The lack of concrete progress in the amyloid clearance approach to Alzheimer's disease, despite significant investment and many clinical trials over the past decade, has led to a great deal of theorizing in the research community. Is it that the dominant anti-amyloid strategy of immunotherapy is intrinsically challenging when applied to the brain at this point in the progress of medical biotechnology, or is it that amyloid is not the best target? In the SENS view of aging, amyloid accumulation is a primary difference between old and young tissue, and it should be removed. But Alzheimer's is a very complicated condition, involving multiple forms of altered protein aggregation, immune system issues, and other changes in cellular activity. There is plenty of room to advance novel interpretations of the order of causation, or the identification of new agents of causation, without denying that the presence of amyloid is a problem. Ultimately, the proof will lie in the effectiveness of therapies; those based on a correct model of the disease and targeted at the true root cause should in principle produce better outcomes for patients.
Researchers have recently proposed a novel role for biofilms - colonies of bacteria that adhere to surfaces and are largely resistant to immune attack or antibiotics - in eczema. It was suggested that because biofilms block skin ducts and trigger innate immune responses, they may cause the stubborn skin condition. Other recent work shows that Lyme spirochetes form biofilms, which led the researchers to wonder if biofilms might also play a role in Alzheimer's disease. When they stained for biofilms in brains from deceased Alzheimer's patients, he found them in the same hippocampal locations as amyloid plaques.
Spirochetes, common members of the oral microbiome, belong to a small set of microbes that cross the blood-brain barrier when they're circulating in the blood, as they are during active Lyme infections or after oral surgery. However, the bacteria are so slow to divide that it can take decades to grow a biofilm. This time line is consistent with Alzheimer's being a disease of old age, researchers reasons, and is corroborated by syphilis cases in which the neuroinvasive effects of spirochetes might appear as long as 50 years after primary infection.
Work on biofilms contributes to the revival of a long-standing hypothesis concerning the development of Alzheimer's. For 30 years, a handful of researchers have been pursuing the idea that pathogenic microbes may serve as triggers for the disease's neuropathology. Most came across the connection serendipitously, and some have made it their life's work, in spite of scathing criticism and related challenges in attracting funding and publishing results.
The Alzheimer's field seems primed for a fresh look at a theory that might account for the disease's pathogenesis. Researchers still cannot say with confidence which features of the disease, such as neuroinflammation, tau tangles, and amyloid plaques, are involved in disease progression and thus would make effective targets for treatment. So far, most drugs that have made it to clinical testing have targeted the amyloid-β peptide, the main component of the amyloid plaques that characterize Alzheimer's brains. The idea is that a build-up of amyloid-β causes the neuropathology and that removing amyloid-β - by decreasing its production, impeding aggregation, or aiding removal of the molecule from the brain - will improve, or at least stall, symptoms of dementia. But so far, researchers have come up empty-handed.
In light of continued failures to develop effective drugs, some researchers think it's high time that more effort and funding go into alternative theories of the disease. "Any hypothesis about Alzheimer's disease must include amyloid plaques, tangles, inflammation - and, I believe, infection." And, slowly but surely, Alzheimer's researchers finally seem to be giving the pathogen hypothesis a good, hard look. There remain more questions than answers at this point in terms of the causative factors in Alzheimer's, however. "The pathology is a mess. The brain has been diseased for a long time by the time we see it. We're looking at the end product and trying to determine how it got that way. Most of the resources in this field are spent on a few biomarkers. All the evidence shows that amyloid is important. But causality and centrality are two different things."