Can an Infection Hypothesis Explain the Beta Amyloid Hypothesis of Alzheimer's Disease?

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 (A beta) and intracellular neurofibrillary tangles composed of pTau. These findings led to the beta-amyloid hypothesis that proposes that A beta is the major cause of AD. Clinical trials targeting A beta in the brain have mostly failed, whether they attempted to decrease A beta 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 A beta 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 A beta 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 A beta decrease over time due to microglial senescence and microbial biofilm formation. We propose that this biofilm aggregates with A beta to form the plaques in the brain of AD patients. In this review, we will develop this connection between Infection - A beta - AD and discuss future possible treatments based on this paradigm.