Abstract Background Although lysosome dysfunction has been implicated in Alzheimer's disease (AD), it is unclear what level or type of dysfunction is pathogenic. We hypothesize that haploinsufficiency of lysosomal enzymes is associated with AD and that CNS‐directed, AAV‐mediated gene transfer can be an effective treatment. Method Although lysosome dysfunction has been implicated in Alzheimer's disease (AD), it is unclear what level or type of dysfunction is pathogenic. We hypothesize that haploinsufficiency of lys…

Abstract There is growing evidence suggesting that the lysosome or lysosome dysfunction is associated with Alzheimer’s disease (AD). Pathway analysis of post mortem brain-derived proteomic data from AD patients shows that the lysosomal system is perturbed relative to similarly aged unaffected controls. However, it is unclear if these changes contributed to the pathogenesis or are a response to the disease. Consistent with the hypothesis that lysosome dysfunction contributes to AD pathogenesis, whole genome sequenc…

Abstract The risk of developing Alzheimer’s disease is mediated by a combination of genetics and environmental factors, such as stress, sleep abnormalities and traumatic brain injury. Women are at a higher risk of developing Alzheimer’s disease than men, even when controlling for differences in lifespan. Women are also more likely to report high levels of stress than men. Sex differences in response to stress may play a role in the increased risk of Alzheimer’s disease in women. In this study, we use in vivo micro…

Abstract Background Amyloid‐beta (Aβ) plaque formation is a well‐established hallmark for Alzheimer’s disease (AD). However, the processes behind plaque formation are not understood. Previous work from our group identified rare coding variants for PLD3, with one variant in particular, p.A442A, disrupting a splicing enhancer binding site within the mRNA transcript. In this study, we present findings that PLD3 regulates Aβ clearance in the brain through both cell autonomous and non‐autonomous means. Method To replic…

Abstract Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain. AD is also the result of complex genetic architecture that can be leveraged to understand pathways central to disease processes. We have previously identified coding variants in the phospholipase D3 ( PLD3 ) gene that double the late-onset AD risk. However, the mechanism by which PLD3 impacts AD risk is unknown. One AD risk variant, PLD3 p.A442A, disrupts a splicing enhancer-bi…