Cognitive Reserve: White Matter, Microvascular, Glymphatic and Cholinergic Dysfunction in Alzheimer's Disease

Late-onset Alzheimer's disease (LOAD) is a cognitive disorder that leads to the requirement of full-time care. The ever-increasing growth of the LOAD population demands that more research be dedicated to the discovery/design of effective therapeutics. The two major hypotheses that have been evaluated in the clinic include the cholinergic and the amyloid hypotheses. Unfortunately, the therapeutics that have resulted from research in these areas have minimal clinical impact. These are, respectively, the cholinesterase inhibitors and the anti-amyloid therapies. Clearly, a new path forward is needed. To this end, a number of genetic approaches and biochemical investigations are currently being employed to provide new insights into the pathophysiology of dementia. While there currently is a diverse array of dysfunctions that have been reported in LOAD subjects, white matter (WM) dysfunction may be a nodal point that is critical to the pathophysiology of cognitive decline. In this review, I present our current knowledge of WM dysfunction in LOAD. This addresses the potential contributions of microvascular dysfunction to WM abnormalities and neuronal dysfunction. This knowledge base has the potential to lead to a new approach for treating cholinergic dysfunction in cognitive disorders.