The AAIC 2021 meeting of dementia scientists featured several plenary lectures, selected for importance: amyloid-focused therapy, tau in neurodegeneration, innate immunity, social / diversity / education issues, molecular changes in exercise, and biomarkers (not to mention COVID-19). Is there a way to bring those topics together to effectively treat dementia?
Alzheimer’s dementia (AD) is a devastating puzzle of brain destruction that legions of brilliant doctors and scientists worldwide have tried to solve. It affects millions, but does not seem contagious or have an obvious cause. The good news is that some recent studies show that the incidence of new AD cases may be decreasing in first world countries (although the Alz Assn reports that the prevalence will triple worldwide by 2050).
At first glance, AD science presented at meetings seems to be all over the universe, with little that ties concepts together. It might be useful and satisfying to bring disparate research perspectives together, to plan therapeutic priorities. Can Einstein’s historical quest to create an overall theory in physics be a guide?
Einstein had already described general relativity and predicted the existence of black holes by 1916, then famously spent the last decades of his life trying to bring together threads of physics into a unified field theory, one which would combine electromagnetism and the characteristics of relativity in space, time, and gravity (string theory came later, haha). He didn’t succeed, and no one has since then.
How is that related to AD therapy research? One might say that dementia has been a black hole in which candidate drugs get sucked in and disappear. Aside from aducanumab, an anti-amyloid therapy approved with controversy this year, there is an extensive list of over a hundred failed clinical trials. With that metaphor now out of the way, are there other potentially unifying theories on the root cause of AD, to target and exploit?
The prevailing Amyloid Cascade Hypothesis has serious skeptics as a root cause or unifying theory for dementia. For example, amyloid beta is not as abundant in football players’ cognitive issues (as much as tau), or in veterans’ brain trauma [where amyloid might be transient (!?), again with tau predominating], and amyloid can also be found in older folks with normal cognition. Perhaps it’s worthwhile to re-examine basic characteristics of AD, and if not unify them, weave them together a bit, to see if other insights into proximal causes or pathways for novel therapies might be gained.
The National Institute on Aging says that there is no one specific gene problem in typical AD, suggesting it might be polygenic, with multiple “risk factor” genes involved. AAIC sessions suggest that not all risk factors are genetic; some might be situational, social or environmental. Diabetes and atherosclerosis are also thought to be polygenic, with a delay in problems that can take decades…but that may also allow a multi-pronged approach over time.
AlzheimerGadfly will present some observations and descriptions of characteristics that seem puzzling, but could be clinical aspects to unify. Considering naive questions in this arena might be an interesting exercise [with an oncologist’s comments, an obvious non-neurologist, in brackets]:
- Initial signs and symptoms are usually vague or minor [many neurologic diseases, like stroke, seizures or tumors are specific]: the affected person might be self-aware, but what folks notice are subtle judgment problems, math issues, time to complete tasks, or recent memory recall, in the context of otherwise normal functioning.
- AD is relentless and progressive [MS and ALS are too, but many neurologic diseases are “static” and don’t change much]. It’s damn slow, though. In fact, preservation of skills for a time can include social interactions, self-care, the five senses, muscular abilities, general communication, sense of humor, work performance and even driving. Early Onset AD is thought to be a low percentage of the AD population, but it seems to have the same set of functional losses; it’s unclear whether the progression is faster or slower. [But what delays the onset for decades, and what keeps the progression on-going? Serial brain imaging seems to show a pattern of progression, but how and why? Neither brain infections nor leptomeningeal metastases spread like that. Is it glial or neuronal “recruitment” in a bad way? Might there be a way to stop the spread?]
- Cognitive activities seem to be affected in a patchy manner [almost like being depressed, drugged or drunk]. Variations are seen in specific functions and duration (days in which things are better or worse). The patchy nature seems to defy localization [and neurologists love localization]. Skills also seem to decline at different rates over time. [ The “trajectory” of decline is given to individual variation, but the overall outcome seems the same. Perhaps some folks are just better at compensating for declining skills. In late stages, when many higher functions are lost, core functions seem more preserved, giving the appearance of a “locked in” syndrome].
- Behavioral and mood issues seem to wax and wane [manifestation of changing positive / negative feedbacks, or “inner strife and frustration”?] This includes wandering, verbal / motor agitation, personal aggression and / or apathy. Some call them BPSD, Behavioral and Psychological Symptoms of Dementia. Mood issues, from weeping to laughing might be considered appropriate, or might be forced and sardonic. [Do symptoms seem to disappear only because of the loss of ability to express them?]
- AD seems to affect one system mainly, the central nervous system [unlike systemic AL amyloidosis, affecting the heart, kidneys and liver]. In AD, the cerebrum is typically more affected than the cerebellum until late stages, and it seemingly spares the peripheral nervous system, heart, lungs, kidneys, skin, etc. [Maybe that’s the blood-brain-barrier in reverse, or is the cerebrum uniquely vulnerable?] Other body systems seem to maintain themselves at baseline (wound healing, infection fighting, endocrine metabolism, heart-lung and kidney function, digestion, elimination, etc).
- Conventional medicine has been frustrating and frustrated in AD [especially compared to cancer medicine]. With all the advances in chemo- and immunotherapies, the AD medicine chest seems bare. Last year alone in 2020, FDA approved 16 new cancer treatment indications. Over the past twenty-one years, FDA has approved only five separate drugs for AD: rivastigmine 2000, memantine 2003, galantamine 2004, donepezil 2010, aducanumab 2021. The first four are considered symptomatic treatments, not curative, and three are in the same class (cholinesterase inhibitors); one combination agent approved doesn’t count.
So, an oncologist finds AD unlike many other diseases, and quite confusing (not surprisingly). Not to mention its nomenclature: DSM-5 folks want to call it “major neurocognitive disorder,” ICD-10 gives dozens of synonyms, and AD imaging folks want to create a classification based on PET/MRI scans (the AT[N] system).
AlzheimerGadfly will stop at six characterizations, in deference to Pirandello’s absurdist chaotic play Six Characters in Search of an Author, hoping this story won’t also turn out to be a tragedy.
Maybe the characteristics in Alzheimer’s don’t need a unifying theory, if someone could just find a treatment that really works, stops progression, and then figures out effective rehabilitation. The brain can remain a “black box” and keep its absurd secrets. Perhaps the group in St. Louis, with McDade’s review and “call to arms”, can coordinate the strategy, but they seem to be focused on the worthy goal of prevention, rather than treatment.
And OK, we don’t have a unifying theory of cancer proliferation, but we have ways to halt progression. Even without knowing specific etiologies in childhood lymphoblastic leukemia, we cure >90%. Kids and families don’t care about theories anyway, but are grateful for things that work. It all seemed to start with an observation that young patients seemed to get worse on folic acid vitamins. Back in the 1940’s, who could imagine the medical successes in cancer?
Even without Einstein’s Unified Field Theory, astronauts made it to the moon and back, billionaires can get into nearer space and back, and folks send successful probes into deeper space. One hears that most of the useful computations necessary to accomplish all that are basically Newtonian (centuries old).
The NIH is spending ~$3B on AD research, so maybe someone will do something a little old school, align some stars, set up to start with observations, try to find effective therapies for symptoms empirically, and hope to help some folks halt their progression, repair a few functions, and maybe even help get them their cognitive bearings again.
Some of Einstein’s contemporaries thought his quest for a unified field theory was quixotic and maybe even misguided. Perhaps the idea of discovering an AD “cure” is just as unrealistic; on the other hand, with aducanumab somehow skirting around scientific futility criteria to get approved and its true utility still to be determined, it might be a first step.
Einstein once said: “Imagination is more important than knowledge. For knowledge is limited, whereas imagination embraces the entire world, stimulating progress, giving birth to evolution.” [Calaprice, The Expanded Quotable Einstein, 2000 ed., pg 10].
So imagining a cure, like in the early days of cancer therapy, might be worth thinking about, even as time squeezes us into a space tightly defined by the gravity of our limits. (Yeah, too cutesy, but YOLO, right?)
