First and foremost, it is important to say that Cogstate's...

First and foremost, it is important to say that Cogstate's fundamentals are not linked to the success or failure of the beta amyloid hypothesis. Secondly. the doubts around the hypothesis have been debated and examined for at least 15 years so none of this is new. Thirdly, there is not a binary outcome.

As to the video you posted and its title it is pure and utter clickbait, for AD tourists who want to distill just about the most complex condition to affect the body into a couple of sentences or a singular word. Firstly, it is a hypothesis (i.e unproven), secondly the guest seems to suggest that a reversal of cognitive decline (i.e a cure) has been promised by the beta amyloid hypothesis. this is nonsense it has always been seen as a tool to slow decline, never as a cure. Thirdly, it is becoming increasingly clear that there are many types of AD and as a result of technology such as Cogstate's, improved scanning, genetic analysis etc we are able to stratify patients into subgroup that were unknown to us 20 years ago and it seems likely that each subgroup will require differing approaches and different MOA in order to have a therapeutic effect.

You can argue about the benefit, vs the costs vs the risks, which I will not get into here. But scientifically, given all of the trials conducted to date it is clear there is a subset of patients who see a measurable decrease in their rate of cognitive decline from certain beta amyloid clearing therapies. In particular I think there is some general misunderstanding about the upcoming Lacanamab read out, the was designed with the learnings from the Adcanamab experience built into it and also works on very different targets. Many seem to think it is just another verion of Aducanumab.

Just as a reminder, although both are anti-amyloid beta antibodies, lecanemab preferentially target soluble protofibrils (large oligomers) over plaques. Based on clinical trial results to date, lecanemab appears to have some advantages over Aduhelm, these include fewer side effects: lower incidence of ARIA-E. Can be initiated at the therapeutic dose without titration: Aduhelm requires titration. May be quicker at removing amyloid beta: When administered over 18 months in Study 201, there was a sharp reduction in amyloid beta plaque at 12 months. From a convenience standpoint, though, lecanemab probably is at a disadvantage to Aduhelm, as it needs to be administered once every two weeks rather than once a month. Eisai is also developing a subcutaneous injection of lecanemab, which may lead to greater convenience, if successful.

In Lacanamabs favour is the use of ADCOMs as endpoint, this much more sensitive to detecting change in the early stages of the disease. Secondly it is clear from the Study 201 that the effect on ApoE4 carriers was much more pronounced, and their carriers will make up @65% tp 70% of the trial, and it is possible if these results are repeated in the Clarity study that approval may be sort only for ApoE4 carriers.

Just as a reminder in subgroup analysis of Study 201, efficacy (CDR-SB) in the treatment arm (10 mg/kg biweekly) relative to the placebo arm was: Greater in mild AD patients: Reduction in clinical decline was 14% in MCI due to AD and 51% in mild AD (statistical test results undisclosed) Greater among ApoE4 carriers: Reduction in clinical decline was 60% in ApoE4 carriers and -7% in ApoE4 non-carriers If there are similarly large differences between subgroups in the Clarity study, there will be a debate over whether usage should be limited to certain groups such as (1) early-stage AD patients, and/or (2) ApoE4 carriers.

Now if you were to combine lecanamab with say Aricept, which may soon be available as a prodrug thus avoiding the need for titration and many of GI side effects, you might have something that will provide a much slower decline path and possibly a period of stabilization.