Protein Aggregation versus Infection Hypotheses of Alzheimer's Disease

The amyloid hypothesis has dominated the past twenty years of failed attempts to build therapies to treat Alzheimer's disease. However, it is only very recently that immunotherapies and other methods of reducing amyloid-β levels in the aging brain have started to show signs of working. As a consequence, the field is in a state of some upheaval when it comes to choice of strategy going forward. Alternative views of Alzheimer's and its development have emerged and gained enough support to raise sufficient funds to compete. In the long run, this is all to the good, I think. A diversity of approaches always beats out a top-down monoculture when it comes to finding viable paths forward. The open access paper noted here examines a few different hypotheses that have risen to prominence.

In this review, we focus on four Alzheimer's disease (AD) hypotheses currently relevant to AD onset: the prevailing amyloid cascade hypothesis, the well-recognized tau hypothesis, the increasingly popular pathogen (viral infection) hypothesis, and the infection-related antimicrobial protection hypothesis. In briefly reviewing the main evidence supporting each hypothesis and discussing the questions that need to be addressed, we hope to gain a better understanding of the complicated multi-layered interactions in potential causal and/or risk factors in AD pathogenesis.

As a defining feature of AD, the existence of amyloid deposits is likely fundamental to AD onset but is insufficient to wholly reproduce many complexities of the disorder. A similar belief is currently also applied to hyperphosphorylated tau aggregates within neurons, where tau has been postulated to drive neurodegeneration in the presence of pre-existing Aβ plaques in the brain.

Although infection of the central nervous system by pathogens such as viruses may increase AD risk, it is yet to be determined whether this phenomenon is applicable to all cases of sporadic AD and whether it is a primary trigger for AD onset. Lastly, the antimicrobial protection hypothesis provides insight into a potential physiological role for Aβ peptides, but how Aβ/microbial interactions affect AD pathogenesis during aging awaits further validation. Nevertheless, this hypothesis cautions potential adverse effects in Aβ-targeting therapies by hindering potential roles for Aβ in anti-viral protection.

Unlike familial AD, sporadic AD may evolve from a combination of various genetic and environmental factors. Neuroinflammation, tau pathogenesis, and viral infection have all been implicated to play important roles in AD; however, these factors do not appear to be pathogenic triggers that are specifically relevant to AD. Thus, specific causal mechanisms that drive AD onset have yet to be clearly defined, which may lead to the identification of new therapeutic targets. It is now widely accepted that sporadic AD is a complicated syndrome.

Link: https://doi.org/10.1186/s40035-018-0139-3

Comments

It seems that the correct hypothesis should explain the recent finding that frequent sauna use dramatically reduces Alzheimer's risk. Possibly, sauna heat mimics the anti-viral effects of fever.

Posted by: L Pagnucco at January 9th, 2019 2:15 PM

@Lee

Be careful with statistics, according to the following, I would conclude that dementia/Alzheimer's is concentrated in those who do not use the sauna --

Sauna bathing is inversely associated with dementia and Alzheimer's disease in middle-aged Finnish men.
https://www.ncbi.nlm.nih.gov/pubmed/27932366

Also interesting is that there are similar results for Japanese who frequent the hot baths. And, possibly related, are the recent finding that anti-viral drugs appear to slow Alzheimer's progression in some.

Posted by: L Pagnucco at January 10th, 2019 12:19 PM

I have studied AD for many years and when the viral theory first presented itself back around 2010 I did not give it much credence. FYI .. There were other references to possible virus cause as far back as the early 1900s but not via studies. Anyway over the last year much has changed and it appears that Herpes virus 6 & 7a seems to be quite common in AD brains.

It makes sense when you compare it to a similar virus condition with shingles, which lays dormant for decades. Treatment is supporting this to some degree as well. Minocycline, an old line antibiotic, seems to have positive effect, not just on AD but also a number of neuro related maladies like Parkinson's, depression, etc. It's possible that the mincocyline is working as an anti inflammatory as well as an antibiotic, and some have speculated that it's metabolism produces a protein that is the effective part. Either way it appears that mincocyline is one of few drugs/supplements that seems to help.

I believe that APOE4 breaks down the pericytes around the BBB and that allows the virus into the brain. Of course similar things can happen via trauma or other means as well but there has to be an underlying reason for APOE4 to be so instrumental.

Posted by: John Whitling at January 17th, 2019 4:19 PM

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