An analysis of 22 large-scale gene expression datasets pointed to exercise and activity in general as the most effective theoretical treatment for reversing gene expressions typical of Alzheimer’s disease. Fluoxetine, a well-known antidepressant, also showed effect, particularly when combined with exercise. Curcumin showed positive effects as well. The study was published in Scientific Reports.
Alzheimer’s disease is a complex neurodegenerative disorder that affects multiple brain regions. It is the most common disease that causes dementia and is very difficult to treat. In the course of the disease, abnormal collections of proteins called tau accumulate inside neurons.
Another type of protein clumps together to form so-called amyloid plaques that collect between neurons and disrupt cell functions. These and other changes harm the functioning of the brain across different regions and lead to dysfunction and death of brain cells.
“Alzheimer’s disease is a devastating disease for individuals, but also negatively impacts family members. We were interested in exploring the basis of the disease and possible treatments,” said Stephen C. Gammie, a professor at the University of Wisconsin-Madison and the corresponding author of the new study.
Alzheimer’s disease is a complex disorder that involves dysregulated expression of thousands of genes across many brain regions. Although specific brain regions have specific gene expression profiles, as is also the case with individual cells, there are common patterns of dysregulation that are found across the central nervous system in patients suffering from Alzheimer’s disease.
Scientists study gene expression patterns to identify those that are characteristic for a particular disease. One of the ways to do that is a technique called signature matching. It can also be used to find treatments that can reverse the patterns of gene expression that are characteristic for a particular disorder. There is, however, no guarantee that a reversal of disease-related gene expression patterns will lead to the reversal of the disease symptoms.
The authors of this study used the mentioned signature matching technique to try to identify gene expression patterns typical of Alzheimer’s disease, to create a “gene expression portrait” of Alzheimer’s disease. They compared data from people with the disease to controls, people without Alzheimer’s disease. Studies such as this can primarily be done after a person has died i.e., postmortem.
Therefore, brain samples in the 22 datasets used in the study were taken from people who died while suffering from Alzheimer’s disease and these were compared to controls – brain samples from people who died without Alzheimer’s disease.
“The portrait was made to identify consistent changes in dysregulated Alzheimer’s disease genes across multiple brain regions and multiple studies. To accomplish this, a scoring system was used that highlighted the top 1,000 up and downregulated genes from each study, but also included information from the top 8000 up and down regulated genes. In brief, a ranking system was used whereby genes within the top 1,000 and increments of 1,000 up to 8,000 were assigned a decreasing value,” the study authors explained.
The results showed that the “three most dysregulated genes in the AD portrait were the inositol trisphosphate kinase, ITPKB (upregulated), the astrocyte specific intermediate filament protein, GFAP (upregulated), and the rho GTPase, RHOQ (upregulated).” Alzheimer’s disease gene expression portraits for males and females were very similar.
When treatments were considered, the study authors report that out of over 250 considered possible treatments, exercise and activity in general were identified as the top theoretical treatment via the reversal of certain large-scale gene expression patterns. The researchers found that exercise reversed expression patterns of hundreds of Alzheimer’s disease-related genes.
“Although this is an indirect, theoretical study that merges data from disparate datasets, it was interesting that exercise emerged as the top theoretical match for treatment for Alzheimer’s disease. This finding is consistent with current direct studies that are finding positive effects of exercise on cognition,” Gammie told PsyPost.
Fluoxetine, a well-known antidepressant, sold commercially under names such as Prozac, also had good scores as a treatment. In combination with exercise, the researchers report that fluoxetine reversed 549 Alzheimer’s disease genes. One more positive treatment substance was curcumin.
“We were surprised that both exercise and fluoxetine performed so well,” Gammie said. “We also found that a theoretical combination of the two could be useful and this is consistent with studies by some groups that are now combining the two treatments and testing the effects.”
The study gives an important contribution to the knowledge of the genetics of Alzheimer’s disease and possible treatments through gene reversal. It should be noted, however, that data came from postmortem samples and that gene expression reversal in the case of diseases such as Alzheimer’s does not necessarily mean that the course of the disease associated with a certain gene expression portrait will reverse as well.
“One caveat is that we are looking for treatments that reverse gene expression patterns in Alzheimer’s disease at the large scale level, but it is possible that only a small number of specific genes need to be reversed,” Gammie explained. “If that is the case, then we’d need to refine how we score the treatments.”
“Also, it is possible some patterns in AD are occurring because the brain is trying to combat Alzheimer’s disease and one wouldn’t want treatments that disrupt those protective efforts. Finally, this approach may provide insights into how treatments would work or highlight potential new treatments, but it is theoretical and only direct studies can address effectiveness of treatments.”
The paper “Alzheimer’s disease large‑scale gene expression portrait identifies exercise as the top theoretical treatment” was authored by Mason A. Hill and Stephen C. Gammie.
