Delineating systemic roles of APOE genotypes on CNS health

/Abstract: APOE4 and aging are the among the strongest risk factors for Alzheimer’s disease (AD). As the aging population continues to grow in the coming decades, novel approaches based on uncovering new AD pathobiology will be needed to meet the increased number of cases. An emerging concept with accumulating support is that AD pathobiology is not limited to dysfunction occurring within the CNS. These studies demonstrate that the activity of youth-associated proteins in young blood revitalizes function in aged tissues, including various processes within the brain. Using plasma transfer and parabiosis models, aged mice sharing young blood exhibit improved behavioral function, including hippocampus-dependent memory, and improved synaptic plasticity. Aged amyloid-bearing mice exhibit reduced AD pathology and improved synaptic integrity following exposure to young blood. Conversely, factors in the aged systemic environment drive aging phenotypes in the young healthy brain, including microgliosis and deficits in cognition, together arguing that blood-borne factors are relevant to neuroimmunological changes relevant to AD pathogenesis. While these studies argue that the systemic environment may represent a target for novel AD therapies, little is known about the drivers of these phenotypes or other critical modifiers of blood-CNS communication that regulate AD pathology. Our preliminary data provide strong support for the concept that the systemic environment differs according to APOE genotype and that sharing blood from opposing APOE genotypes differentially alters hippocampal function. We will address the role of both APOE4-associated and APOE3-associated mediators of blood-CNS neuroimmune communication in the healthy brain and in the context of AD pathology to clarify the link between common risk factors and AD pathomechanisms. We hypothesize that hippocampus-dependent behavioral and neuroimmunological function is regulated by communication between the periphery and brain in a manner that depends on APOE genotype. We will address this in several aims: (1) To examine deleterious APOE4-associated blood-borne mediators of changes in brain function at multiple levels of analysis (molecular, cellular, and behavioral); (2) to similarly characterize the impact of protective APOE3-associated blood-borne mediators on neuroimmunological and behavioral function; and (3) to examine the impact of APOE genotype on the efficacy of young blood-borne factors in revitalizing function in the aged brain and in the context of AD pathology. Our aims incorporate the use of sophisticated transcriptomic, behavioral, and morphometric approaches to comprehensively define cellular and pathological responses to APOE genotype in the systemic environment, potentially opening novel avenues for AD therapy development. Project Number: 1RF1AG096837-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Joseph Castellano | Institution: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI, NEW YORK, NY | Award Amount: $2,944,007 | Activity Code: RF1 | Study Section: Special Emphasis Panel[ZRG1 AN-J (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11376435