Shortly after retiring three years ago, I got interested in the growing field of research into some promising new preventative approaches to Alzheimers Disease (AD). My initial acquaintance with the latest preventative drug research came via an episode of the “Nova” science show on PBS. I was so intrigued that I immediately investigated clinical trials in the Washington, DC area where I live. Sure enough, an NIH-sponsored trial at Georgetown University Hospital was currently open and after a few encouraging phone calls, I decided to enroll.
My interest in AD prevention is personal. My mother was diagnosed in her early 70’s (I’m 69). She would live almost two decades longer, suffering the ravages of Alzheimers dementia such that she couldn’t recognize any of her ten children by her late 70’s. One of my father’s sisters was diagnosed with early-onset AD in her 50’s.
It took about four months between my first inquiry until I was called to make my first visit to Georgetown Hospital in DC. There was a lot of preliminary paperwork as well as interview sessions with a Nurse Practitioner and various Research Assistants. The first session confirmed my eligibility in three of the four main criteria: 1) a family history of AD , 2) age 65 or over and 3) no indication of present cognitive impairment. I didn’t realize it at the time, but my final acceptance was contingent on the result of a PET-scan to detect any existing amyloid plaque in my brain. I had this PET-scan soon after my first visit to Georgetown.
I went for another visit to Georgetown about two weeks later with my required “study partner” – my wife Andrea. The study partner was to report to staff on my ongoing, day-to-day mental performance. To verify my mental competence, Andrea met separately with a staff person and was asked to describe any notable event we had experienced recently. The staff person then met privately with me to ask if I could fill in some details about the reported event. In addition, I took another battery of cognitive tests using an iPad, and person-to-person memory testing. I was feeling pretty good about my overall mental competence at that point.
The last part of that second visit proved to be quite disturbing, however. The Nurse Practitioner told me and my wife the results of my recent PET-scan, which had used a very expensive radioactive dye to determine if I had any amyloid plaque in my brain. Beta-amyloid plaques are a primary indicator of the likelihood of AD. Unfortunately, I was in the 15% of people in my age bracket who had detectable amyloid. This bad news was deeply sobering, but Andrea, a four-time cancer survivor, reassured me by saying: “John, it’s not brain cancer!”
I spent the next few months in various stages of fearful rumination about my long-term mental status. I kept picturing the last decade of my mother’s deterioration and contemplating the very real possibility that the same fate could be awaiting me. I had always prided myself on my intellect. My ego took a big hit from accepting the possibility that I might become mentally incompetent. At some point, I had to admit my arrogance in thinking that I was just too smart for all of this. I took some comfort from remembering that Nova television program I had been so impressed by, especially by the camaraderie of those who had volunteered for the preventive clinical trials.
I somehow hadn’t realized it, but if I’d tested negative for amyloid, I would have been eliminated from the clinical trial. Now I had satisfied all four criteria of this new anti-amyloid drug trial, aptly called the “A4” – Asymptomatic Alzheimers Anti-Amyloid. The test drug, solenazumab, was created by the pharmaceutical company Eli Lilly. This monoclonal-antibody drug had proven amyloid-eliminating properties but had as yet failed to produce any statistically significant improvements in people with Alzheimers dementia. Current thinking about AD was that a brain deterioration process developed for decades before noticeable declines in cognition. The A4 was designed for people like me who are asymptomatic despite high risk factors. Perhaps if amyloid plaque could be removed before it had a chance to proliferate, AD dementia could be delayed, or even indefinitely forestalled.
Monthly IV Drug Infusions
I started my monthly trips to Georgetown in the fall of 2016. I had worked in downtown DC for decades, and I was happy enough to ride a DC Metro train from my home in the outer suburbs down to Dupont Circle, from where I walked the 2.5 miles over to Georgetown Hospital. The Clinical Trials section is on the top floor and I quickly learned my way around. The project staff for the A4 were universally friendly and professional.
My appointments were for 10am, starting with taking vital signs, queries regarding medications and supplements, and then insertion of an IV needle. The test drug had to be ordered from the hospital pharmacy and could take up to an hour to arrive. The standard hospital rooms were comfortable and featured wide windows overlooking the Georgetown University campus and surrounding neighborhoods.
In addition to the IV drip, there were periodic cognitive tests. These were pretty straightforward yet required a degree of mental concentration and stamina that I found initially quite challenging. I found my performance improved when I stopped off for a Starbucks coffee on my way in.
The A4 is a “gold standard” double-blind drug study. This means that 50% of participants get the test drug, the other 50% a placebo. Neither participants nor staff knew which group any participant was in. The IV bags themselves were labelled “Solanezumab or placebo”. In the beginning, the 400mg infusion took only about a half-hour. But in the second year of my participation, the dosage was increased to 800mg and then 1600mg, requiring well over an hour for the full infusion and flush.
One of the questions I was asked at the beginning of each visit was whether I was feeling any effects from the drug. A long list of possible physical reactions and side-effects was recited. I answered no to all these queries, and after a few months, I began suspecting that I was receiving a placebo. Even after the dosage was increased four-fold, I still felt nothing.
I realized when I entered the trial that I had a 50% chance of getting the placebo. I thought hard about this and decided to participate anyway. Even if I didn’t benefit persoally, I felt that I was contributing to the greater good of scientific research. If solanezumab proved effective, my participation would have contributed to that conclusion. And an effective Alzheimers prevention drug could benefit the many millions of fellow-boomers who, like me, were entering their twilight years with the cloud of Alzheimers menacing the horizon.
Deciding to Opt Out of the A4
As I approached the end of my second year of participation in the A4, I began feeling burdened by the monthly outings to Georgetown. In my “retirement”, I was continuing a small counseling practice, started writing this blog, and was becoming much more active politically. In addition, we had four grandchildren we wanted to see more, and a spiritual community that Andrea and I were both committed to. My concern about Alzheimers was still real, and I had implemented some significant lifestyle changes to keep my mind and body active and healthy. These included a low-carb diet, daily exercise, daily meditation, improved sleep, and conscious cultivation of new friendships and new interests.
I wanted to find out my possible genetic pre-disposition for AD, so I signed up for one of the Web-based, commercial genetic testing services. I was chagrined to find out that I had two of the APOE4 mutations that indicated a higher likelihood for AD. Statistically, my genetic cohort had a 27% chance of having AD dementia by age 75; 55% by age 85. I reported this to the A4 staff and they noted it in my record without comment.
Receiving this news was a factor in keeping me participating in the A4 for a few more months. In the end though, weighing the benefits versus my increasing time constraints, I decided to opt out. The Georgetown staff took my decision without much fanfare. The study was currently geared for four years, but participation was completely voluntary, and participants could terminate their involvement at any time.
A New Focus: Cognitive Resilience
I was still of two minds about continuing in the A4 when I consulted informally with a friend who is a medical research administrator and who had some expertise in the latest AD research. He reminded me that the “amyloid hypothesis” was just that, a hypothesis. Even though 80% or more of AD brain autopsies indicated the presence of amyloid plaques, there was no real scientific understanding of amyloid as a causative agent. Some AD researchers regarded amyloid as part of an inflammatory response in the brain. Removal of amyloid, in and of itself, was no guarantee that AD would be averted. And removing it might also contribute to more inflammation.
My friend also pointed out that autopsies were revealing a significant percentage (20-30%) of mentally healthy, non-demented individuals who nevertheless had significant amyloid plaque deposits in their brains. This puzzling phenomenon had led him to seriously doubt the efficacy of the amyloid hypothesis.
My friend shared that researchers were using the term “cognitive resilience” to describe the large set of people who, despite amyloid and family history and higher genetic risk, never manifested symptoms of AD dementia. He noted that the research was showing that the population manifesting this resilience were mostly among those who had opted for a healthy, active lifestyle.
“Cognitive resilience” has become the mantra in my current attitude towards AD. Much of my initial motivation for entering the A4 clinical trial was a pervading fear that I was doomed to have AD like my mother, starting in my early 70’s. I no longer feel that sense of doom. Though I’m still very consciously aware of my AD risk factors, I no longer shrink in fear at the prospect of dementia. Instead, I’ve chosen to live my remaining years with hope and commitment, no matter what transpires. As my focus on resilience grows, day by day, I’m becoming much more sanguine about my prospects for a healthy, productive aging process.
John Bayerl, 9/9/2018