Abstract WP262: White Matter Stroke and Alzheimer’s Pathology Synergize to Worsen Outcomes in the First Clinically Relevant Mouse Model of Mixed Vascular and Alzheimer’s Disease Dementia

Abstract

Introduction: Microvascular stroke and Alzheimer’s disease (AD) account for the majority of dementia diagnoses with 50% of patients having mixed dementia with features of both microvascular stroke in white matter and AD pathology. Clinico-pathologic studies indicate that white matter hyperintensities present on magnetic resonance imaging correlate with the degree of AD pathology in patients supporting pathologic overlap. This significant co-morbidity indicates an interactive neurobiologic relationship yet it is unclear if these two pathologies synergize or simply co-exist. Prior studies to model stroke and AD pathology have struggled to identify clinically relevant paradigms and time courses that could reasonably link the two disorders. Hypothesis: Subcortical white matter stroke synergizes with AD to worsen outcomes. Methods: We have established a clinically relevant model of mixed dementia by introducing subcortical white matter stroke into EFAD transgenic mice that harbor 5 common AD-associated mutations and knock-in human ApoE alleles under control of the murine ApoE promoter. Strokes were introduced either before or after significant amyloid plaque accumulation and the additive effect of stroke determined. Results: In E4FAD mice (with ApoE4 allele) that have already developed amyloid pathology (>6 months of age), white matter strokes are 70% larger in size (p=0.06) but not associated with worsening gliosis or impaired survival of oligodendrocytes in the peri-infarct region. The molecular organization of axons adjacent to stroke is markedly worse in mice with AD pathology. In younger E4FAD mice, the introduction of a white matter stroke prior to the significant accumulation of amyloid pathology results in worsening plaque burden both globally and in overlying cortex. Conclusions: These data suggest that AD and white matter stroke synergize to worsen both the outcome of stroke occurring in the setting of AD. Similarly early stroke synergizes with amyloid generation to accelerate plaque deposition. This clinically relevant model of mixed dementia will be useful in both preclinical drug disease for both AD and stroke therapies as well as crucial to the discovery of neurobiologic pathways that combine to promote stroke and AD pathologies.