Fixing a broken bone is straight forward, you bring together the bones with the aid of a cast and eventually your body will “weld” the pieces together. But what about a more complicated disease like Alzheimer’s? Alzheimer’s is characterized by proteins that misfolded and aggregate creating a “sticky” substance that blocks the pathways in the brain, this creates roadblocks that make the connections in the brain that signal movement and even memories less than optimal.  This is not as straightforward to fix as setting a bone. If the topic for this post is evolution, why did we evolve to develop these misfolded proteins?
The largest known genetic risk factor for developing Alzheimer’s disease is having multiple copies of the Apolipoprotein E4 gene, this lipoprotein gene is inherently pro-inflammatory. Having constant inflammation was an advantage for our tree dwelling ancestors that began to venture and explore the land. Walking around meant interactions with more and more microbes, we needed to have continuous inflammation to be able to “neutralize” these new pathogens. It also meant that they could feed on carcasses, and since their immune system was constantly on alert, they were able to take advantage of this dense (and dirty) source of nutrition.  This makes total evolutionary sense!
Fast forward to our current environment, we do not have the constant microbe pressure, our world is more sterile, and our APO-E4 adaptation is now mismatched to our environment. This is not a maladaptation; a maladaptation would be something that more than likely would be incompatible with life. The APO-E4 is an adaptation that is not fit for our current environment. We will refer to these “maladaptations” as mismatches.
Let’s look at an example of mismatch. Beebak and Makolo, two gorillas at the Cleveland zoo experienced a really bad case of mismatch when they were taken from their natural environment and into captivity. They began to experience what can only be described as “stress”.  They began to gain weight, have heart problems and they even began to pluck their hair, a behavior never seen in the wild.
The zookeepers had a few options. They could give the gorillas toupees; they could strap them down to prevent the hair picking or they could fix the mismatch. They started to feed the gorillas food that resembled their natural diet, and lo and behold, the symptoms began to disappear. Since gorillas are endangered, sending them back to their natural environment was not an option, the scientists minimized the effects of mismatch by changing their nutrition.
Back to Alzheimer’s! Having multiple copies of Apolipoprotein E4 is not a sentence for dementia. Only about 14% of the population have this gene, and of that small subset, only 37% of the APO-E4 gene carriers actually develop Alzheimer’s.  The mismatch is simple, we live in a cleaner world, and we don’t need a pro-inflammatory gene to keep us safe. Since we cannot change the world (face it, you don’t want to live in a world without sewage systems) you should look at feasible ways to decrease your risk. For example, factors that increase incidence of Alzheimer’s in people that have the APO-E4 variation are high cholesterol and low physical activity [5,6]. Apo-E4 carriers that lower their high cholesterol and increase their physical activity will lower their chances of getting Alzheimer's, no need to eat rotten meat.
Now let’s look at another condition that might be abnormal because of mismatch. A study found that hunter gatherers with ADHD were better nourished than those who did not show this trait.  This makes perfect sense to me, the people that demonstrated this trait are probably more impulsive and more likely to explore and thus find more sources of nutrition.  In our mismatched world, we tell kids with the ADHD trait to sit at a school desk for five-hours a day concentrating on a lecture. When they don’t behave, we medicate them. We should help these kids explore and take advantage of their genetic advantage.
Finally, one of the presenters at the Ancestral Health Symposium in Boulder Colorado asked the audience to “raise their hands if they were wearing gloves”, no one raised their hand, then she asked “raise your hand if you are wearing shoes”. Almost everyone raised their hand. Then she proclaimed “Shoes are not Paleo”. This got me thinking. Imagine all of the mismatches that we create in our daily life, that could be easily surpassed if we just took into consideration our evolutionary adaptations. Maybe we would not need medicine as we know it.
1. Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell. 2012;148(6):1204-1222. doi:10.1016/j.cell.2012.02.040.
2. Antón SC. Natural history of Homo erectus. Am J Phys Anthropol. 2003;Suppl 37:126-170. doi:10.1002/ajpa.10399.
3. Less EH, Bergl R, Ball R, et al. Implementing a low-starch biscuit-free diet in zoo gorillas: the impact on behavior. Zoo Biol. 33(1):63-73. doi:10.1002/zoo.21116.
4. Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 278(16):1349-1356. http://www.ncbi.nlm.nih.gov/pubmed/9343467. Accessed August 28, 2016.
5. Notkola IL, Sulkava R, Pekkanen J, et al. Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer’s disease. Neuroepidemiology. 1998;17(1):14-20. http://www.ncbi.nlm.nih.gov/pubmed/9549720. Accessed August 28, 2016.
6. Raichlen DA, Alexander GE. Exercise, APOE genotype, and the evolution of the human lifespan. Trends Neurosci. 2014;37(5):247-255. doi:10.1016/j.tins.2014.03.001.
7. Eisenberg D, Campbell B. Medicine for Midlife The Evolution of ADHD.
8. Shelley-Tremblay JF, Rosén LA. Attention deficit hyperactivity disorder: an evolutionary perspective. J Genet Psychol. 1996;157(4):443-453. doi:10.1080/00221325.1996.9914877.