Different Colored Eggs in One Basket is Still Risky

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An interesting paper was recently published by Dr. John Hardy, the father of the amyloid cascade hypothesis, introducing a hypothesis for explaining late-onset neurodegenerative diseases (NDDs) based on the failure of degradation of amyloidogenic proteins. This adds to the list of other interesting hypotheses aiming to explain the etiology and pathophysiology of NDDs, especially the prevalent sporadic forms. The list includes the inflammation hypothesis, the antimicrobial hypothesis, the innate immune hypothesis, and the autoimmune hypothesis.

All are interesting and each has its own merits; however, they all have one common problem. They are all gain-of-toxic-function (GOF) hypotheses. They all assume that either amyloids are toxic or that they trigger other toxic cascades that ultimately kill neurons. At the same time, they all ignore the very plausible possibility that these peptides and proteins have original functions that are lost due to their aggregation, and that loss-of-function (LOF) mechanisms should at least receive some, if not equal, attention. 

This unilateral focus on one aspect of the pathology is risky in three ways: 

1. It focuses the research investment in one direction. Despite their diversity, all the above-mentioned hypotheses are variations on the same theme of GOF. However, if GOF mechanisms turned out to be secondary, or late in the pathology or not easily druggable or non-disease-modifying even when druggable, then all the research investment in terms of time and money, and most importantly patients wait and suffering, all is lost. We are still putting all our eggs in the same GOF basket, they just have different colors.


2. It wastes a potentially helpful therapeutic avenue, at least at some disease stages, where the patients can benefit from replacement therapies.

3. Importantly, ignoring the original functions of these proteins will lead to therapeutics that might not only be suboptimal but potentially harmful, as we are targeting endogenous proteins. Did we forget the time when γ-secretase inhibitors worsened, rather than enhanced, patients' cognition? Now, based on the clearance hypothesis, Dr. Hardy is suggesting (in the abovementioned paper) that we target the "substrate", i.e. the soluble protein, which can even be more harmful to the patients.

I don't think we can afford to keep ignoring LOF disease mechanisms and keep pushing harder and harder in just one direction, which so far has led nowhere. We need to think not just out of the amyloid cascade box, but outside the entire GOF box. We need to diversify our research investment and move some focus towards the LOF pathways, because no matter how many colors we have in the GOF basket, it's still a unilateral risky investment. 

*More information about LOF mechanisms can be found in our review here: Disentangling the Amyloid Pathways: A Mechanistic Approach to Etiology

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