Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging–Alzheimer's Association describes a biomarker‐based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood‐brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.

There is no practical and reliable premortem test for Creutzfeldt–Jakob disease and the related transmissible spongiform encephalopathies. Two proteins, designated 130 and 131, which have been detected in low concentrations in cerebrospinal fluid from patients with Creutzfeldt–Jakob disease, appear to be sensitive and specific markers for the disease. Attempts to identify these proteins, however, have been unsuccessful. We hypothesized that they may be present in the normal brain.

The no-reflow phenomenon refers to the observation that when an organ is made ischemic by occlusion of a large artery supplying it, restoration of patency in that artery does not restore perfusion to the microvasculature supplying the parenchyma of that organ. This has been observed after prolonged arterial occlusions in the heart (30–90 min), brain, skin, and kidney. In experimental models, zones of no reflow in the heart are characterized by ultrastructural microvascular damage, including focal endothelial swelling obstructing the lumen of small vessels. Blood elements such as neutrophil plugs, platelets, and stacking of erythrocytes have also been implicated. No reflow is associated with poor healing of the myocardial infarction. In patients, no reflow is associated with a poor clinical outcome independent of infarct size, suggesting that therapy for no reflow may be an important approach to improving outcome for ST elevation myocardial infarction. No reflow occurs after reperfusion of experimental cerebral ischemia and may be observed after only 5-min episodes of ischemia. Aggregation of blood elements may play a greater role than in cardiac no reflow. No reflow in the brain may involve cortical spreading depression with disturbed local vascular control and high, vasculotonic levels of extracellular K⁺ concentration, postischemic swelling in endothelial cells and abutting end feet of pericytes, pericyte contraction and death, interstitial edema with collapse of cerebral capillaries, and inflammatory reaction. New guidelines suggesting that reperfusion for stroke may be considered as late as 24 h after the onset of symptoms suggest that clinicians may be seeing more no reflow in the future.