With the continued failure of clinical trials of therapies for Alzheimer's disease, largely immunotherapies, that aim to clear amyloid-β, a growing faction of researchers are rejecting the amyloid hypothesis. In that mainstream view of the condition, the accumulation of amyloid-β causes the early stages of Alzheimer's, but in addition to disrupting the function of neurons, it also causes immune cells in the brain to become inflammatory, dysfunctional, and senescent. This in turn sets the stage for the aggregation of tau protein into neurofibrillary tangles, which causes widespread cell death and the much more severe manifestations of later stage Alzheimer's disease.

Why do only some old people exhibit the condition? In the mainstream view, this is equivalent to asking why only some old people have significantly raised levels of amyloid-β in the brain. This might be due to different rates at which drainage of cerebrospinal fluid becomes impaired with aging, preventing molecular waste from leaving the brain. But many researchers are starting to consider that infectious pathogens are the most important cause, as amyloid-β has now been shown to be an antimicrobial peptide, a part of the innate immune system. The more infection, the more amyloid-β. There is good evidence for persistent infections such as forms of herpesvirus to be associated with Alzheimer's risk.

In today's open access paper, the infection hypothesis is extended further to bypass amyloid-β. The authors suggest that infection leads directly to the stage of chronic inflammation and senescent immune cells in the brain. Amyloid-β accumulation is not necessary for the progression of Alzheimer's in this view of the condition, and may be just a side-effect. As is usually the case in such matters, the best way to find out what is actually going on is to repair or block one mechanism in isolation of all of the others and see what happens. This is quite challenging in the case of Alzheimer's disease, as the animal models are all highly artificial: mice don't naturally suffer Alzheimer's or any similar condition. Thus one can reverse a mechanism or pathology that was introduced into the model, but that doesn't say much about what happens in the human condition, as it has quite different origins and progression.

The Post-amyloid Era in Alzheimer's Disease: Trust Your Gut Feeling