Peripheral Pathways to Neurovascular Unit Dysfunction, Cognitive Impairment, and Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is the most common form of dementia. It was first described more than a century ago, and scientists are acquiring new data and learning novel information about the disease every day. Although there are nuances and details continuously being unraveled, many key players were identified in the early 1900's by Dr. Oskar Fischer and Dr. Alois Alzheimer, including amyloid-beta (Aβ), tau, vascular abnormalities, gliosis, and a possible role of infections. More recently, there has been growing interest in and appreciation for neurovascular unit dysfunction that occurs early in mild cognitive impairment (MCI) before and independent of Aβ and tau brain accumulation. In the last decade, evidence that Aβ and tau oligomers are antimicrobial peptides generated in response to infection has expanded our knowledge and challenged preconceived notions. The concept that pathogenic germs cause infections generating an innate immune response (e.g., Aβ and tau produced by peripheral organs) that is associated with incident dementia is worthwhile considering in the context of sporadic AD with an unknown root cause. Therefore, the peripheral amyloid hypothesis to cognitive impairment and AD is proposed and remains to be vetted by future research. Meanwhile, humans remain complex variable organisms with individual risk factors that define their immune status, neurovascular function, and neuronal plasticity. In this focused review, the idea that infections and organ dysfunction contribute to Alzheimer's disease, through the generation of peripheral amyloids and/or neurovascular unit dysfunction will be explored and discussed. Ultimately, many questions remain to be answered and critical areas of future exploration are highlighted.

Keywords: Alzheimer’s disease; germs; infection; modifiable risk factors; neurovascular dysfunction; peripheral amyloid hypothesis.

FIGURE 1

Alzheimer’s disease is characterized by gross pathologies (e.g., brain atrophy and ventricular enlargement, blue box), microscopic neuropathologies (e.g., amyloid-β plaques, tau tangles, and TDP-43 aggregates, green box), neurovascular unit dysfunction (e.g., blood-brain barrier breakdown, pericyte loss, neurodegeneration, and gliosis, pink box), and changes to subcellular players (e.g., blood-brain barrier transporters, mitochondria, autophagy, and post-translational modifications, yellow box). Created with BioRender.com.

FIGURE 2

Humans are complex, variable organisms who sum up to have differential neurovascular function, immune status, and neuronal plasticity that impacts cognitive status (blue box). Furthermore, beneficial, pathogenic, and commensal germs also play a pivotal role. There are modifiable behaviors that may help in maintaining and promoting healthy cognition. A healthy balance of both self and non-self is key for a healthy body and mind. Created with BioRender.com.

FIGURE 3

The peripheral amyloid hypothesis to cognitive impairment and AD states that amyloids (e.g., Aβ, tau, and perhaps TDP-43) are produced in the periphery as an innate immune response to infection or organ dysfunction, inducing neurovascular dysfunction, neurodegeneration, cognitive impairment, and ultimately AD. An individual may have risk factors that provoke and promote infection and/or organ dysfunction or that directly impact neurovascular unit function. A healthy lifestyle may help mitigate this pathological cascade. Created with BioRender.com.