The biochemistry of the brain is enormously complex and still poorly understood at the detail level. This is also true of the mechanisms of Alzheimer's disease. Treating Alzheimer's is, more or less, the unified banner under which the research community raises funds to map and catalog the brain. It is why so much funding pours into the study of this one condition in comparison to others. In the research mainstream it is expected that only with much greater understanding of neurobiology will effective therapies emerge. Since the molecular biology involved is so very complicated, there are many gaps into which new theories of disease progression can fit without much challenge. Building theories is a lot easier and cheaper than running studies, and so there will always tend to be more theorizing than construction of potential therapies. This is especially true when, as is the case today, the dominant paradigm of amyloid clearance has yet to produce results despite years of trials. Perhaps that indicates it is harder than expected, or perhaps it indicates that it is a wrong direction.
Some of the more interesting alternative theories include the idea that amyloid clearance channels in tissues close to the brain fail with age for many of the same reasons that blood vessels accumulate damage in aging issues. This is a putative cause and possible fix for increasing amyloid levels. The Methuselah Foundation is funding a test of that theory, as such a test should be cheap and fairly conclusive one way or another.
Another set of theories argues that Alzheimer's has a meaningful microbial contribution to its development, that progression of the condition is sped up by exposure to fungal and other pathogens. In the paper here, this is presented as a new category of Alzheimer's disease rather than as a contributing factor to a single unified condition called Alzheimer's. I think it pretty likely that Alzheimer's will be formally split up into categories in the years ahead. Neurobiochemistry is a big enough space to fit numerous distinct paths leading to a similar end result in which aggregates like amyloid overrun the brain and harm its cells, and that seems a more likely reality than one path.
Identifying subtypes of Alzheimer's disease may aid in the development of therapeutics, and recently three different subtypes have been described: type 1 (inflammatory), type 2 (non-inflammatory or atrophic), and type 3 (cortical). Type 3 is very dissimilar to the other two types, and may be mediated by a fundamentally different pathophysiological process (although, by definition, still β-amyloid positive and phospho-tau positive): the onset is typically younger (late 40s to early 60s); ApoE genotype is usually 3/3 instead of 4/4 or 3/4; the family history is typically negative (or positive only at much greater age); symptom onset usually follows a period of great stress, sleep loss, anesthesia, or menopause/andropause; presentation is not predominantly amnestic but is instead cortical, with dyscalculia, aphasia, executive dysfunction, or other cortical deficits; and the neurological presentation is often preceded by, or accompanied by, depression.
Over the past two decades, elegant work has demonstrated unequivocally that biotoxins such as mycotoxins are associated with a broad range of symptoms, including cognitive decline. These researchers and clinicians identified a constellation of symptoms, signs, genetic predisposition, and laboratory abnormalities characteristic of patients exposed to, and sensitive to, these biotoxins. The resulting syndrome has been designated chronic inflammatory response syndrome (CIRS). The most common cause of CIRS is exposure to mycotoxins, typically associated with molds.
Our findings suggest that patients with presentations compatible with type 3 Alzheimer's disease should be evaluated for CIRS (as well as other toxic exposures, such as mercury and copper). These are treatable etiologic agents, and thus treatable causes of Alzheimer's disease. Furthermore, it may be particularly important to identify or exclude these toxins in patients with type 3 Alzheimer's disease since amyloid may be protective against toxins, especially metals, so reducing the amyloid burden without reducing the toxic exposure may potentially exacerbate the pathophysiology. Conversely, the exclusion of patients with type 3 Alzheimer's disease may potentially enhance the group efficacy of anti-amyloid therapies.
It is noteworthy that there has been direct detection of fungi in the brains of patients who had died with Alzheimer's disease, contrasting with a lack of detection of fungi in control brains. This finding raises the possibility that the mycotoxic effects that occur in CIRS associated with type 3 Alzheimer's disease may be accompanied by active infection. However, unlike in the case of CIRS, there is as yet no indication that treating the putative fungal infection has any ameliorative effect on the cognitive decline. The increasing number of reports of various pathogens identified in the brains of patients with Alzheimer's disease raises the possibility that what is referred to as Alzheimer's disease may actually be the result of a protective response to various brain perturbations. Thus amyloid may function as part of an inflammatory/antimicrobial response.