Scientists have demonstrated that “the Alzheimer’s allele” APOE e4 helps cognition earlier in life prior to the onset of the disease [1]. This might point at a possible reason for some aspects of aging.
What makes us stronger kills us later
The risk of developing Alzheimer’s, one of the deadliest age-related diseases, is considerably elevated in people carrying one of the four alleles of the APOE gene: APOE e4 [2]. People heterozygous for this allele have a three to four-fold higher risk of developing Alzheimer’s, and homozygous people have a 12 to 16-fold higher risk. APOE e4 is also the ancestral allele, the oldest one among the alleles of this gene.
If APOE e4 is so harmful, why wasn’t it weeded out by evolution long ago? The answer might be antagonistic pleiotropy. This theory of aging stipulates that some genetic variants might be beneficial earlier in life and become deleterious only in old age, which is why they keep being passed down from generation to generation. If something helps us while we are young, from the standpoint of evolution, it does not matter if it kills us later. As cruel as it sounds, nature does not seem to care what happens to us past our reproductive age.
Scientists have already found some evidence in support of this theory. The peculiar case of APOE e4 might be another piece of it: a group of researchers has just shown that people with APOE e4 enjoy an advantage in some cognitive tasks over people with other alleles – at least prior to the development of clinical Alzheimer’s.
What was where?
The researchers recruited around 400 people from the longitudinal British study Insight 46, so called because it involves people born in one week back in 1946. These people have been periodically assessed by scientists since they were children, which makes it one of the longest-running longitudinal studies in the world. This enabled the authors of this new paper to control for various factors, such as childhood cognitive ability and lifestyle.
The age of the participants provided an additional benefit: at this age, the rates of dementia are still low, but a substantial proportion of people are already showing signs of preclinical Alzheimer’s disease. This enabled the researchers to catch the moment when both the beneficial and the deleterious effects of APOE e4 are visible. The idea of documenting the interplay between those effects also dictated exclusion from the study of people who had already developed severe cognitive symptoms. Of the 398 subjects who made it to the study, 120 – around 30% – carried the APOE e4 allele.
Alzheimer’s is strongly associated with the accumulation of the protein amyloid ß in the brain. The beginning of this accumulation precedes the clinical stage of the disease by several years. Not surprisingly and consistent with previous research, subjects carrying APOE e4 showed abnormal amyloid ß accumulation much more often: in 37.5% of the cases vs. 9.7% among people with other alleles.
What was surprising, though, is that APOE e4 carriers actually fared better in a cognitive test that involved seeing objects on the screen for a short time and then correctly recalling their shape and location (the so-called What Was Where test). In this test, people with abnormal amyloid ß levels on average fared slightly worse than the others, but this effect was not pronounced enough to offset the seeming benefits of APOE e4. Yet, the results suggest that later in life, the balance probably shifts, with the “dark side” of the allele taking over.
Not the only advantage
This was not the first study that showed APOE e4 having some benefits for its carriers. Several advantages have been previously reported, including increased fertility, resistance to infections, decreased perinatal and infant mortality, and also some slight cognitive advantages [3].
Certainly, this is not an ironclad proof of the antagonistic pleiotropy theory of aging. Cognitive ability has many faces, and one test can only get us so far. We also cannot know how significant the cognitive advantage that APOE e4 seems to provide is in terms of survival. The study itself had some limitations – for instance, it only included people who were willing and able to visit a research facility, and this created a selection bias. The researchers also wish they had more subjects who are homozygous for APOE e4, but such people are a rarity.
Conclusion
This study provides evidence that antagonistic pleiotropy is a factor in aging. How much of a factor it truly is remains to be seen, but at least it offers an interesting explanation as to why nature seems to be focused on killing us after we stop reproducing.
Literature
[1] Lu, K., Nicholas, J. M., Pertzov, Y., Grogan, J., Husain, M., Pavisic, I. M., … & Crutch, S. J. (2021). Dissociable effects of APOE e4 and ß-amyloid pathology on visual working memory. Nature Aging, 1-8.
[2] Frisoni, G. B., Manfredi, M., Geroldi, C., Binetti, G., Zanetti, O., Bianchetti, A., & Trabucchi, M. (1998). The prevalence of apoE-e4 in Alzheimer’s disease is age dependent. Journal of Neurology, Neurosurgery & Psychiatry, 65(1), 103-106.
[3] Rusted, J. M., Evans, S. L., King, S. L., Dowell, N., Tabet, N., & Tofts, P. S. (2013). APOE e4 polymorphism in young adults is associated with improved attention and indexed by distinct neural signatures. Neuroimage, 65, 364-373.
