities that develop many years before dementia onset in individuals from families centered in the Antioquia region of Colombia who share a pathogenic mutation that causes ADAD. These abnormalities may help to indicate whether investigational drugs administered to ADAD individuals are resulting in positive effects.

Prevention trials also are possible in individuals at risk for the far more common form of late-onset AD where pathogenic mutations are absent. Such trials enroll cognitively normal individuals who are at elevated risk for developing AD dementia because they demonstrate molecular brain changes that are associated with the disease. These biological changes (“biomarkers”) can be identified with imaging studies that reveal abnormal brain deposits of the proteins that are mis-aggregated in AD: amyloid-beta and tau. Changes in the concentration of these proteins also can be identified by assays of the cerebrospinal fluid (CSF), obtained by lumbar puncture. Gil Rabinovici, MD, has led seminal studies using positron emission tomography (PET) with radioligands for amyloid-beta and tau that indicate which cognitively normal older adults have cerebral deposits of these proteins and thus have preclinical AD. Ultimately, it would be highly beneficial to have a blood-based biomarker to screen for the likelihood of AD and reserve PET imaging or CSF examinations for those individuals who screen positive with the blood test. The laboratory of Dr. Bateman is among the leaders for the development of such blood-based biomarkers.

Q.   What work is your lab undertaking to move understanding or treatment for Alzheimer’s disease going forward?

The failure of drug trials to demonstrate benefit for AD dementia may relate to the fact that they were initiated too late in the disease process. Hence, the three currently active AD prevention trials (two in ADAD individuals, one in older adults with preclinical AD) are being followed with great anticipation, as the premise is that the interventions occur before substantial neuronal damage and loss has occurred.

Q. What does the public need to understand about Alzheimer’s disease that it often doesn’t?  

AD is by far the leading cause of dementia but it is not the only cause of dementia. When brain cells start to die due to the AD process, brain function fails and memory loss occurs. But other illnesses that damage neurons in areas of the brain responsible for memory and other cognitive functions also can cause dementia. For example, brain injury due to strokes can cause vascular dementia. Other neurodegenerative causes include Lewy body dementia and frontotemporal dementia. Moreover, many individuals with AD dementia have additional pathologies, including strokes, that may contribute to the cognitive dysfunction.

It is under-appreciated that AD is a devastating experience not only for the patient but also for the family. Caring for a person with AD dementia is emotionally and physically taxing and very expensive. The annual cost of caring for people with Alzheimer’s disease is estimated to be $280 billion a year in the United States alone.

AD dementia is not part of normal aging. It is true that age is the greatest risk factor for AD, but many people live into their ninth and tenth decades of life without developing dementia.

Q. How are treatment options for Alzheimer’s disease different today from 10 years ago?

They’re not. Currently available drugs for the symptomatic treatment of AD dementia were approved by the FDA between 1996 and 2003. However, these approved drugs have modest benefit at best and do not address the underlying mechanisms of the disease.

Q.   How has the ANA supported your career?    

I was fortunate, when I began my career at Wash U in the 1980s, that I had as my mentor and role model Leonard Berg, MD, who was the founding director of our Alzheimer’s Disease Research Center. Leonard always believed that the annual meeting to attend was that of the ANA. Even before I was elected to ANA membership, Leonard took me as a guest and introduced me to many of the legends in neurology. It was a very heady experience for me and cemented my commitment to academic neurology. When I became a member it was—and remains—a tremendous honor.