Multi-Modal MRI to Assess Alzheimer's Disease Prevention in an APOE4 Mouse Model

Apolipoprotein å4 (APOE4) allele is the strongest genetic risk factor for Alzheimer’s disease (AD)1. Neuroimaging studies in humans have shown that cognitively normal APOE4 carriers develop vascular, metabolic and structural deficits decades before the aggregation of beta-amyloid (Aâ) and neurofibrillary tau tangles2. Interventions that can restore these deficits to normal would be critical to potentially prevent the development of AD related neuropathology and cognitive impairment. However, before interventions in humans can be done, more information about the temporal development and molecular mechanisms underlying these deficits need to be defined. Studies with animal models, especially transgenic mouse models that develop AD-like pathology and impairments, would provide flexible, rigorous and systematic approaches for exploring the underlying pathophysiology. Historically, development of mouse neuroimaging methods relevant to humans has been challenging because of the small size of the mouse brain. Over the past decade, we have successfully “reversely” translated the MRI technology used in humans to mice. We have used this MRI technology to quantitatively determine in vivo cerebrovascular, metabolic and microstructural functions, and to identify treatment efficacy thereof with various pharmacological and dietary interventions. Of relevance to this project, we recently reported that Rapamycin, a compound that extends lifespan in animal models, was able to restore cerebral blood flow (CBF), vascular density, blood-brain barrier (BBB) integrity, glucose metabolism and white matter (WM) integrity, as well as reduce Aâ accumulation and improve memory in symptomatic mice modeling human AD5. However, the effects of this promising compound have not been well characterized in asymptomatic mice that express the human APOE4 allele. Because human APOE4 carriers develop vascular, metabolic, and structural deficits very early in disease progression, it is critical to determine whether early intervention with Rapamycin can prevent these deficits and/or restore normal functions.