Why is Alzheimer's Disease Peculiarly Human?

Recent (and not yet fully accepted) evidence suggests that chimpanzees and dolphins might suffer Alzheimer's disease, or at least a condition that is similar enough to be comparable. Other than possibly those two species, humans are the only mammals to experience Alzheimer's, the aggregation of amyloid-β and tau proteins into solid deposits that alter brain biochemistry for the worse. Why is this the case? What is it about our particular evolutionary path that resulted in this outcome? Might that teach us anything that could be used to suppress the development of the condition?

In this article, Alzheimer's is painted as a consequence of antagonistic pleiotropy during the divergence of our species from other primates. Antagonistic pleiotropy is the name given to the theorized tendency for evolution to produce systems that are advantageous to young individuals but harmful to old individuals. Examples include systems that do not maintain themselves well, such as cells that lack enzymes to digest certain harmful forms of molecular waste, systems that have finite resources that run out, such as the adaptive immune system's capacity to remember past pathogens, and systems that interact poorly with the damaged environment of old tissues, causing further damage - which is just about everything else.

While granting human species some advantages over our primate cousins, recent genomic adaptations appear to have come at a cost. "I find the idea that genes that have been involved in the development of the human brain and in making the human brain different from the brains of great apes might also be genes that have the byproduct of raising the risk of Alzheimer's is one of those ironic twists that seem to be pretty common in evolutionary biology."

In 1957, evolutionary biologist George Williams proposed a theory: adaptations that made species more fit in the early years of life likely made them more vulnerable to diseases in the post-reproductive years. However, there has been little research to support his theory. As a test of this theory, researchers started by focusing on enhancers, pieces of DNA with the ability to boost the activities of certain genes, and therefore, the levels of resulting proteins. Previous research had identified enhancers as key to as key to human evolution after diverging from the last common ancestor with chimpanzees. Using FANTOM, an annotated database with information on expression levels of human-specific enhancers, researchers compared human data with that of primates to find the fastest evolving enhancers. Comparisons with primates including chimpanzee, gorilla, orangutan, and macaque genomes revealed 93 such enhancers expressed within neurons and neuronal stem cells that had evolved rapidly in humans.

Genes lying close to these enhancers, and therefore possibly under their control, were important for brain development. It is plausible that the enhancers were positively selected for during evolution because of their effects on these brain-related genes. However, they also found evidence of proximal associations between the enhancers and genes implicated in Alzheimer's, Parkinson's disease, type 2 diabetes, hypertension, and osteoporosis. According to Williams's theory, these aging-related diseases would manifest later in life and would go unnoticed during the Darwinian selection process because of the advantage they bestowed in the early years.

In order to see if there is indeed a functional (rather than merely correlative) connection between the enhancers and aging-related diseases, the team used the Cancer Genome Atlas and GTEx, both large databases, to draw up gene maps highlighting all the genes coexpressed with each enhancer. The researchers targeted one such enhancer associated with brain development and also with genes known to be linked to brain diseases. When the researchers used CRISPR to delete the enhancer in human cell lines, protein abundance from its related genes fell. Importantly, some of these genes are usually suppressed by a gene called REST, which keeps Alzheimer's at bay. However, in the presence of the functional enhancer, these genes are boosted. Thus, while this enhancer may be important for brain development, it seemingly opposes REST's protective function against Alzheimer's.

Link: https://www.the-scientist.com/?articles.view/articleNo/54716/title/Aging-Related-Diseases-May-Be-a-Negative-Outcome-of-Human-Evolution/


High prevalence of Alzheimer's in humans could have something to do with the brain size and the number of neurons. Of course then we works withes it within elephants and cetacea. It could be something about the unique primate metabolism or simply selection bias where in the wild the sick individuals works be dying...

Regardless, the reason is some unfortunate coincidence and the historical average human lifespan of less than sixty years.

Posted by: Cuberat at June 4th, 2018 7:50 AM

Antagonistic pleiotropy always made sense to me and all the performance/longevity trade-offs that crop up seem to be supportive (if not conclusive evidence) of the theory.
It would be interesting to know if this research has implications for Down syndrome (Down syndrome patients have a very high rate of developing Alzheimer's).

Posted by: CD at June 4th, 2018 8:53 AM

Looks like fitting the data to a pre-conceived idea to me. Antagonistic pleiotrophy only works if evolution CANNOT find a way around it. Clearly evolution can increase both fertility and longevity for example, (proven in flies) long supposed the strongest of opposing forces in evolution.

I expect that evolution is also currently selecting for a lower rate of Alzheimer's disease in humans, because even if only a few men have children late in life, this will still be enough to drive the incidence down. I don't see the children of older men without Alzheimer's somehow being less intelligent.

The only thing that is peculiar about humans is that we live so long for our body size. This means we experience things like immuno- senescence and other things that probably contribute to AD.

Posted by: Mark at June 4th, 2018 10:48 AM

Presumably you are referring to laboratory studies, where the flies are not exposed to the natural environment and all its vagaries (various changing parasites and other predators, changing temperature, variation in food type and availability, etc.) Antagonistic pleiotropy is meant to address evolution in natural environments.

You would not notice lower intelligence in people without Alzheimer's (or their children); lower IQ is a risk factor for Alzheimer's and so is, as I pointed out, Down syndrome. Down syndrome patients have impaired neurogenesis, but other developmental disorders display increased levels of early neurogenesis and macrocephaly (e.g., autism spectrum disorders). Comparing changes in brain development across species is quite a bit different from looking into variations in brain development patterns and pathologies within a species, though it would be interesting to know exactly what those differences are.

Posted by: CD at June 4th, 2018 11:56 AM

Yes I'm referring to lab fly experiments. You're suggesting that selecting for longer lived flies, which also produces greater fertility in the lab, would produce fies unsuitable in a natural environment? That may be so; I merely pointed out that fertility and lifespan, which are often inversely correlated (particularly in mammals), need not be so. That is a problem for the antogonistic pleiotropy 'nature couldn't do any better' argument.

As for intelligence and Alzheimer's, I agree there are too many factors to pin down a relationship; I think it is unlikely selecting for greater intelligence must also select for late life dementia.

Posted by: Mark at June 4th, 2018 12:34 PM

The antagonistic pleiotropy theory of Williams does not imply that lifespan cannot be extended through technology, though I have seen this notion suggested by Stephen Stearns of Yale. He is, of course, wrong. Unfortunately I have found that many apparently intelligent and erudite professors lack imagination; there is probably something in the selection process in academia that causes this to be the case. I do think that attempting to merely tweak certain pathways could* result in engaging in a kind of physiological whack-a-mole, which is one of the reasons why SENS seems necessary for radical life extension (the other is that there are age-related types of damage for which humans seem to have no innate repair mechanisms).

* I say 'could' since George Church has stated that he has seen some remarkable results from altering the function of just two genes ... in lab mice, of course.

Posted by: CD at June 4th, 2018 3:47 PM

Agreed - academics are largely conservative and reputation sensitive, hence they are unlikely to say or do anything too revolutionary that could see us defeat aging anytime soon. Nonetheless there are some very good papers on aspects of aging out there for more ambitious types to use as a spring board to effective therapies.

I think you are probably right and that as we push out the limits of healthy aging, say by telomere elongation/stem cell replenishment, senescent cell clearance, etc., we will come up against other barriers; various metal accumulations, other imperishable products of metabolism, which would eventually kill even someone otherwise kept perpetually youthful. It is hard to say whether Alzheimer's is a consequence of that or simply the failure of youthful levels of amyloid clearance. I suspect failure of clearance is most of it, but perhaps some form of dementia would eventually occur regardless.

Posted by: Mark at June 5th, 2018 2:44 AM

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.