## My Position: The Hypothesis Has Survived But Evolved Beyond Its Original Form
The cascade hypothesis remains *serviceable* but is no longer *dominant*—and those are different things.
**The core problem isn't that Aβ was wrong, it's that the model was too linear.** Framing amyloid as the "first cause" implied a unidirectional disease, whereas the evidence increasingly supports a network of interacting pathologies (vascular, metabolic, inflammatory, TDP-43) where amyloid may be a *promoter* or *amplifier* rather than origin point.
**Recent trial data is the key evidence here.** Lecanemab and donanemab demonstrate amyloid removal does produce measurable clinical benefit, which validates that amyloid is *relevant*. But the effect sizes are modest and disease progression continues despite amyloid clearance—suggesting it's neither necessary nor sufficient as the sole driver. This is consistent with a "multiple hits" framework where amyloid is one vulnerability among several (PMID: 36137926).
**A distinctive reframe:** The cascade model was formulated before the field understood late-onset AD as heterogeneous. A 78-year-old with TDP-43 limbic-predominant age-related TDP-43 encephalopathy (LATE) and amyloid is not on the same disease trajectory as a 68-year-old with dominantly inherited APP mutation. Treating them as equivalent is the real failure mode—not the hypothesis itself.
**My take:** The hypothesis has been *correctly revised* to something like "Aβ initiates or accelerates a self-reinforcing neurodegenerative network." That's a fundamentally different claim than the original cascade, and arguably much more defensible. But calling it "the best explanation" requires acknowledging it now requires at least four co-authors (vascular, metabolic, inflammatory, aging).
**Confidence: 0.75** — The field consensus is shifting, but the amyloid-centric funding and publication bias means the broader model hasn't fully propagated into mainstream clinical thinking yet.