Theory and evidence for persistent infection as a cause of Alzheimer's disease continues to grow in scope and plausibility. In general this supports rather than replaces past thinking on amyloid-β and its role in the development of Alzheimer's. It provides an explanation as to why it is that levels of amyloid-β rise over time to produce the early disruptions and changes in the biochemistry of the brain that are necessary for later neurodegeneration to take place. Other compelling lines of work provide evidence for entirely separate mechanisms by which levels of amyloid-β can grow in later life, such as declining drainage of cerebrospinal fluid. It seems plausible that all may be correct to some degree, and that many of these proposed processes are significant, each adding their own contribution to the progressive decline of the brain.
Alzheimer's disease (AD) is the most frequent type of dementia. The pathological hallmarks of the disease are extracellular senile plaques composed of beta-amyloid peptide (Aβ) and intracellular neurofibrillary tangles composed of phosphorylated tau (pTau). These findings led to the "beta-amyloid hypothesis" that proposes that Aβ is the major cause of AD. Clinical trials targeting Aβ in the brain have mostly failed, whether they attempted to decrease Aβ production by BACE inhibitors or by antibodies. These failures suggest a need to find new hypotheses to explain AD pathogenesis and generate new targets for intervention to prevent and treat the disease.
Many years ago, the "infection hypothesis" was proposed, but received little attention. However, the recent discovery that Aβ is an antimicrobial peptide (AMP) acting against bacteria, fungi, and viruses gives increased credence to an infection hypothesis in the etiology of AD. We and others have shown that microbial infection increases the synthesis of this AMP. Here, we propose that the production of Aβ as an AMP will be beneficial on first microbial challenge but will become progressively detrimental as the infection becomes chronic and reactivates from time to time. Furthermore, we propose that host measures to remove excess Aβ decrease over time due to microglial senescence and microbial biofilm formation. We propose that this biofilm aggregates with Aβ to form the plaques in the brain of AD patients.