Dear Scott,
Thanks on your variety feedback and for posing an vital query for debate (see 20 Dec Open Letter). Your alternative of “Open Letter” to 1 particular person is a bit whimsical, a primary for me. I’m unsure why you singled me out, however I settle for the controversy within the constructive spirit you conveyed. I view your subject as distinct from the Perspective that 12 of us wrote for Alzheimer’s & Dementia on the case for regulatory approval of recent AD immunotherapies based mostly on sturdy biomarker outcomes (lowered amyloid and tau proteins) plus security. Accordingly, I’ll solely reply right here to your “Open Letter.” I’ll reply individually later to a number of the extra feedback on the A&D Perspective.
As you say, Scott, we agree on a number of factors favoring a key function for the buildup of Aβ-protein within the growth of AD. But you query whether or not extracellular Aβ accumulation could be thought-about causative (as I consider) or as a substitute represents “one defining function of AD that has confirmed cognitively detrimental,” whereas the precise causative course of is neurodegeneration per se. I disagree. The genetics of AD, to which your and your colleagues’ work on SORL1 has contributed importantly, means that dyshomeostasis within the manufacturing versus clearance of Aβ is the earliest demonstrated molecular change in these familial kinds (FAD). In people born with missense mutations in APP or presenilin or with trisomy 21, the elevated relative manufacturing of Aβ42 begins in utero and results in the quintessential neuropathology of AD, together with neurodegeneration, years to many years later. Here, clear proof of the neurodegenerative course of begins after the primary incidence of Aβ dyshomeostasis at delivery (e.g., infants born with Down’s syndrome have elevated plasma Aβ42). I’ve little doubt that the next neurodegenerative course of, together with early endosomal alterations, tau deposition, and astrocytic and microglial irritation, happen lengthy earlier than onset of signs and assist drive them ahead, however these options comply with Aβ dyshomeostasis.
I don’t consider we will show that early endolysosomal defects, that are well-documented in AD mind tissue, start earlier than or with none extra- or intracellular accumulation of Aβ oligomers (which can’t be simply imaged by amyloid PET and even by amyloid histochemistry within the mind). We can’t make certain that no Aβ oligomers are current when endosomal modifications start in AD, significantly since Aβ oligomers and fibrils steadily accrue in all folks with AD as we outline the illness. One might opine that “sporadic” AD is mechanistically unrelated to FAD, however the info that “sporadic” AD carefully phenocopies the mutant APP and PS kinds and that some instances as soon as categorized as “sporadic AD” might embody people with dysfunction of wild-type presenilin and results of wild-type apolipoprotein E4 recommend that the “sporadic” AD organic course of is mechanistically much like that of FAD. Neurodegeneration is essential to the manufacturing of neurological deficits, however I and plenty of others hypothesize that the initiating issue previous it’s altered Aβ economic system.
Another method to convey my view of causality is to think about the etiology of different continual illnesses the place scientific settlement about causal occasions has emerged. Inheritance of particular mutations in hemoglobin is universally thought-about to be the molecular reason for sickle cell illness, not the hematologic and microvascular occasions and organ harm that produce its intermittent signs. All instances of Huntington’s illness could be recognized in utero or at delivery as attributable to polyglutamine growth mutations of the huntingtin protein, with neurodegeneration slowly ensuing from this molecular etiology. Having the SARS-CoV-2 virus enter and take maintain in a single’s physique is the start of all of the advanced downstream cytopathology of COVID-19, together with lengthy COVID with its “mind fog,” so we forestall the illness by neutralizing the causative virus. Heart assaults generally contain myocardial harm and dysfunction together with low left ventricular ejection fractions, however these will not be thought-about the “trigger” of the dysfunction; reasonably, they’re the tissue penalties (results) of the causative cholesterol-rich plaques and thrombi that block coronary arteries. In quick, we will describe the attribute tissue pathology of continual illnesses and the organ failure that ensues, however we don’t declare that these occasions are the proximate trigger the illness. And so it’s for neurodegeneration in AD.
In my view, “neurodegeneration” contains an ill-defined, extremely advanced, slowly evolving spectrum of mobile alterations that’s proximal to signs however lengthy preceded by biochemical occasions that provoke it. In AD, a number of traces of proof from labs and clinics worldwide point out that elevation, oligomerization, and fibrillization of Aβ42 leads step by step to irritation, neurodegeneration, and tissue atrophy. We can debate whether or not the cytotoxicity of Aβ represents principally an extracellular accumulation, as traditional neuropathology, mind imaging, and fluid biomarkers all recommend, or additionally includes Aβ accumulation inside neurons, for which there has lengthy been revealed proof. There’s no motive why each can’t contribute.
Cell organic research have proven that Aβ is basically generated in mildly acidic endosomal vesicles by which the 2 required aspartyl proteases (b-secretase and presenilin) cleave the APP substrate effectively, and Aβ peptides are then quantitatively secreted by recycling endosomes, a traditional intracellular course of. As you rightly say of the FAD gene defects, “all of them reliably coax neurons to supply and secrete extra Aβ peptides from neuronal endosomes, and … as soon as secreted, they find yourself forming extracellular aggregates.” It is that this irregular Aβ42 accumulation over time, each extra- and intracellularly, that initiates the neurodegenerative course of within the illness we name Alzheimer’s. As you emphasize, Scott, “concentrating on a causal mechanism guarantees to have the best therapeutic advantages.” While therapeutics that ameliorate the downstream neuronal and glial alterations of AD are extremely fascinating, decreasing the manufacturing of Aβ42 (e.g., with GSMs) and/or clearing amyloid deposits (e.g., with antibodies and vaccines) each goal the molecular trigger.
So, as you say, “the pathologies that happen outdoors or inside neurons set off AD’s defining neurodegenerative course of,” however I don’t view the latter as causative, in distinction to the telltale accumulation of Aβ dimers/oligomers effectively earlier than neurodegeneration.
Your reference to an “obvious uncoupling of amyloid and neurodegeneration based mostly on the obvious anatomical mismatch between the place extracellular amyloid aggregates are before everything discovered, versus the place neurodegeneration happens before everything” is, for my part, an older and inaccurate simplification, in {that a}) rising diffusible Aβ oligomers possible happen broadly throughout mind areas, together with within the entorhinal cortex and hippocampus; and b) each proximal and extra anatomically distal results of extracellular Aβ aggregates might subtly compromise neuronal operate (together with glutamate receptor recycling) and construction.
I disagree that we could be sure the Aβ42-lowering trials have failed on readouts of neurodegeneration; reasonably, falling phosphotau, some decreases in tau-PET, and blunting of astrocytosis (falling plasma GFAP)—together with slower medical development—are a number of the findings suggesting a slowing of neurodegeneration. And not all Aβ42-lowering medical results are “delicate” as you say, for the reason that evaluation of some individuals in CLARITY AD who at baseline had no tau deposition past the medial temporal lobe and/or had amyloid-PET ranges <60 CL seem to have skilled digital arrest of medical development over 36 months within the open label extension (van Dyck et al, AAIC, August 28, 2024), far past the “handwringing over 30 p.c slowing” you cite. Let’s see what deltas emerge from our practices.
Finally, I agree that “Future trials testing medicine that both filter amyloid or clear up visitors jams, early within the illness course of, are required.” But the outcomes of the previous strategy are in: It works. And many people consider it’ll work even higher earlier—in secondary prevention mode.
Thank you, Scott, for this chance to change opinions, whether or not or not we’re “altering our minds”. This letter contains my full response to your piece.
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