The Vascular-Immune Hypothesis of Alzheimer's Disease

• Published in: Biomedicines Vol. 11; no. 2; p. 408
• Main Authors: Mehta, Rashi I, Mehta, Rupal I
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 30.01.2023; MDPI
• Subjects: Alzheimer's disease; Autopsy; beta-amyloid (βA); Brain; Brain injury; Cell cycle; Clinical trials; Dementia; Dementia disorders; Epidemiology; Etiology; FDA approval; glymphatic–lymphatic system; Hypotheses; Lesions; mixed pathologies; Neurodegenerative diseases; Neurofibrillary tangles; Neurons; Neuropathology; neurovascular unit (NVU); Peptides; perivascular unit (PVU); Physiological aspects; Proteins; Review; Tau protein; β-Amyloid; United States; perivascular unit (PVU); Alzheimer’s disease; glymphatic–lymphatic system; mixed pathologies; tau; beta-amyloid (βA); neurovascular unit (NVU)
• ISSN: 2227-9059; 2227-9059
• DOI: 10.3390/biomedicines11020408

Alzheimer's disease (AD) is a devastating and irreversible neurodegenerative disorder with unknown etiology. While its cause is unclear, a number of theories have been proposed to explain the pathogenesis of AD. In large part, these have centered around potential causes for intracerebral accumulation of beta-amyloid (βA) and tau aggregates. Yet, persons with AD dementia often exhibit autopsy evidence of mixed brain pathologies including a myriad of vascular changes, vascular brain injuries, complex brain inflammation, and mixed protein inclusions in addition to hallmark neuropathologic lesions of AD, namely insoluble βA plaques and neurofibrillary tangles (NFTs). Epidemiological data demonstrate that overlapping lesions diminish the βA plaque and NFT threshold necessary to precipitate clinical dementia. Moreover, a subset of persons who exhibit AD pathology remain resilient to disease while other persons with clinically-defined AD dementia do not exhibit AD-defining neuropathologic lesions. It is increasingly recognized that AD is a pathologically heterogeneous and biologically multifactorial disease with uncharacterized biologic phenomena involved in its genesis and progression. Here, we review the literature with regard to neuropathologic criteria and incipient AD changes, and discuss converging concepts regarding vascular and immune factors in AD.