Amyloid: An evolutionarily conserved protein to fight infection or a toxic protein that causes Alzheimer's disease?

The etiology of Alzheimer's disease (AD) is incompletely understood. While it is widely accepted that amyloid beta (Aβ), the peptide making up the hallmark plaques of the disease, is involved in AD development, its precise role is not fully elucidated. There still exists controversy among the scientific community regarding whether it is a toxic aggregate whose removal would provide clinical benefit to AD patients, or an incidental byproduct of AD's underlying pathogenic mechanism. However, the prevailing theory remains that Aβ is critical to the development of neurodegeneration seen in AD. In recent years, there has been ongoing investigation into potentially physiologic functions of Aβ, which may identify contexts and triggers of its aggregation in the brain. This narrative review compiles converging biochemical, experimental, and epidemiological evidence suggesting that Aβ may serve as an innate immune effector. Aβ has both structural and functional similarities with anti‐microbial peptides, and there is both in vitro and in vivo evidence demonstrating both the formation of Aβ in response to infection as well as a reduction of microbial load when incubated with Aβ. Furthermore, population studies have demonstrated an association between infection exposure and AD risk, with Aβ potentially playing a critical role in these correlations. However, these compelling findings have thus far failed to translate to clinical practice, with no direct causal relationship between an infection‐modulating therapy and cognitive impairment elucidated in clinical trials. Thus, this growing body of evidence supports a nuanced view of Aβ: that its accumulation may represent an immune response to infection, though with more investigation needed to better characterize the clinical impact of Aβ’s interaction with pathogens.