Study Susceptibility and Resistance to ApoE4 in Alzheimer's Disease

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SUMMARY The complexity and multifactorial nature of Alzheimer’s disease (AD) pose unique challenges for mechanistic studies and developing therapies. Efforts to target AD-related pathways, mostly focusing on Ab production or clearance, have largely failed in human trials. There is a pressing need to identify novel mechanisms and therapeutic targets for AD. Apolipoprotein (apo) E4—the major genetic risk factor for AD—lowers the age of onset in a gene dose–dependent manner. Remarkably, the risk of developing AD by age 85 is ~70% in people with two copies of the apoE4 allele (~2–3% of the population) but only ~10% in those with two copies of the apoE3 allele. However, ~25% of apoE4 homozygotes remain asymptomatic over age 85. Understanding the mechanisms that govern susceptibility or resistance to the detrimental effects of apoE4 would help decipher its roles in AD pathogenesis and could lead to new therapies to treat or prevent AD—the focus of this project. This proposal builds on four novel findings in our lab. (1) Aged female apoE4 knock-in mice (referred to apoE4 mice) have fewer hippocampal sharp wave ripple (SWR) events—which are critical for memory replay and consolidation—than apoE3 knock-in mice (referred to apoE3 mice) and less of the SWR-associated slow gamma (SG) activity that helps coordinate SWRs. (2) Reductions in SWR activity and in associated CA3 SG power predict spatial learning and memory impairments, respectively, in aged apoE4 mice. (3) Reduction of SWR- associated CA3 SG activity in apoE4 mice starts as early as 5–6 months of age and predicts cognitive deficits at 16 months of age. (4) Using low levels of SWR-associated CA3 SG activity as a functional biomarker, we have been establishing two new apoE4 mouse lines—one with low and one with high SWR-associated CA3 SG activity, referred to apoE4-susceptible (apoE4-S) and apoE4-resistant (apoE4-R) line, respectively—for studying the mechanisms underlying susceptibility and resistance to apoE4’s detrimental effects in Alzheimer’s disease. In Aim 1, we will fully characterize the apoE4-susceptible and apoE4-resistant lines at the neurophysiological, behavioral, and neuropathological levels and explore sex-dependent effects. In Aim 2, using both lines, we will determine the mechanisms that govern susceptibility or resistance to apoE4’s detrimental effects at the genomic and single-nucleus transcriptomic levels and explore sex-dependent modifications of the mechanisms. The knowledge gained from these studies will help elucidate the mechanisms of apoE4’s roles in AD pathogenesis and identify potential targets for therapies to treat or prevent AD related to apoE4.