Is Alzheimer's Disease Primarily a Result of Infection-Driven Inflammation?

Many diseases of aging are strongly associated with chronic inflammation, and inflammatory signaling is involved in disease pathology. Unresolved low-grade inflammatory signaling and excessive immune system activation increases with advancing age, producing the state of immune dysfunction known as inflammaging. Many different factors contribute to this chronic inflammation of aging. They include the presence of lingering senescent cells that actively produce inflammatory secretions, as well as mitochondrial dysfunction resulting in mislocated mitochondrial DNA fragments that can cause an innate inflammatory response. It is also the case that one-time or persistent infections can spur greater lasting inflammation.

Inflammatory signaling is essential to health in the short term, a necessary part of the immune response to infection and injury, but when sustained over the long term it changes cell behavior for the worse and degrades tissue function.

Is Alzheimer's disease a condition primarily driven by infection and consequent inflammation, particularly chronic inflammation? Or is inflammation only one of a number of factors, and possibly a consequence of other disease pathology? These and related questions are much debated these days, given the failure to achieve significant patient benefits by clearing amyloid-β from the brain. Alzheimer's disease has long been known to have a strong inflammatory component, but could it be near all a matter of chronic inflammation, with pathologies such as protein aggregation trailing along as consequences?

The role of peripheral inflammatory insults in Alzheimer's disease: a review and research roadmap

Alzheimer's disease (AD), a neurodegenerative condition that affects approximately 24 million people worldwide, accounts for 60 to 70% of all dementia cases. Despite tremendous recent advancements in neurodegenerative disease research, the understanding of AD biology remains incomplete. Although amyloid-beta (Aβ) plaques and tau neurofibrillary tangles are considered hallmark features of AD, the past two decades have seen a surge in genomic studies that consistently point to the central role of microglia and neuro-immune dysfunction in the pathogenesis of AD. Concurrently, a large body of work has highlighted the potential relevance of peripheral immune changes, particularly pro-inflammatory signaling, in AD pathogenesis.

Evidence for a relationship between peripheral immune factors and AD has come primarily from epidemiological and observational research studies which demonstrate associations between circulating inflammatory markers and neurocognitive features. However, there is a growing body of literature supporting the role of acute inflammatory insults as potential catalysts for cognitive decline and AD. Here, we define acute inflammatory insult as an immune challenge - typically tissue injury or exposure to a pathogen - that produces, in most cases, a time-limited inflammatory response.

This review focuses on the evidence from clinical and translational research linking acute inflammatory insults to cognitive decline and AD. We review evidence for the role of both pathogen- and damage-mediated inflammatory insults in AD and provide current conceptualizations of mechanisms for and treatment of immune-mediated cognitive decline. Importantly, we outline critical next steps for understanding how acute inflammatory insults might impact AD pathological processes and influence clinical presentation. We provide guidelines to address gaps in the literature, outline methods for appraisal of infection-mediated outcomes, and highlight future studies that may accelerate therapeutic interventions.

Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.