Alzheimer's Disease as a Condition of Many Subtypes and Contributing Causes

Neurodegeneration in late life is a very complex phenomenon, and its complexity strains against the nice neat clinical definitions of disease found in the textbooks. Different patients with Alzheimer's disease can exhibit quite different mixes of various forms of pathology, developing at different paces and times: aggregates of amyloid-β, tau, and α-synuclein; vascular degeneration; markers of neuroinflammation; metabolic disruption similar to that of diabetes, and so forth. One case of Alzheimer's might be different enough from another to require a different designation. Thus researchers talk about defining subtypes of Alzheimer's disease, or that individual patients have Alzheimer's that is exacerbated by a comorbidity arising from other neurodegenerative processes.

Another way of looking at this is to categorize mechanisms that contribute to Alzheimer's. To what degree is a given set of mechanisms important in a given patient? A sizable amount of work has gone into investigation of processes and feedback loops other than the primary amyloid cascade hypothesis of the condition. It is an open question as to where all of these contributing aspects of the condition fit into a chain of cause and consequence, or whether the ordering of that chain is similar from patient to patient. Alzheimer's disease may well be a collection of distinct conditions that all happen to wind up in a similar end state.

The authors of this paper draw the gloomy conclusion that this complexity, and continued failures in the development of therapies based on the amyloid cascade hypothesis, imply that there are no silver bullets. I would argue otherwise, and say that instead comparatively simple points of intervention have not yet been developed fully. Senolytic therapies that clear senescent glial cells from the brain seem quite effective in animal models, for example. The approach of restoring lost drainage of cerebrospinal fluid, to clear out aggregates from the brain, also looks promising. There will be others. The complexity of aging emerges from simpler root causes, and there will always be some clever way to intervene at a point of maximum leverage.

Multi-Loop Model of Alzheimer Disease: An Integrated Perspective on the Wnt/GSK3β, α-Synuclein, and Type 3 Diabetes Hypotheses

Alzheimer's disease (AD) is among the most ominous of modern health epidemics. AD is not alone in its ascent. Other chronic diseases, particularly Parkinson's disease (PD), a neurodegenerative disorder associated with the build-up of α-synuclein protein and death of dopaminergic neurons, and type 2 diabetes mellitus (T2DM) are increasing in prevalence at similarly alarming rates. Although AD, PD, and T2DM share common risk factors, chief among these being age, there is more to their relationship. Evidence suggests that the pathophysiological mechanisms underlying AD, PD, and T2DM interact synergistically.

In addition to the well-known amyloid cascade hypothesis of AD, other hypotheses have been proposed that include: (1) the Wnt/Glycogen Synthase Kinase 3β (GSK3β) hypothesis, (2) the α-synuclein hypothesis, and (3) the type 3 diabetes hypothesis. Dsfunctional Wnt-signaling can contribute to the development of AD and its two pathological hallmarks, plaques and p-tau tangles. The canonical PD-associated protein α-synuclein may be locked in pathological positive feedback loops with Aβ and tau. Finally, insulin resistance in the brain, "type 3 diabetes," may contribute to development and exacerbation of AD. Each model interacts with the others. These interrelationships, make it clear that the pathology of AD is not a linear cascade, nor a simple feedback loop, but rather a network of cross-talking models and overlapping vicious cycles.

Given the cooperative and reinforced nature of this complex network, it is no surprise that the prototypical monotherapeutic approach to AD has reliably failed. Certainly, drugs that target key nodes within the network, such as GSK3β inhibitors or AKT activators, have shown promise in animal models, and this important work affords us valuable mechanistic insights. However, these pre-clinical successes generally have not translated into clinical success, at least not with the same degree of efficacy. This is likely because animal models harboring distinct AD-causing mutations and dysfunctions in particular linear pathways do not accurately recapitulate the complex pathologies underlying sporadic human AD. In brief, we are proposing that the single-target silver-bullet approach to AD drug discovery is doomed to fail and that we may only be able to treat or prevent AD by developing new multifaceted treatment options.

Comments

I'm quite annoyed by the term "Alzheimer's" and think this disease is best referred to by its original designation of "senility".

Posted by: Zan at September 29th, 2019 8:36 PM

"The complexity of aging emerges from simpler root causes, and there will always be some clever way to intervene at a point of maximum leverage."

Does it? I think what we know about aging at this point suggests that's only close to being true in tissues that actively turn over in their entirety, and there are many tissues where certain ECM components aren't turned over. In cases where there's complete turnover, we can collapse all the numerous and varied forms of stochastic damage to the phenomena of clonal drift and the loss of the epigenetic information which encodes the youthful phenotype; on that front there is cause for optimism as work with iPSCs gets us closer and closer to conclusively showing that old cells without functionally significant base pair level alterations to DNA can be made "good as new" through interventions which can be achieved in vivo.

However, in tissues which do not fully turn over, we see species of damage so numerous and varied that trying to target them all may be futile, even if it's still worth trying. We can hope that there will be some that have a higher impact than others, but my suspicion is that there is not going to be many (or any) silver bullets found in conventional damage repair approaches, which don't actually differ very much or at all from conventional geriatric medicine; whether it's amyloids, oxysterols, glucosepane, or lipofuscin, clearance of these damages by cell, gene, or pharmacological therapies may not have effects on lifespan that are more substantial than dietary or lifestyle interventions or pharmacological interventions which imitate those. They may enable us to close the book on individual diseases that are due in large part to a specific kind of damage.

Induced regeneration of tissues which are not normally capable of turning over during adulthood (see the recent work on in vivo reprogramming of astrocytes into functional neurons), perhaps in concert with other reprogramming therapies and transient telomerase expression coupled with targeted destruction of dysfunctional and senescent cell populations seems likely to be the only feasible way of addressing degenerative aging as a whole instead of just treating symptoms or individual pathologies.

but that will come at a price, specifically the risk of cancer, and while that may be partially alleviated by rejuvenation of the immune system, it cannot be perfect, and any increase in imperfection with time will invariably lead to either degenerative or hyperplastic aging. At what point this fundamental dilemma facing multi-cellular life becomes a limiting factor for humans is uncertain; we observe species like the Greenland Shark which are capable of living for >400 years, but we have a faster rate of metabolism than them, are already the longest lived land animal mammal, and have exceptional longevity for our body size and metabolic rate.

The fact that cancer rates start falling off with extreme age is potentially suggestive of this already being what limits human lifespan; if this is the case those who have greater intrinsic rejuvenation capacity die of cancer in their 70s or 80s, those who have less and manage to escape specific diseases can go further, but only until their body gives out from stochastic damage.

now, there's a potential way around this dilemma through the use of exogenous cells with artificially curated genomes to replace increasingly dysfunctional endogenous cells (and to gain the benefits of continuous growth without the drawback of increasing energy requirements that eventually kills lobsters), proposed methods of stabilizing the genome against clonal drift, and conventional oncology that's good enough to be nearly bulletproof against all types of cancer. But nowhere will you find a silver bullet, something that serves as a quick and easy solution to the problem of aging.

These damage clearance strategies may have merit in things like microplastic bioaccumulation (and other sorts of bio-accumulation processes involving manmade substances) should that turn out to have adverse health effects that require a solution. In specific diseases it may be beneficial, and it may have substantial benefits to the extent that we might be able to remove damage that constrains regeneration or rescue systems like immune surveillance that appear to play a key role in quality control, so I certainly don't oppose these research directions, but we must be realistic about what they can achieve.

Posted by: Dylan Mah at October 2nd, 2019 12:06 PM

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