Op-Med is a collection of original articles contributed by Doximity members.
Chicago hosted nearly 6,000 researchers from around the world at the 2018 Alzheimer’s Association International Conference last month.
Here are some highlights from my perspective, culled from several thousand papers, posters and lectures presented at the meeting. Maybe these findings will eventually prompt insurance coverage for the brain equivalent of the popular “Silver Sneakers” fitness program, which I will dub the “Silver Synapses.”
The bottom line: we are making progress!
Scientists continue to elucidate the risk factors for and evolution of Alzheimer’s disease. At a microscopic level, significant changes include brain cell (neuronal) death or dysfunction, failure and loss of synapses, formation and extracellular deposition of abnormally processed amyloid proteins, intracellular deposition of abnormal tau proteins, and aberrant inflammation, among others.
Nearly 1,000 abstracts addressed why, how, and when the amyloid pathway goes sour, how to measure it, and what to do about it. Nearly 800 addressed the same questions for the tau pathway. These gains, in turn, have helped identify new biomarker measures and treatment targets.
Genetic risk factors are teaching us a great deal. Three rare autosomal dominant mutations lead, with virtual certainty, to the onset of symptoms of Alzheimer’s at a young age (about age 45). Conversely, even more rare mutations that block amyloid dysregulation are associated with a markedly reduced risk of developing Alzheimer’s symptoms. These data provide a strong rationale for developing amyloid-based therapies.
New data from the Alzheimer’s Prevention Initiative (API) and the Dominantly Inherited Alzheimer’s Network illustrated just how early and in what sequence amyloid and tau measures change. (Amyloid deposits can be discerned as early as 15-to-20 years before symptoms emerge; tau is seen about 5-to-7 years before symptoms.)
Generally similar findings are being reported for the much more common form of late onset Alzheimer’s, for which the APOE4 gene increases risk of symptoms as well as amyloid accumulation. One line of thinking is that the accumulation of amyloid may trigger the tau cascade. Notably, it is the accumulation of tau that is correlated with impaired cognition. (More on this below.)
Biomarkers are booming. Instead of waiting for an autopsy to confirm the presence of amyloid and/or tau deposits, we can now image these in the living human brain with PET scans, and measure the proteins in spinal fluid. Labs are reporting, as well as hinting behind closed doors, that they are zeroing in on batteries of blood tests that can improve detection and tracking of Alzheimer’s. A topical example is neurofilament light chain, which shows a strong correlation with measures of neurodegeneration due to Alzheimer’s as well as other disorders. Stay tuned for the likely possibility of markedly improved biomarkers in the next few years.
At the same time, techniques are evolving to improve our measurement of memory and other thinking abilities. These include self-administered tests for people worried about themselves, as well as measures obtained passively by iPhones, computers, or in-home monitoring devices. Wouldn’t it be remarkable, for example, if measures of our gait speed, navigation in the house, or eye tracking could unveil an emerging brain problem!?
What about treatment?
Arguably the headliner at the meeting was a presentation showing that an immunotherapy targeting amyloid, called BAN 2401, showed robust clearance of brain amyloid with tantalizing hints of clinical benefit as well. This is something of a milestone, as this is only the second anti-amyloid agent to show such results.
A small study showed that another immunotherapy had desirable effects on spinal fluid measures of amyloid. On the other hand, several recent large trials of so-called BACE inhibitors, or oral agents that block production of abnormal amyloid, failed to show benefit in people with symptoms of Alzheimer’s and already-elevated brain levels of amyloid. It may be that immunotherapies could show benefit in people with symptoms of Alzheimer’s and elevated brain amyloid, while BACE inhibitors may have to be deployed earlier. For this reason, the remaining BACE inhibitors are being tested in early symptomatic stages of the disease, alone or in combination with immunotherapy, as well as in prevention trials. The largest prevention effort is the API Generation Program, which consists of two international trials (which are still enrolling) that are studying a BACE inhibitor in cognitively healthy people, between ages 60 and 75, who carry the best-known risk factor for late-onset Alzheimer’s, the APOE 4 gene.
The hope is that intervening very early in the disease process — in people who are at elevated risk but with no symptoms yet — may be the best time to deploy an anti-amyloid therapy, and may preclude “downstream” changes such as tau accumulation, neuronal damage, and possibly, symptoms. This is also the aim of the so-called A4 trial, which is testing an immunotherapy in unimpaired older people with elevated brain amyloid, and of the API Autosomal Dominant Alzheimer’s Disease trial.
An analogy used to capture the amyloid story goes something like this: “Amyloid is to Alzheimer’s as cholesterol is to cardiovascular disease.” It seems to be a key player, but not the only one.
The NIH-funded “SPRINT-MIND” study showed that more intensive management of blood pressure, compared to standard management of hypertension, was associated with decreased incidence of mild cognitive impairment as well as all-cause dementia. Since prior results showed that more intensive treatment was associated with better renal and cardiovascular outcomes, these important new findings might not result in changes in treatment recommendations. They do, however, provide further evidence of the connection between vascular function and Alzheimer’s, and that “what’s good for your heart is good for your brain.”
Finally, and along these lines, there is a steady drumbeat of data showing that diet and exercise may have a big impact on brain health as well. The healthier the diet and the more vigorous the exercise, the better for brain health. Sleep quality seems to matter, perhaps even socialization.
All in all, the meeting provided confirmation that we are getting closer to finding new diagnostic tools, that plausible experimental therapies are being tested in treatment as well as prevention trials, that we need large numbers of volunteers (see endalznow.org to learn about prevention trials), and that new treatment targets are being discovered that will need to be tested in future trials.
Lastly, there is mounting but not incontrovertible evidence that your grandmother was right: eat properly, get some exercise, and go to bed early.
Dr. Pierre N. Tariot is the director of the Banner Alzheimer’s Institute in Phoenix, AZ. He is a research professor of Psychiatry at the University of Arizona.
Disclosure: Dr. Pierre N. Tariot is co-director of the NIH-funded Alzheimer’s Prevention Initiative, which receives support from several pharmaceutical companies.