Monday, May 12, 2025
5/12/2025
Characterizing microvascular impairment in adults with elevated genetic risk for Alzheimer's Disease - PROJECT SUMMARY Alzheimer’s disease (AD) represents a significant public health crisis that currently affects more than 6 million Americans over the age of 65 years with a projected increase to 13.8 million by 2050. This anticipated increase in the prevalence of AD emphasizes the need for a more complete understanding of disease etiology. Possession of an APOE-ε4 allele is the strongest common genetic risk factor for developing late-onset AD. APOE-ε4 also represents a significant risk factor for vascular disease. As a result, cognitive decline in ε4+ individuals may arise through classical AD pathways as well as independently through vascular-related mechanisms. A high prevalence of white matter lesions in ε4+ individuals is thought to be an indicator of microvascular impairment that results in tissue hypoxia and reduced oxygen availability to the brain. However, microvascular physiological mechanisms that lead to reductions in cerebral oxygen availability in ε4+ individuals are not yet fully understood. Hypoperfusion has been thought to be the source of such hypoxia, and cerebral blood flow (CBF) has been extensively investigated as a potential marker of hemodynamic impairment in ε4+ adults. Meanwhile, CBF represents only one factor governing cerebral oxygen availability, and the efficiency of oxygen extraction in the capillaries also plays an important role. The long-term goal of our work is to elucidate physiological mechanisms through which APOE-ε4 contributes to microvascular impairment, white matter lesion burden, and associated cognitive decline. We have previously proposed venous hyperintense signal (VHS) on perfusion-weighted arterial spin labeling (ASL) magnetic resonance imaging (MRI) as a novel marker of microvascular flow disturbances in older adults. More specifically, individuals with VHS exhibited a higher white matter burden with older age than those without VHS, and this elevated lesion burden was related to both a reduction in CBF and a decrease in oxygen extraction efficiency uniquely in those with VHS. Based on these studies and preliminary data indicating that ε4+ individuals may exhibit unique physiology based on the presence or absence of VHS, our central hypothesis is that reduced oxygen extraction efficiency and impaired CBF regulation are important contributors to microvascular impairment in APOE-ε4. We will enroll a well-characterized cohort of adults between 40-80 years of age who at varying risk for AD based on APOE genotype to investigate the physiological mechanisms surrounding VHS and microvascular impairment in APOE-ε4, including how these may vary by age, be related to AD biomarkers and cognitive function, and differentially affect white matter lesion burden. Successful completion of this work may inform the development of therapeutics aimed at mitigating microvascular contributions to cognitive decline in APOE pathology and identify candidate hemodynamic biomarkers for stratification of at-risk individuals at an earlier age.
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