In this wide-ranging interview, conducted by contributing editor Malorye Allison Branca, [researcher Rudy] Tanzi doesn’t hold back. Gathering evidence from whole-genome sequencing studies and 3D Alzheimer’s-in-a-dish models, Tanzi argues where the pharma industry has gone wrong.
Branca: What are some things that are making people optimistic about Alzheimer’s research now?
Tanzi: This optimism is also controversial regarding which hypothesis about the disease is correct. But if you follow the genetics, you won’t go wrong.
The genetics doesn’t just tell you what needs to be addressed, it also tells you when it must be addressed. And it’s that second part of when to address each pathology that a many people miss—they want to just be binary and say, “this is right, that’s wrong,” and throw out the baby with the bath water.
I’m first referring to β-amyloid, the gene for which I discovered back as a student at Harvard (amyloid precursor protein, APP).
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How does it start? Some folks are making normal amounts of Aβ and tangles, but they have genes that ramp up their neuroinflammatory response. Others have genes that just ramp up the amyloid early on. Others we just found have genes that make synapses more vulnerable to amyloid and neuroinflammation.
There are many different routes to get there, but in the end it’s neuroinflammation that takes you out. If you want to treat a patient who is symptomatic, no matter how you got there, you have to stop neuroinflammation or protect against it.
At the pre-symptomatic, early-intervention stage, that’s where heterogeneity comes in. In some folks, it may be more important to stop amyloid. In others it may be more important to stop the amyloid or the tau pathology from spreading.
My guess is that if you have drugs that safely promote amyloid clearance by microglia—a little white powder that does what aducanumab does for a 100 × less money—or a drug that stops the tangles from spreading, any drugs that stop initiating pathologies despite the heterogeneity will be useful in everyone, early on, despite the early heterogeneity.
