Neurovascular integrity, including cerebral blood flow (CBF) and blood-brain barrier (BBB) function, plays a major role in determining cognitive capability. Recent studies suggest that neurovascular integrity could be regulated by the gut microbiome. The purpose of the study was to identify if ketogenic diet (KD) intervention would alter gut microbiome and enhance neurovascular functions, and thus reduce risk for neurodegeneration in young healthy mice (12–14 weeks old). Here we show that with 16 weeks of KD, mice had significant increases in CBF and P-glycoprotein transports on BBB to facilitate clearance of amyloid-beta, a hallmark of Alzheimer’s disease (AD). These neurovascular enhancements were associated with reduced mechanistic target of rapamycin (mTOR) and increased endothelial nitric oxide synthase (eNOS) protein expressions. KD also increased the relative abundance of putatively beneficial gut microbiota (Akkermansia muciniphila and Lactobacillus), and reduced that of putatively pro-inflammatory taxa (Desulfovibrio and Turicibacter). We also observed that KD reduced blood glucose levels and body weight, and increased blood ketone levels, which might be associated with gut microbiome alteration. Our findings suggest that KD intervention started in the early stage may enhance brain vascular function, increase beneficial gut microbiota, improve metabolic profile, and reduce risk for AD.

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Alzheimer's disease (AD) is the sixth leading cause of death in the United States. Although AD research is bustling, a concrete and effective treatment has yet to be discovered. This study aimed to assess vascular magnetic resonance imaging (MRI) as an early detection method for AD, and to then test the potential of FDA‐approved drug Rapamycin (Rapa) in treating pre‐symptomatic AD. Rapa is capable of increasing lifespan in mammals and inhibiting unwanted cell mobility, such as cancer cell growth. This study is the first to connect Rapa's capabilities with AD. In order to analyze Rapa's efficacy, neuroimaging and behavioral tests were conducted on mice that carry the apolipoprotein E4 gene (APOE4), the strongest genetic risk factor for AD. Methodology included MRI, magnetic resonance spectroscopy (MRS), Blood‐Brain Barrier (BBB) integrity and neuroinflammation determinations, Radial Arm Water Maze (RAWM), and Novel Object Recognition Test (NOR). These methods provided a comprehensive analysis of the subjects' neurological health and cognitive functions by giving insight into cerebral blood flow, brain metabolites, spatial memory, recognition memory, and neuroinflammation. Vascular MRI effectively pinpointed vascular defects and therefore accurately identified early AD. Data strongly supported the initial hypothesis that with the introduction of Rapa, APOE4 mice will show improved cognition, memory, and neurological health. Cerebral blood flow and crucial brain metabolites were restored in Rapa mice; Rapa mice exhibited cogent memory in comparison to their counterparts in cognitive tests; Rapa reduced neuroinflammation‐‐all with significance. Thus, vascular neuroimaging is a promising early AD detection technique and Rapa holds high potential in preventing AD development.Support or Funding InformationThe work was supported by funding from the National Institute on Aging (NIA) of NIH (K01AG040164 to A‐LL) and NIH CTSA at the University of Kentucky (UL1TR0000117; pilot grant to A‐LL).