Human cognitive performance is known to decline with age. The severity of this cognitive decline is typically associated with genetic variances of the individual and involves impairments in memory, processing speeds, and reasoning. Additionally, cognitive decline in aging patients can be indicative of Alzheimer’s disease (AD), a neurodegenerative disease. Aims of studying cognitive aging include understanding the associated neural mechanisms and genetic factors along with trying to develop treatments to prevent and slow the progress of AD and cognitive decline. With decades of research on Alzheimer’s disease, there still remains several mysteries in understanding its underlying mechanisms and ways to approach treatment.
A 2016 study conducted by Neuner & Kaczorowski et al. sought out genetic explanations for cognitive aging in mice and humans using a series of cognitive tests complemented with genetic analyses. The study found a part of chromosome 4 related to contextual fear memory in middle-aged mice, while no association was found in younger mice. This finding was narrowed down to a specific gene, Hp1bp3, linking the gene to cognitive aging. Using this result, western blots were performed on hippocampal tissue of cognitively impaired humans and matched controls to see if the findings in mice were present in humans. Hp1bp3 levels were found to be significantly lower in cognitively impaired humans compared to controls, supporting the idea that Hp1bp3 is important in cognitive aging in both mice and humans. Understanding a genetic basis of cognitive aging can provide a key target in finding treatments for Alzheimer’s disease. The study described a previous finding in which a medication known to increase Hp1bp3 expression was administered to mice and showed results of enhanced memory. With this finding, it's interesting to wonder: could such a medication be given to humans to slow or even reverse cognitive decline in patients with AD?
While Dr. Kaczorowski looked at genetic modifiers of cognitive decline prevalent at midlife in humans and mice, other recent studies have attempted to find genetic factors that can be seen years before symptoms of AD develop. A 2020 study from Columbia University Irving Medical Center analyzed over 4,000 genomes of people whose brains had already started to develop deposits of amyloid plaque (one of the earliest known signs of Alzheimer’s disease) before experiencing any symptoms of AD. Trying to find the genes that cause these early amyloid deposits, the study found associations with APOE, a gene already known to be related to AD, along with the novel gene RBFOX1. Interestingly, lower amounts of RBFOX1 were associated with greater increases in amyloid plaque deposits and increased cognitive decline. Understanding the underlying genetic components of early amyloid plaques can help in finding treatment to prevent Alzheimer’s disease and cognitive decline years before symptoms develop. The article mentions that APOE has been known to be related to Alzheimer’s disease; however, it is still not well-understood even after years of research. On the other hand, researchers believe RBFOX1 may be significantly easier to understand and can provide insights to preventing Alzheimer’s early in the course of the disease. Preventing AD early in its development is important because by the time symptoms appear, Alzheimer’s has already been altering the brain for at least a decade, and such alterations are practically impossible to treat.
Taken together, these two findings provide an understanding of some of the genes involved with the development of cognitive decline and Alzheimer’s disease. Dr. Kaczorowski’s study found variations in Hp1bp3 at midlife related to cognitive decline, whereas the study conducted at Columbia University Irving Medical Center found genetic alterations present far earlier in the course of cognitive decline. Hopefully, these findings can assist in unraveling the complex story of Alzheimer’s disease and potentially lead to treatment in preventing the disease altogether.
References
Columbia University Irving Medical Center. (2020, June 22). Alzheimer's: New gene may drive earliest brain changes. ScienceDaily. Retrieved March 4, 2021 from www.sciencedaily.com/releases/2020/06/200622194349.htm
Neuner, S. M., Garfinkel, B. P., Wilmott, L. A., Ignatowska-Jankowska, B. M., Citri, A., Orly, J.,... Kaczorowski, C. C. (2016). Systems genetics identifies hp1bp3 as a novel modulator of cognitive aging. Neurobiology of Aging, 46, 58-67. doi:10.1016/j.neurobiolaging.2016.06.008
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