This is a thorough and well-written review of the evidence that supports this hypothesis. However, I think that you oversimplified a bit and missed the big problem, which is disease heterogeneity. You correctly state the obvious, that some patients respond much better than the average response, but neglect to mention that a significant number of patients do not respond at all (why such a big difference?). The trials of the existing drugs had to be huge (900 per arm!) and extremely expensive in order to average out the variability and arrive at a statistically significant result. This is not a sustainable model for development of new AD drugs. The problem is that Alzheimer's disease is not a single entity. We need to tackle this issue before we discuss novel targets or combination therapies.
There is a garden variety type and soon enough will be better defined based on plasma cut offs as opposed to abeta PET. Amnestic MCI with positive AD biomarkers and a "typical" AD pattern on MRI or FDG PET. Take the Evoke trials, the placebo arms had a very predictable decline with a sample size of 900. Within 5 years, trials will be cheaper and smaller.
Thanks. This applies to many chronic diseases, take diabetes. It has many subtypes but drug development focuses on the garden variety. ultimately, we rely on simple and cheap biomarkers.
Any thoughts on whether Trontinemab would work work differently for APOE4/4 if there is evidence of mild chronic microangiopathy and vascular calcifications in the anterior and posterior circulate. I am trying to help my sister decide if this is the best clinical trial to enter into and feel strongly that the benefit/risk analysis does not suggest that it is. Not sure that clearing the amyloid plaques will result in actual cognitive benefit if not targeting vascular issues. I can't find actual data on side effects for Aria-H for the trial. Are there any trials that are combining targets? She is very scared that she is nearing a "tipping point" in the progression of the disease which is what she is being told by the trial and that it is important to begin trials before then. (Currently plasma Tau positive but Tau Pet neg and amyloid pet positive with minimal cognitive issues) Are there any defining cutoffs for efficacy? Thank you.
Regarding the appreciation for neuroinflammation and neurodegeneration: Would you expect to see autonomic nervous system dysfunction/failure earlier in disease?
Dear Amy, in classic AD, you do not see autonomic system failure early in the disease. However, a small brain area called the locus coeruleus begins to malfunction very early, sometimes many years before memory problems appear. This region helps control attention, alertness, sleep, and stress responses by releasing a chemical called norepinephrine that supports communication between brain cells and helps protect the brain from inflammation. tau starts to build up in these cells, causing them to weaken or die. Because the locus coeruleus connects to many parts of the brain, its early damage may contribute to problems like sleep changes, mood symptoms, and difficulty focusing, and may also help the disease spread to areas involved in memory. But sometimes these changes are subtle.
This is a thorough and well-written review of the evidence that supports this hypothesis. However, I think that you oversimplified a bit and missed the big problem, which is disease heterogeneity. You correctly state the obvious, that some patients respond much better than the average response, but neglect to mention that a significant number of patients do not respond at all (why such a big difference?). The trials of the existing drugs had to be huge (900 per arm!) and extremely expensive in order to average out the variability and arrive at a statistically significant result. This is not a sustainable model for development of new AD drugs. The problem is that Alzheimer's disease is not a single entity. We need to tackle this issue before we discuss novel targets or combination therapies.
There is a garden variety type and soon enough will be better defined based on plasma cut offs as opposed to abeta PET. Amnestic MCI with positive AD biomarkers and a "typical" AD pattern on MRI or FDG PET. Take the Evoke trials, the placebo arms had a very predictable decline with a sample size of 900. Within 5 years, trials will be cheaper and smaller.
Thanks. This applies to many chronic diseases, take diabetes. It has many subtypes but drug development focuses on the garden variety. ultimately, we rely on simple and cheap biomarkers.
Plasma AD biomarkers with a simple brain imaging tools such as FDG PET can provide several dementia subtypes. https://www.neurology.org/doi/10.1212/WNL.0000000000213831?__cf_chl_tk=312brAo_8RU2s6e27bFTCLIC3P2s0ThDEeH1kfd9Gps-1778545079-1.0.1.1-zL2j9jYYY0rwv1J88BZdh7LEgjnPfzbMm6Zyvygdgns
I’m not sure that there is a garden variety of AD
Thanks for this. I’m obviously not a clinician.
Also, maybe you should publish this in a "traditional" journal too after elaborating on some more details.
Will be glad to review it 😇
Thank you Jungsu!
Traditional journals will become obsolete
Some are by invitation only due to prestige. Clubs.
Others are charging an arm and a leg or no one can read it.
We need an open peer review system and I kind of like my freedom at slack
But it is dangerous to go unchecked! So feel free to peer review me!
A very well balanced article 👏 👍
I appreciate your tremendous efforts to educate the public!
I have a suggestion. Maybe list the take home messages at the start of the article especially when an article is quite lengthy 🤔
Any thoughts on whether Trontinemab would work work differently for APOE4/4 if there is evidence of mild chronic microangiopathy and vascular calcifications in the anterior and posterior circulate. I am trying to help my sister decide if this is the best clinical trial to enter into and feel strongly that the benefit/risk analysis does not suggest that it is. Not sure that clearing the amyloid plaques will result in actual cognitive benefit if not targeting vascular issues. I can't find actual data on side effects for Aria-H for the trial. Are there any trials that are combining targets? She is very scared that she is nearing a "tipping point" in the progression of the disease which is what she is being told by the trial and that it is important to begin trials before then. (Currently plasma Tau positive but Tau Pet neg and amyloid pet positive with minimal cognitive issues) Are there any defining cutoffs for efficacy? Thank you.
Pam (3/4)
Dear Pam, thank you for reaching out. I would suggest a thoughtful discussion with the neurologist about the risks and benefits of such treatments.
Regarding the appreciation for neuroinflammation and neurodegeneration: Would you expect to see autonomic nervous system dysfunction/failure earlier in disease?
Dear Amy, in classic AD, you do not see autonomic system failure early in the disease. However, a small brain area called the locus coeruleus begins to malfunction very early, sometimes many years before memory problems appear. This region helps control attention, alertness, sleep, and stress responses by releasing a chemical called norepinephrine that supports communication between brain cells and helps protect the brain from inflammation. tau starts to build up in these cells, causing them to weaken or die. Because the locus coeruleus connects to many parts of the brain, its early damage may contribute to problems like sleep changes, mood symptoms, and difficulty focusing, and may also help the disease spread to areas involved in memory. But sometimes these changes are subtle.