Reversal of cerebral hypoperfusion: a novel therapeutic target for the treatment of AD/ADRD?

Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRD) are emerging global health care crises and are primarily found among aging, especially with diabetes and hypertension. However, treatments based on current understanding have not been effective. The importance of vascular contribution to AD/ADRD has been recommended by the NINDS and NIA to be a focused research area. A recent study identified that phosphatidylinositol 4,5-bisphosphate (PIP2) or its analogs could reverse cerebral hypoperfusion at the neurovascular unit in AD mice. Although more studies are needed to validate if PIP2 analogs have sustained effects on CBF and can rescue cognitive impairment in AD/ADRD, and to elucidate and clarify whether targeting the retrograde (capillary-to-arteriole) pathway is beneficial to BBB function in AD/ADRD with poor CBF autoregulation, this finding provides exciting progress in understanding vascular contributions to AD/ADRD and suggests that reversal of cerebral hypoperfusion could be a novel therapeutic target for the treatment of AD/ADRD.