Why do only some older people develop the elevated levels of amyloid-β that start the amyloid cascade of Alzheimer’s disease, leading to tau aggregation and consequent death and dysfunction of brain cells? If amyloid-β is the result of persistent infection by pathogens such as herpesviruses and lyme spirochetes that are, collectively, only present in 20% or so of the population, then perhaps that is the answer. This is the core of the microbial hypothesis of Alzheimer’s disease, that amyloid-β is a feature of the innate immune system, and thus persistent infection of brain tissue will result in higher levels of amyloid over time.
The microbial hypothesis can be balanced against other views on the rise of amyloid-β aggregation with age, such as the contribution of immune aging, in which the immune cells responsible for clearing out these aggregates falter in that work. Or consider the evidence for drainage of cerebrospinal fluid to decline due to age-related changes in fluid passages, and thus aggregates can no longer be effectively removed from the brain via these routes. It is plausible that all of these theories, each backed by a good amount of evidence, are to some