The neuropathology and cerebrovascular mechanisms of dementia

Abstract

The prevalence of dementia is increasing in our aging population at an alarming rate. Because of the heterogeneity of clinical presentation and complexity of disease neuropathology, dementia classifications remain controversial. Recently, the National Plan to address Alzheimer’s Disease prioritized Alzheimer’s disease-related dementias to include: Alzheimer’s disease, dementia with Lewy bodies, frontotemporal dementia, vascular dementia, and mixed dementias. While each of these dementing conditions has their unique pathologic signature, one common etiology shared among all these conditions is cerebrovascular dysfunction at some point during the disease process. The goal of this comprehensive review is to summarize the current findings in the field and address the important contributions of cerebrovascular, physiologic, and cellular alterations to cognitive impairment in these human dementias. Specifically, evidence will be presented in support of small-vessel disease as an underlying neuropathologic hallmark of various dementias, while controversial findings will also be highlighted. Finally, the molecular mechanisms shared among all dementia types including hypoxia, oxidative stress, mitochondrial bioenergetics, neuroinflammation, neurodegeneration, and blood–brain barrier permeability responsible for disease etiology and progression will be discussed.

Figure 1.

Classifications of dementia subtypes and associated neuropathologic features. A hierarchy listing the four major categories of dementia with corresponding neuropathologic findings. A mixed phenotype represented by double-sided arrows indicates a shared disease neuropathology between two dementia types. Aβ, amyloid-β; AD, Alzheimer’s disease; APP, amyloid precursor protein; α-synuclein, alpha-synuclein; CAA, cerebral amyloid angiopathy; DLB, Lewy body dementia; ET, endothelial; FTD, frontotemporal dementia; FUS, inclusions of fused in sarcoma; NFTs, neurofibrillary tangles; p-tau, hyperphosphorylated tau; TDP-43, transactive response DNA-binding protein-43; VaD, vascular dementia.

Figure 2.

Neurovascular factors driving neuropathology and dementia. A schematic representing the mechanisms of cerebrovascular injury because of hypoxia/hypoperfusion, metabolic dysfunction, and altered cerebrovascular hemodynamics with corresponding neuropathologic hallmarks leading to dementia. Additional pathologic markers of dementias include amyloid-β, cerebral amyloid angiopathy, phosphorylated-tau, Lewy Bodies, transactive response DNA-binding protein-43, fused in sarcoma inclusions, and reactive oxygen species such as nitric oxide, superoxide, and nitrogen peroxide.