31 Dec 2024

Dear Dennis,

I thank you for your response, for its thoughtfulness and thoroughness.

The first round of a debate is most useful for isolating the crux. I therefore kindly ask for one more public round. This would be most beneficial, not just for me, but also for the many Alzforum readers who are following our conversation.

The Crux
It seems that it all boils down to "when and where."

The When

The easiest way to track down "when" in a chronic disorder like AD is with the causal quartet, those carrying disease-causing mutations in APP, PSEN1, PSEN2 and SORL1, and, as you expand, including those with trisomy 21.

Yes, in them, their neuronal endosomes start overprocessing APP and secreting Aβ at birth, if not earlier. And it is biologically just as true that this coincides with when endosomes begin the jamming process. This pathophysiological coincidence has been empirically established and is unsurprising, because endosomal APP processing and endosomal traffic jams appear to be in a vicious cycle.

So, if coincidental, if a vicious cycle, can’t we simply substitute the times you reference "Aβ production" as the earliest event, with "endosomal traffic jams" as the earliest event?

The Where
It is the "where" question, inside or outside of neurons, that is more pressing with immediate relevancy for drug development.

I agree with what I think you imply, that compared to drugs that clear extracellular amyloid, those that target the production of Aβ and other APP fragments inside neurons are better, because it is inside neurons where the process starts. Because either those, or drugs that unjam endosomes, will break the vicious cycle, a cycle that leads to Aβ secretion and neurodegeneration through intraneuronal mechanisms.

Genetics support this intracellular mechanistic conclusion. Whether as shown with protective BACE1 variants, which break the pathogenic cycle by reducing intraneuronal APP processing in endosomes. Or, as more recently reported, by protective SORL1 haplotypes, which break the pathogenic cycle by increasing SORL1 expression which is known to unjam the endosome.

(I refrain from referencing recent observations suggesting that APOE protective variants might unjam endosomes because other papers propose neuroimmune mechanisms. The neuroimmune network does appear to mediate neurodegeneration and is the current focus of our ADRC and my lab.)

The therapeutic advantage of intracellular drugs:
I am hesitant to "argue by analogy." But since you invoke analogies, shouldn’t we be developing the equivalent of "statins for the brain"?

That is, targeting the most upstream intracellular pathogenic trigger, which we agree starts inside neurons. Even if clearing amyloid plaques does confer benefits.

So, Dennis, in an attempt at forging synthesis from our opening statements, can we agree on this point: Our field should be developing drugs that target AD’s intracellular pathologies.

Intraneuronal drugs might include the new generation of γ-secretase modulators, safe BACE1 inhibitors, endosomal recycling enhancers, or any other drug designed to break the intraneuronal vicious cycle. It can also, however, extend to include intraglia drugs, since the neuroimmune network appears to mediate neurodegenerative process.

May I wish you, and the rest of the field who are listening, a productive 2025 in our collective crusade, battling one of the most dreaded diseases of our generation.

One Last Round in an Open Debate: Attempt at Synthesis

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