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 degree correct. Alzheimer's will turn out to be a condition with multiple significant causes, and addressing all or most of those causes will be required to produce reliable benefits across the patient population.
The "germ theory" of Alzheimer's has been fermenting in the literature for decades. Even early 20th century Czech physician Oskar Fischer - who, along with his German contemporary Alois Alzheimer, was integral in first describing the condition - noted a possible connection between the newly identified dementia and tuberculosis. If the germ theory gets traction, even in some Alzheimer's patients, it could trigger a seismic shift in how doctors and understand and treat the disease. For instance, would we see a day when dementia is prevented with a vaccine, or treated with antibiotics and antiviral medications? Some researchers think it's worth looking into.
The hallmark pathology of Alzheimer's is accumulation of a protein called amyloid in the brain. Many researchers have assumed these aggregates, or plaques, are simply a byproduct of some other process at the core of the disease. Other scientists posit that the protein itself contributes to the condition in some way. Researchers have shown that amyloid is lethal to viruses and bacteria in the test tube, and also in mice. Evidence suggests that the protein is part of our ancient immune system that like antibodies, ramps up its activity to help fend off unwanted pathogens.
So does that mean that the microbe is the cause of Alzheimer's, and amyloid a harmless reaction to it? It's not that simple. In many cases of Alzheimer's, microbes may be the initial seed that sets off a toxic tumble of molecular dominos. Early in the disease amyloid protein builds up to fight infection, yet too much of the protein begins to impair function of neurons in the brain. The excess amyloid then causes another protein, called tau, to form tangles, which further harm brain cells. The ultimate neurological insult in Alzheimer's is the body's reaction to this neurotoxic mess. All the excess protein revs up the immune system, causing inflammation - and it's this inflammation that does the most damage to the Alzheimer's-afflicted brain.
So what does this say about the future of treatment? Possibly a lot. Researchers envision a day when people are screened at, say, 50 years old. "If their brains are riddled with too much amyloid, we knock it down a bit with antiviral medications. It's just like how you are prescribed preventative drugs if your cholesterol is too high." Any treatment that disrupts the cascade leading to amyloid, tau, and inflammation could theoretically benefit an at-risk brain. The vast majority of Alzheimer's treatment trials have failed, including many targeting amyloid. But it could be that the patients included were too far along in their disease to reap any therapeutic benefit.