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.