Figure 2: Hypothetical model based on the collective evidence available showing how cardiovascular risk factors give rise to disturbed hemodynamic flow patterns inducing cerebral hypoperfusion. Chronic insufficiency of blood flow to the brain may reach a critically attained threshold of cerebral hypoperfusion (CATCH) [19] responsible for lowered energy substrate delivery and creation of a neurono-glial energy crisis, initially in brain regions where memory and learning are localized. Further downstream, an increase in protein pathology (↑ proteinopathy), featuring protein misfolding of Abeta peptide, ensues followed by impaired clearance of waste products including Abeta [175]. Reduced Abeta clearance from the brain is possibly due, as we predicted, to an impaired microcirculation causing an ineffective efflux of waste products [121]. Deficits () of nonmemory executive function, verbal and mental abilities, and psychomotor speed are ostensibly the first subclinical changes in cognitive dysfunction prior to more advanced cognitive impairment.