As U.S. regulators prepare to consider whether to approve the first new treatment for Alzheimer’s disease in two decades, the latest in a long line of failures has experts taking a closer look at the field’s only purported success.

In a clinical trial, two treatments from Eli Lilly (LLY) and Roche (RHHBY) failed to help patients with a rare, inherited form of the disease, the companies said Monday. Each drug relied on the theory that targeting a toxic brain plaque called amyloid can slow cognitive decline in Alzheimer’s. And thus the focus quickly shifted to Biogen (BIIB), which made global headlines last year after claiming a controversial victory with an amyloid-targeting therapy of its own. With that treatment expected to undergo Food and Drug Administration review this year, do the results from Lilly and Roche poke holes Biogen’s case for approval?

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  • Each drug relied on the theory that targeting a toxic brain plaque called amyloid can slow cognitive decline in Alzheimer’s.

    It’s not a plaque — it’s a plaque-forming protein. Amyloid Hypothesis 1.0 (early 1990’s) was plaques composed of amyloid protein cause AD. Does not explain why lots of cognitively normal elderly die with brains full of plaques. Amyloid Hypothesis 2.0 (mid- to late-1990’s) was the toxic effects of fibrils of amyloid protein cause AD. This was a short-lived hypothesis that never was popular like 1.0 and 3.0. Amyloid Hypothesis 3.0 (around 2000) is that small oligomers of amyloid protein cause AD. Accumulation of these oligomers is an early event in AD, long before the plaques. This is the current dominant hypothesis. I think Amyloid Hypothesis 4.0 (around 2010) is becoming the next dominant hypothesis. This is the notion that the problem in AD is not amyloid generation (except in the genetic forms of AD) but its clearance. This explains both why amyloid accumulates in the brain in AD and why the level of amyloid in CSF is actually lower in AD than in normals. Advocates would say amyloid is lower in CSF because it’s not being cleared from the brain. Amyloid has a very high turnover. Nearly all of the amyloid in your brain was made in the last two weeks, and it will all be replaced in another two weeks. Anything which impairs clearance obviously could cause major problems as all that amyloid and its oligomers back up, like a drain clogged with hair.

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