Puzzling out Alzheimer's Onset

"Humans co-evolved with a number of different parasites, but today, in our sedentary city life, we've removed those parasites from the mix."
"It doesn’t make sense. You’d have thought that natural selection would have weeded out ApoE4 a long time ago. The fact that we have it at all is a little bizarre."
"That’s the big problem with gene-environment studies. In most hunter-gatherer populations, there just aren’t enough older individuals. The Tsimane are an interesting test case because more than 1,300 are over 40. And since they have no birth control, and now access to metal axes and motorized canoes, they’re growing faster than the baby boom in the U.S. That’s one of the reasons we started working with them."
"This highlights the importance of accounting for the wide variety of environments in which humans lived for most of our evolution, [perhaps the variant’s benefits have since diminished as societies embraced sanitation, clean water, and refrigeration], and in which we currently live. Post-industrial city life is just a blip in our history."
"This may be our last chance to understand whether chronic conditions of aging like Alzheimer's and cardiovascular disease have always impacted humanity, or whether they're connected with industrialization."
Dr. Ben Trumble, anthropologist, evolutionary disease, Arizona State University

"Ten years ago, very few scientists were looking at whether the immune system was related to Alzheimer's, but that question has just exploded."
"At every scientific meeting I'm at, everyone's talking about this question: Why are some people with lots of amyloid plaques -- the people who, according to our models, should get Alzheimer's -- protected from this runaway immune response? I think the answer will come from looking at immune cells of humans around the world living in different environments."
"For our ancestors, an ApoE4 gene could have been beneficial. [This new focus will lead to] a rapid production of effective treatments [for Alzheimer's.]"
Dr. Shane Liddelow, co-author, published study

Edgard Garrido / Reuters   A researcher holds a brain with Alzheimer's disease

As a case study, an indigenous Bolivian people called the Tsimane whose lifestyle continues to resemble how they lived aeons ago as hunters and food-foragers, presented Dr. Trumble with a living laboratory. A people with the ApoE4 gene named popularly the Alzheimer's gene, and despite their carrying the gene, their cognitive tests results were outstanding. Parasites affect about 70 percent of the Tsimanes; they host gut worms, other types of parasites burrowing into their skin.

This combination inspired Dr. Trumble to consider, might infections such as this alter the genes that affect our bodies? Might it mean that the ApoE4 gene was endowed by nature as an advantageous addition to aid survival in hostile environments? A single copy of the ApoE4 gene has been inherited by roughly 24 percent of any population, with about two people in a hundred carrying a double dose of the gene; translating to making them ten times likelier to develop late-onset Alzheimer's.

Ancient bones undergoing DNA analysis reveals that thousands of years ago the ApoE4 gene which also generates cholesterol -- in evolutionary terms a critical function of larger energy-requiring brains being developed -- was present in humans and likely because it had a vital role defending brains from pathogenic invaders. Dr. Trumble had discovered that all Tsimane volunteers testing positive for parasites also had better cognitive health, leading him to conclude that those with infections remained likelier to exhibit mental fitness, carrying or or two copies of the gene.

The ApoE4 gene now considered by modern medical science as a sign of the "Alzheimer's gene" was back then an advantage in protecting the brain from decline. Those within the studied population in Bolivia, with the ApoE4 gene, whose systems were free of parasitic infection experienced cognitive decline. Dr. Trumble's findings leading to his theory are matched by research coming out of other university laboratories.

In 2016 and 2017 dementia was being studied by scientists not merely as a disease culminating from gradual cell breakdown, but as a disorder where the brain turns against itself. At Northwestern University in Evanston, Illinois, Dr. Changiz Geula, professor of neuroscience, discovered some individuals with sharp minds who die over age 90 have brains clogged with the plaque associated with Alzheimer's pathology.

To the educated mind in this abstruse scientific study this translates to the position that one can possess an "Alzheimer's brain", without dementia resulting. In instances such as this, believes Dr. Geula, some function in the brain protects neurons from damage, and it could be the astrocytes -- cells whose function it is to support neurons and synapses -- maintaining them in a healthy state even where plaques and tangles exist.

Researchers from Stanford University in California described these cells flipping into a "killer mode", in a 2017 paper published in Nature, thus transforming into killers spewing toxins, destroying the cells they were tasked to protect. This propensity of the astrocytes to change from benign to harmful likely developed thousands of years ago so they could fight infections invading our ancestors' brains, according to Shane Liddelow.

The reaction of the astrocytes when danger enters the picture of the brain's system, is to attack, destroying everything they encounter; unfortunately sometimes including healthy brain tissue. In current lifestyle circumstances where people live in fairly sterile environments this function no longer fights pathogens, responding instead to the amyloid plaques and tangles, part of normal aging.

Dr. Liddelow is convinced the hypothesis of the ApoE4 gene as a brain-protection evolutionary response to the presence of parasitic infection represents an acceptable interpretation. His study partner, Dr. Trumble, anticipates his work may lead to treatments beneficial to those suffering from dementia. He envisions designer parasites to reflect for the brain what cancer scientists are working on in designer viruses to attack tumours.

He believes that exposures to infections act as an inoculation against brain damage. "I don't know. I'm definitely not going to run out and infect myself with more parasites, since the science isn't there yet, [but] I certainly hope, before I get to age 80, w are able to figure out the mechanism [behind a pathogenic therapy."