Our results confirm the importance of microvascular pathology in AD. Deteriorating microvascular hemodynamics may cause hypoxia, which is known to precipitate amyloid retention.

Alzheimer's disease (AD) is characterized by the accumulation of hyperphosphorylated tau and neurotoxic Aβ in the brain parenchyma. Hypoxia caused by microvascular changes and disturbed capillary flows could stimulate this build-up of AD-specific proteins in the brain. In this study, we compared cerebral microcirculation in a cohort of AD and mild cognitive impairment (MCI) patients with that of age-matched controls, all without a history of diabetes or of hypertension for more than 2 years, using dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI). Vascular flow disturbances were quantified using a parametric model and mapped to the mid-cortical surface for group-wise statistical analysis. We found widespread hypoperfusion in patients compared with controls and identified areas of increased relative capillary transit time heterogeneity (RTH), consistent with low tissue oxygen tension. Notably, RTH was positively correlated with white matter hyperintensities and positively correlated with symptom severity in the patient cohort. These correlations extended over large parts of the temporal, parietal, and frontal cortices. The results support the hypothesis of disturbed capillary flow patterns in AD and suggest that DSC-MRI may provide imaging biomarkers of impaired cerebral microcirculation in AD.

Introduction Cardiovascular disease increases the risk of developing Alzheimer's disease (AD), and growing evidence suggests an involvement of cerebrovascular pathology in AD. Capillary dysfunction, a condition in which capillary flow disturbances rather than arterial blood supply limit brain oxygen extraction, could represent an overlooked vascular contributor to neurodegeneration. We examined whether cortical capillary transit‐time heterogeneity (CTH), an index of capillary dysfunction, is elevated in amyloid‐positive patients with mild cognitive impairment (prodromal AD [pAD]). Methods We performed structural and perfusion weighted MRI in 22 pAD patients and 21 healthy controls. Results We found hypoperfusion, reduced blood volume, and elevated CTH in the parietal and frontal cortices of pAD‐patients compared to controls, while only the precuneus showed focal cortical atrophy. Discussion We propose that microvascular flow disturbances antedate cortical atrophy and may limit local tissue oxygenation in pAD. We speculate that capillary dysfunction contributes to the development of neurodegeneration in AD.

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