Most of us have wondered about what causes Alzheimer’s. As commonly happens, we stumble badly when we make assumptions, even in asking questions, let alone in trying to answer those questions. The question “what causes Alzheimer’s?” presupposes that there is a single such disease (Alzheimer’s) and that we can define it well enough to ask […]
Alzheimer’s: One Disease?
Most of us have wondered about what causes Alzheimer’s. As commonly happens, we stumble badly when we make assumptions, even in asking questions, let alone in trying to answer those questions. The question “what causes Alzheimer’s?” presupposes that there is a single such disease (Alzheimer’s) and that we can define it well enough to ask about “its” cause. Neither of these is probably an accurate assumption. The reality is that there is considerable difficulty in agreeing on the “hallmarks” (the pathognomonic characteristics that define AD) and the “boundaries” between AD and other somewhat similar diseases on the differential diagnosis. Comparing Alzheimer’s to many other age-related neurological diseases can be humbling – and it should be. Small wonder we have so much trouble understanding the cause, let alone finding a cure when we don’t really know what we’re looking at.
Rather than just reinforce our preconceptions, let’s look at reality a bit more closely.
One of the things that has become clearer over the past century – and especially so over the past two decades – is that there is a remarkable amount of overlap in the pathology found in what we have thought of as different age-related neurological problems. This has become grudgingly accepted as we compare not only Alzheimer’s and Parkinson’s disease, but a host of other clinical problems, such as microvascular infarcts, vascular dementia, frontotemporal dementia, hippocampal sclerosis, Huntington’s disease, amyotrophic lateral sclerosis, dementia with Lewy bodies, and mixed dementia (a term that sort of sums up the problem we’re discussing). Just to restrict ourselves to the two classic diseases – AD versus PD – Alzheimer’s tends to have primarily cognitive rather than motor problems, whereas Parkinson’s tends to have primarily motor rather than cognitive problems. In reality, however, both Alzheimer’s and Parkinson’s patients tend to have some of both, particularly as their diseases progress. At the histological level, we tend to distinguish the locations of each disease, and at the neurochemical level we likewise make distinctions, yet there still remains overlap at almost any level, once we look more carefully.
Perhaps there is a single, common, underlying causative pathology that results in BOTH of these diseases. Could both AD and PD be two different manifestations of a shared problem?
This same question surfaces when we look carefully at the vascular dementias: they overlap in many ways with the classical “non-vascular” etiologies. Again: could all of these have a common underlying factor with disparate clinical presentations? We see the same problem when we look at age-related neurological dysfunction in animal models, such as laboratory-created Alzheimer’s models in mice, as well as the “normal” decline in any wild species (such as mice or rats). We go to a lot of trouble to introduce human genes into laboratory species in order to produce a “mouse model of Alzheimer’s”, yet these animals show behavioral declines even in the wild and when we introduce human genes, it’s certainly not clear that we end up with a mouse model that teaches us anything useful when we want to find a cure.
We could put all of these clinical changes together by positing that they derive from a common cellular problem, that of cell senescence. Different patients have different genes and different patterns of gene expression, so their disease expressions differ, some having AD, some having PD, some having any number of other disease phenotypes. Different animals (humans versus mice, for example) likewise have differing genetic and epigenetic settings, so their disease expressions also differ, humans showing beta amyloid and tau protein changes, mice showing a different pattern, but all showing behavioral and cognitive decline over time, whatever the individual pathway the pathology uses to express itself.
Consider our diagram of the “Common Pathological Pathways in Age-Related CNS Failure” (see figure A). The proposition illustrated in this diagram is that of a single underlying problem, with multiple possible pathways, and a shared outcome: age-related CNS failure. One cause, multiple pathways (often defined as different diseases), but one outcome. Whatever the pathway chosen, the outcome is an increasing neurological dysfunction with age.
In the case of particular diseases (or particular species), the clinical phenotype depends on which cells are senescing fastest (e.g., glial cells in the brain, endothelial cells in the arterial tree, etc.) and which protein products (e.g., beta amyloid, tau protein, alpha synuclein, etc.) are most likely to cause problems first, depending upon the genetic landscape and the epigenetics of the individual patient or the individual species. If we now label the common diagram with specific diseases and species, we get something like the second diagram (see figure B).
If we really want to understand, and cure, Alzheimer’s, then we need to start by understanding (and curing) our own preconceptions. It is only when we look at not only the clinical data, but a wide panoply of species that we can truly understand any of the diseases that we see day-to-day.
One cause, multiple pathways, and a single shared outcome: CNS failure.
Curing Alzheimer’s becomes – as it has been for a century – a fool’s errand if all we target are the specific genes and proteins that we (naively) think of as the hallmarks of the disease. If we truly want cure Alzheimer’s, then it’s time we understand the disease and it’s high time we target the actual causes of not only Alzheimer’s disease, but the entire spectrum of age-related neurological diseases that should be labelled under a common rubric, diseases of cell senescence.
It’s time we understand Alzheimer’s and time we cure it.