Multimodal Optical Imaging and AI Analytics to Uncover APOE4 Etiology and Therapeutic Targets in Late Onset Alzheimer's Disease

SUMMARY Alzheimer’s disease (AD) afflicts more than 55 million people worldwide and already accounts for up to 80% of all dementia cases. As populations age, its societal and economic burden will soar. Late-onset AD (LOAD) is the predominant form, and inheritance of the APOE ε4 allele (APOE4) increases lifetime risk up to 15-fold. Although APOE4’s influence on amyloid-β (Aβ) and tau proteinopathy is well documented, converging human and animal data now indicate that microvascular failure is the first domino to fall—often years before plaques or tangles appear. Yet the mechanisms by which APOE4 disrupts vascular resilience, and how best to intervene, remain unclear. Pilot work from our laboratory using label-free optical coherence tomography angiography (OCTA) shows that APOE4 mice—especially females—lose critical microvascular “back-up routes,” making single-capillary stalls more catastrophic. These topology shifts emerge before observable cognitive decline. Why the network fails remains unknown; we hypothesize that APOE4-driven cholesterol accumulation may blunt endothelial calcium (Ca²⁺) waves and Connexin-43 gap-junction communication, undermining adaptive vascular remodeling. To dissect this hypothesis and create actionable biomarkers we will build an open-source imaging-plus-AI platform and apply it in a rigorous, longitudinal study: (1) Optimize high-throughput OCTA for awake mice to map vascular topology and flow heterogeneity from 12 to 48 weeks, while tracking Aβ/tau progression and behavior; (2) Fuse two-photon Ca²⁺ imaging with OCTA risk maps to pinpoint how APOE4 impairs capillary endothelial Ca²⁺ waves and Connexin-43 gap junctions, selectively weakening high-topological-risk capillaries; (3) Test vascular-targeted therapies—statins, PCSK9 inhibition, and SIRT1 activation—alone and combined with Lecanemab (anti-Aβ) or TOMA (anti-tau), using OCTA-TPM biomarkers and cognition to quantify rescue. By integrating near-lifespan OCTA, fast Ca²⁺ imaging, and deep-learning analytics, this project will (i) reveal the earliest, sex-specific vascular liabilities in APOE4 LOAD, (ii) provide mechanistic insight linking the early vascular degeneration to downstream proteinopathy, and (iii) establish whether vascular protection can extend the therapeutic horizon for sporadic AD. These outcomes will provide unprecedented insights into the early vascular mechanisms driving LOAD in APOE4 carriers and may identify novel therapeutic targets to delay or prevent disease progression. Project Number: 1R01AG100278-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Jonghwan Lee | Institution: BROWN UNIVERSITY, PROVIDENCE, RI | Award Amount: $636,372 | Activity Code: R01 | Study Section: Imaging Technology for Neuroscience Study Section[ITN] View on NIH RePORTER: https://reporter.nih.gov/project-details/11342575