| The contribution of genetic variation to the risk for late-onset Alzheimer's disease is well-accepted; however, the roles of specific mutations within established risk genes are not clear. Comprehensive datasets with informative in vivo and postmortem biomarkers now offer the opportunity to understand when, where, and how mutations within these genes individually exert their effects on the brain. Moreover, it is known that many of these genes interact at the pathway level, and therefore genetic effects should also be considered in context using gene-gene interaction approaches. I hypothesized that common functional variants modifying established Alzheimer's risk pathways would demonstrate a) independent effects and b) synergistic effects on human brain structure and other Alzheimer's biomarkers. First, the Apolipoprotein E (APOE) gene epsilon4 mutation was found to be associated with white matter integrity in an age-dependent manner. Second, mutations within the sortilin-like receptor (SORL1) gene were associated with differences in white matter integrity, SORL1 gene mRNA expression, and amyloid neuropathology that suggested an early genetic risk mechanism beginning as early as childhood. Third, a translocator protein (TSPO) gene variant known to alter TSPO binding characteristics was found to have no direct effects on inflammatory and cerebrovascular brain changes in over 2 300 elderly subjects. Finally, based on evidence from recent human stem cell experiments, RNA sequencing was used to identify a novel interaction of gene variants across the SORL1 gene with the brain derived neurotrophic factor (BDNF ) Val66Met polymorphism regulating isoform-specific SORL1 expression related to amyloid pathology and brain structural alterations. Altogether, these experiments demonstrate that some genetic modifiers of AD risk pathways are linked either directly via biochemical function or indirectly via the convergence of pathways they influence. These studies have begun to parse the immense heterogeneity of the Alzheimer's disease diagnosis as well as uncover distinct genetically-defined molecular subtypes of at-risk individuals who should be targeted in future therapeutic trials. Novel interventions designed to engage specific neural circuits or molecular pathways would be of most benefit to the molecular subtypes in which they are most greatly altered. |
