The Resurrection of Aducanumab Doesn't Change the Picture for Amyloid-β Clearance in Alzheimer's Disease

It took a long time and many failed attempts for the research community to get to the point at which amyloid-β could be successfully cleared from the brains of Alzheimer's patients. Unfortunately, the data to date strongly suggests that this isn't an effective approach to therapy, at least not on its own, even though it is clearly the case that the increased levels of amyloid-β in the aging brain should be removed. It is a characteristic difference between old brain tissue and young brain tissue, and there is plenty of evidence for it to be harmful.

This failure to achieve clinical success may be because amyloid-β aggregation ceases to be an important factor in later stage disease, once tau aggregation and neuroinflammation are firmly established. It may be because patients frequently have other neurodegenerative conditions, such as vascular dementia, that mask any benefits obtained by removing amyloid-β. It may be that amyloid-β accumulation is a side-effect of glial cell dysfunction, and it is glial cell dysfunction rather than amyloid-β accumulation that drives the condition from its early to later stages.

There has been a fair amount of discussion over the recent move of aducanumab back across the line of FDA approval, following an earlier declaration of failure. There is the usual skepticism regarding motivation on the part of the biotech companies involved. Yet this doesn't make much difference to the present situation with regard to amyloid-β clearance. Aducanumab is either a marginal therapy that just passes the minimum standards for regulatory approval, or a marginal therapy that doesn't. It is modestly slowing progression, not working miracles. Either way, clearance of amyloid-β on its own isn't enough, or it isn't the right point of intervention for this condition.

'Reports of My Death Are Greatly Exaggerated.' Signed, Aducanumab

On October 22, Biogen stunned the Alzheimer's field by announcing that aducanumab - presumed dead last March after failing a futility analysis - appears to have worked in one of its two Phase 3 trials, after all. Based on the results of a new analysis, and interactions with the FDA, Biogen will file for regulatory approval in early 2020. Why the revival? The interim futility analysis was flawed and did not adequately take into account the effect of two late protocol amendments that boosted the number of people receiving the highest dose of this biologic drug. A new analysis included three more months of data, as well as data from the participants who did not complete the full course of treatment. It showed that one of the two trials, called EMERGE, in fact met its primary and secondary endpoints. Oddly, the identical ENGAGE trial, which started one month earlier, was a tad larger, yet had slightly fewer people who took an uninterrupted course of the maximum dose, remained negative.

In each trial, about half the participants on aducanumab were randomly assigned to titrate up to a low dose of drug - 3 mg/kg for ApoE4 carriers, 6 mg/kg for noncarriers. This difference was because ApoE4 carriers are more susceptible to ARIA, the fluid retention in the brain that accompanies treatment with many amyloid-removing therapies. In the high-dose group, ApoE4 carriers initially titrated up to 6 mg/kg; noncarriers to 10 mg/kg. However, in March 2017, about 18 months into the trial, the protocol was amended to allow ApoE4 carriers to titrate up to 10 mg/kg, as well. This was based on accumulating data from several studies suggesting that ARIA is a manageable side effect that usually resolves without harm.

Analysis of the more recent, larger data set suggested that duration of treatment at the high dose was the key factor. In addition, interruption of treatment played a role. In EMERGE, participants on the low dose had a trend of declining more slowly than those on placebo on the primary outcome, the CDR Sum of Boxes, but this was well shy of statistical significance. Participants on the high dose declined 23 percent more slowly than those on placebo, with a significant p value of 0.01. Secondary endpoints were similar. The high-dose group declined about a quarter less on the ADAS-Cog13, a cognitive battery, and up to 46 percent more slowly on the ADCS Activities of Daily Living, a caregiver assessment.

Comments

@Reason: What about a summary post on the current state of tau removal / tau biomarkers? I think it's the next step for therapies, combining A-beta and tau removal. Regardless whether Aducanumab's effect is small or not, it has the important effect of easing the development and testing of combination therapies. A combination with senolytics instead of tau cleavers would be interesting too.

Posted by: Antonio at October 25th, 2019 3:54 PM

To deem amyloid b removal a failure because it does not reverse symptoms, or that because of this amyloid must not be a cause of alzheimers, is short sighted IMO.

Why is removal of amyloid b as a preventative therapy not being explored more? Once a person is displaying symptoms then damage has clearly been done, but that doesn't mean others can't benefit from earlier intervention.

Would you say that daily brushing of one's teeth was pointless because it has no effect on already existing tooth decay? No.

Posted by: Link at October 25th, 2019 9:31 PM

There is a theory out there that claims amyloid is so highly conserved in the animal kingdom because it protects against infections.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075814/

So maybe the inflamed brain causes amyloid and not the other way around and maybe senescent cells cause brain inflammation. There are a lot of genetic hints that amyloid is problematic, for example the gene for amyloid sits on chromosome 21, people with down syndrome have the gene in excess and they suffer very early from Alzheimer.

Posted by: Tom at October 25th, 2019 11:20 PM

Theres a discussion on reddit where many from gen x and Y want the baby boomers to die. I fear the same is going to happen when I get old. Im gen X.

Posted by: Gekki at October 26th, 2019 9:52 AM

I wish the same for gen x as well:)

Posted by: Robert at October 26th, 2019 1:20 PM

Possibly of interest is the emerging role of tau in this very recent paper --
"Tau deposition is associated with functional isolation of the hippocampus in aging"
https://www.nature.com/articles/s41467-019-12921-z

Posted by: L Pagnucco at October 26th, 2019 10:34 PM

@Tom: I didnt knew about that the gene for amyloid sits on chromosome 21. Think about 1/6 of the population who has mosaicism T21. Im also interested in making better babies with embryo selection. MitoMouse. I donated $10 and I see im below the average so I will donate again $10. I think everyone who have donated $10-15 should double. We have to reach 75k

Posted by: thomas.a at October 27th, 2019 7:35 AM

Once immuontherapies against solid cancers and gardening of the aged immune system start bringing down cancer death rates massively in the next 15 to 25 years, and oxidised LDL removal and glucosepane removal bring down heart attacks, Alzheimer's and neurodegenration will probably become the leading cause of death.

Posted by: jimofoz at October 27th, 2019 9:59 AM

@jimofoz

A lot of brain damage might be happening due to arteriosclerosis. So if you can reduce cholesterol buildup even Alzheimer's might see improvement. Senolytics might hello there too. Of course, of you fix one cause of death and aging you have another one in the list. A more genetic fix for a condition that had multiple downstream affects can bring wider benefits ( collateral buildup, high blood sugar, cross-links be a specific disease like Alzheimer's).

Posted by: Cuberat at October 27th, 2019 10:38 AM

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