Exploring Potential Therapeutics of Cognitive Aging and Alzheimer’s Disease: Mouse to Human Translation

While cognitive aging and the onset of dementias such as Alzheimer’s disease (AD) pose significant health challenges, to date, effective therapeutics are lacking. This dissertation explores potential therapeutic avenues and investigates the genetic, molecular, and neuronal mechanisms underpinning these conditions using a mouse to human translational approach. First, we assessed the impact of lifelong caloric restriction (CR) and intermittent fasting (IF) on late-life cognitive performance in genetically diverse Diversity Outbred (DO) mice. Despite extending lifespan, neither CR nor IF improved cognitive outcomes, with severe CR exacerbating memory deficits, results show that there is individual-to-individual change in response to these dietary restrictions, highlighting the importance of genetic background. Quantitative Trait Loci (QTL) mapping identified Slc16a7, encoding monocarboxylate transporter 2 (MCT2), as a potential genetic mediator of late-life cognitive outcomes. While variants in this locus may prove to have interesting interactions with dietary restrictions and cognitive outcomes, these results show that dietary restrictions alone are not effective promoters of cognitive outcomes on a population level. Building on these insights, cross-species analyses pinpointed DLGAP2, key protein in the postsynaptic densities of dendritic spines, as a potential mediator of age-related memory decline in normal aging and AD. In DO mice, genetic variation in the Dlgap2 locus was associated with age-related cognitive performance, which coincided with reduced thin spine density correlating with memory impairment. Parallel analyses in human cohorts confirmed that higher DLGAP2 protein expression is linked to slower cognitive decline in patients diagnosed with AD. Lastly, we investigated the effects of viral mediated DLGAP2 overexpression in the hippocampus of mice modeling AD. We found that overexpression of DLGAP2 did not rescue AD-related cognitive deficits, but rather exacerbated them. Overexpression also reduced dendritic spine density in wild type controls, indicating that while DLGAP2 supports spine integrity, there are complex interactions with plaque deposition. This research emphasizes the importance of genetic diversity in studying cognitive aging, demonstrates the translational utility of the Diversity Outbred population for human, and identifies Slc16a7 and Dlgap2 as promising targets for future therapeutic development. Our findings advocate for personalized intervention strategies that consider genetic background to mitigate age-related cognitive decline.