3 ms·

There is very good genetic evidence that amyloid oligomers are causative in the rarer dominantly heritable types of Alzheimer's disease. The recent positive re

by zosima 4y ago

There is very good genetic evidence that amyloid oligomers are causative in the rarer dominantly heritable types of Alzheimer's disease. The recent positive results of a Lecanemab phase III study, furthermore provides strong evidence that Amyloid Beta is causative in all forms of Alzheimer's disease. https://en.wikipedia.org/wiki/Lecanemab https://en.wikipedia.org/wiki/Lecanemab

arrosenberg 4y ago
Biogen made the same claims about Aducanumab and there has been a lot of controversy about its' approval to say the least. Why do we believe this compound is different?
- zosima 4y ago
  Because the results of this trial is extremely convincing. The result of the Adecanumab trials was fairly unconvincing, and it was quite possible that the positive results were due to a fluke. The second reason is that Adecanumab did not (as far as I know) differ in approach to many other amyloid beta antibodies which have clearly failed to treat Alzheimer's in trials. Adecanumab binds to and clears amyloid beta tangles or plaques, but there is good evidence that the amyloid beta plaques are not really driving the disease. Lecanemab is different and specifically targets a form or conformation of amyloid beta. so called protofibrils, which are more much likely to be driving the disease process.
legulere 4y ago
With Lecanemab only a relatively small positive effect was able to be shown. With Aducanumab by the same companies, which works similar, even that wasn’t possible even though it’s effective against amyloid oligomers. And there are many more failed treatments targeting amyloid beta. No matter how the causal relationships are, targeting amyloid beta for treatment does not seem to help enough for treatment. I would be very interested how genetic evidence can rule out confounding effects.
- zosima 4y ago
  Lecanemab had an extremely strong effect, from a statistical point of view. The average clinical efficacy could be stronger. But Lecanemab is definitely the largest step in Alzheimer's disease research in a very long time. Well, when you have a large number of different mutations in the amyloid beta gene, and in the genes for the machinery for cutting the precursor protein APP to amyolid beta, that all leads to early and fast progressing Alzheimer's disease, which from a pathological perspective is indistinguishable from normal Alzheimer's disease, then the evidence is quite clear. When you then see that people who have duplicates or triplicates of the amyloid beta gene, also have a much higher risk of Alzheimer's disease and the risk increases with more duplicates, the evidence is extremely strong.
  - legulere 4y ago
    Isn’t the effect small but the significance good? If I understood it correctly there’s no amyloid beta gene, but genes for APP an genes for proteases cutting APP. As a layman that leaves a lot of other explanations open, for instance other byproducts of the proteolysis, other breakdown mechanisms for APP, …

by zosima 4y ago

arrosenberg 4y ago

Biogen made the same claims about Aducanumab and there has been a lot of controversy about its' approval to say the least. Why do we believe this compound is different?

zosima 4y ago
Because the results of this trial is extremely convincing. The result of the Adecanumab trials was fairly unconvincing, and it was quite possible that the positive results were due to a fluke. The second reason is that Adecanumab did not (as far as I know) differ in approach to many other amyloid beta antibodies which have clearly failed to treat Alzheimer's in trials. Adecanumab binds to and clears amyloid beta tangles or plaques, but there is good evidence that the amyloid beta plaques are not really driving the disease. Lecanemab is different and specifically targets a form or conformation of amyloid beta. so called protofibrils, which are more much likely to be driving the disease process.

legulere 4y ago

With Lecanemab only a relatively small positive effect was able to be shown. With Aducanumab by the same companies, which works similar, even that wasn’t possible even though it’s effective against amyloid oligomers. And there are many more failed treatments targeting amyloid beta. No matter how the causal relationships are, targeting amyloid beta for treatment does not seem to help enough for treatment. I would be very interested how genetic evidence can rule out confounding effects.

zosima 4y ago
Lecanemab had an extremely strong effect, from a statistical point of view. The average clinical efficacy could be stronger. But Lecanemab is definitely the largest step in Alzheimer's disease research in a very long time. Well, when you have a large number of different mutations in the amyloid beta gene, and in the genes for the machinery for cutting the precursor protein APP to amyolid beta, that all leads to early and fast progressing Alzheimer's disease, which from a pathological perspective is indistinguishable from normal Alzheimer's disease, then the evidence is quite clear. When you then see that people who have duplicates or triplicates of the amyloid beta gene, also have a much higher risk of Alzheimer's disease and the risk increases with more duplicates, the evidence is extremely strong.
- legulere 4y ago
  Isn’t the effect small but the significance good? If I understood it correctly there’s no amyloid beta gene, but genes for APP an genes for proteases cutting APP. As a layman that leaves a lot of other explanations open, for instance other byproducts of the proteolysis, other breakdown mechanisms for APP, …