A thought-provoking read. As a physician-scientist, I think one of the most fascinating aspects of perception is that our brains are not passive recorders of reality, but they are active prediction engines, continuously integrating sensory input with prior experience, attention, and expectation.
This is why neuroscience has increasingly shifted from asking how the brain receives information to how it constructs our experience of the world. What we perceive is the result of an ongoing dialogue between bottom-up sensory signals and top-down predictions. Most of the time this process is remarkably accurate, but it also explains why context, expectation, and cognitive biases can profoundly shape what we think we see, hear, or understand.
I also think this has broader implications beyond neuroscience. It reminds us to approach our own intuitions with humility. Whether in medicine, science, or everyday life, our first interpretation is not always our most accurate one. The discipline of science exists, in part, because it provides methods for testing perceptions against objective evidence.
Perhaps that’s what makes the study of the mind so compelling: understanding perception isn’t just about learning how the brain works but it’s about learning how we come to know anything at all.
Clarification I’m suggesting doing trials in most at risk , biomarker and genotype defined and rolling these back into the larger community with mass targeted genotyping eg uae would maybe have a better and quicker payoff.
Check my later post on pTau217 and the scientific community's desire to identify a goldilocks zone for prevention. APOE4 has a minor effect once we factor in these blood biomarkers.
Thanks for your reply and I reread that article and your Goldilocks one. I agree that current generation biomarkers are relatively indefinite, hence blurring the makeup of the members of the test group and thanks for update that reviewing the data by the E4 subgroup didn’t add much. Also noted the increased probability by increasing p217 score of dementia in e4 and e4/4 carriers, women in particular. That said I wondered if stratifying and selecting the whole cohort by BDptau217 in combination with e4 carriage changes predictive probability enough that meaningful regimens and potential treatments could be trialled and assessed much more meaningfully and possibly quicker as the cohort would be massively enriched on day one?
Why this would be important might be that it would be highly characterised as a group, and potentially if used as a model, form a replicable group enabling comparable and serial studies.
The potential implication depends on where you sit on the treatment view. By this I mean something like these options for treatment and or prevention: M + T+A , G+M+T+A , G+M+geneT + V+T+A etc.
M= ‘motherhood ‘ ( no disrespect to mothers) but the usual health advice ever evolving and adding re UPfoods etc etc.
T = effective AntiTau therapy age just now beginning to dawn.
A = effective anti Amyloid therapy, maybe trontinemab, maybe a vaccine etc
G= genotyping probably getting ever earlier as benefits arrive (eg see United Arab Emirates program etc),
GeneTherapy is GeneT
But V= Variable and attacking the various sub pathologies eg energy deficit, inflamation etc in E4 , DNA repair mechanisms in HD etc. This is where new agents not Tau or Amyloid related happen and modern ‘bio hacking’ plus biomarkers etc ‘ is part of this like it or not pending more formal research.
It may be that some decent early mass vaccinations against tau tangles, and against APP cleavage etc makes a lot of M and V less potentially useful , but those interventions especially M (intensified as necessary on basis of G etc ) before good GeneT available .
In the case of HD gene therapy is now emerging ( uniqure, Skyhawk splice modulator etc) and Voyagers e4 silence, e2 transfection one shot aav capsid intravenous, may do the job ( noting Lexeo phase 1) but even there in VYGR and in Milversan (Anylam) the focus now seems to be on big A and big T therapies , not the most specific ones for at risk genes. So it’s the old case of silver bullet overall vs nuanced therapeutics in subgroups. However these are commercial operations.
Thats a ramble. The point is that up to 60% of ALZ is E4 ( and to a degreeE3 highly related, I’m suggesting go for the low hanging fruit of the highest risk groups defined by the best tools eg BD217p to best assess what of the things we have now in that list of capital letters above , works to whatever degree. They are also I suspect the most motivated. Intervening when the ship is half sunk means too many different compartments have blown open in an accelerating catastrophic feedback.
Thank you for this analysis. I was wondering if the E4 subgroup was separately reported? Also if obviously at greater cost, with all that means, any of these interventions should look at biomarkers like plasma pTau217 and NfL?As well although again a more specific population, in a future program having e4 /e3 subgroup would pick up 60% of ALZ and allow potential treatments for the most at risk populations? The kicker is that if general type interventions in these trials don’t show a lot ( and agree re avoiding ultra processed etc) maybe the sweet spot of population based progress on actual ALZ is find the interventions in e4 ( not just diet exercise but more) that add the most value in the most at risk groups and roll those *back into the larger community* on the basis of the upcoming massive uptake/ rollout of multibiomarker on a fingerpick card ( ptau217, gfap, nfl etc) that identifies who benefits most. And that 25% at least carry that allele. Doing trials/ interventions from the ground up instead of from the juicy targets back to the general community I think would have the largest quick payoff, since quick gene testing is way cost effective over lifetime care. E4 are the canaries in the ALZ coal mine .
( Obviously also legislated change to air pollution, microplastics, ultra processed food, poverty would be great but keep dreaming.)
A thought-provoking read. As a physician-scientist, I think one of the most fascinating aspects of perception is that our brains are not passive recorders of reality, but they are active prediction engines, continuously integrating sensory input with prior experience, attention, and expectation.
This is why neuroscience has increasingly shifted from asking how the brain receives information to how it constructs our experience of the world. What we perceive is the result of an ongoing dialogue between bottom-up sensory signals and top-down predictions. Most of the time this process is remarkably accurate, but it also explains why context, expectation, and cognitive biases can profoundly shape what we think we see, hear, or understand.
I also think this has broader implications beyond neuroscience. It reminds us to approach our own intuitions with humility. Whether in medicine, science, or everyday life, our first interpretation is not always our most accurate one. The discipline of science exists, in part, because it provides methods for testing perceptions against objective evidence.
Perhaps that’s what makes the study of the mind so compelling: understanding perception isn’t just about learning how the brain works but it’s about learning how we come to know anything at all.
Thanks again!
I am happy to see your comment, and we both agree on the beauty of studying the brain.
Thank you so much for pulling together this information and giving your expert analysis with suggestions for future studies!
Always happy to hear from you Diane!
Part of the original comment is back to front typo
Clarification I’m suggesting doing trials in most at risk , biomarker and genotype defined and rolling these back into the larger community with mass targeted genotyping eg uae would maybe have a better and quicker payoff.
Dear CB
Check my later post on pTau217 and the scientific community's desire to identify a goldilocks zone for prevention. APOE4 has a minor effect once we factor in these blood biomarkers.
Thanks for your reply and I reread that article and your Goldilocks one. I agree that current generation biomarkers are relatively indefinite, hence blurring the makeup of the members of the test group and thanks for update that reviewing the data by the E4 subgroup didn’t add much. Also noted the increased probability by increasing p217 score of dementia in e4 and e4/4 carriers, women in particular. That said I wondered if stratifying and selecting the whole cohort by BDptau217 in combination with e4 carriage changes predictive probability enough that meaningful regimens and potential treatments could be trialled and assessed much more meaningfully and possibly quicker as the cohort would be massively enriched on day one?
Why this would be important might be that it would be highly characterised as a group, and potentially if used as a model, form a replicable group enabling comparable and serial studies.
The potential implication depends on where you sit on the treatment view. By this I mean something like these options for treatment and or prevention: M + T+A , G+M+T+A , G+M+geneT + V+T+A etc.
M= ‘motherhood ‘ ( no disrespect to mothers) but the usual health advice ever evolving and adding re UPfoods etc etc.
T = effective AntiTau therapy age just now beginning to dawn.
A = effective anti Amyloid therapy, maybe trontinemab, maybe a vaccine etc
G= genotyping probably getting ever earlier as benefits arrive (eg see United Arab Emirates program etc),
GeneTherapy is GeneT
But V= Variable and attacking the various sub pathologies eg energy deficit, inflamation etc in E4 , DNA repair mechanisms in HD etc. This is where new agents not Tau or Amyloid related happen and modern ‘bio hacking’ plus biomarkers etc ‘ is part of this like it or not pending more formal research.
It may be that some decent early mass vaccinations against tau tangles, and against APP cleavage etc makes a lot of M and V less potentially useful , but those interventions especially M (intensified as necessary on basis of G etc ) before good GeneT available .
In the case of HD gene therapy is now emerging ( uniqure, Skyhawk splice modulator etc) and Voyagers e4 silence, e2 transfection one shot aav capsid intravenous, may do the job ( noting Lexeo phase 1) but even there in VYGR and in Milversan (Anylam) the focus now seems to be on big A and big T therapies , not the most specific ones for at risk genes. So it’s the old case of silver bullet overall vs nuanced therapeutics in subgroups. However these are commercial operations.
Thats a ramble. The point is that up to 60% of ALZ is E4 ( and to a degreeE3 highly related, I’m suggesting go for the low hanging fruit of the highest risk groups defined by the best tools eg BD217p to best assess what of the things we have now in that list of capital letters above , works to whatever degree. They are also I suspect the most motivated. Intervening when the ship is half sunk means too many different compartments have blown open in an accelerating catastrophic feedback.
Hope to hear your thoughts.
Thank you for this analysis. I was wondering if the E4 subgroup was separately reported? Also if obviously at greater cost, with all that means, any of these interventions should look at biomarkers like plasma pTau217 and NfL?As well although again a more specific population, in a future program having e4 /e3 subgroup would pick up 60% of ALZ and allow potential treatments for the most at risk populations? The kicker is that if general type interventions in these trials don’t show a lot ( and agree re avoiding ultra processed etc) maybe the sweet spot of population based progress on actual ALZ is find the interventions in e4 ( not just diet exercise but more) that add the most value in the most at risk groups and roll those *back into the larger community* on the basis of the upcoming massive uptake/ rollout of multibiomarker on a fingerpick card ( ptau217, gfap, nfl etc) that identifies who benefits most. And that 25% at least carry that allele. Doing trials/ interventions from the ground up instead of from the juicy targets back to the general community I think would have the largest quick payoff, since quick gene testing is way cost effective over lifetime care. E4 are the canaries in the ALZ coal mine .
( Obviously also legislated change to air pollution, microplastics, ultra processed food, poverty would be great but keep dreaming.)
What a compelling article. Thank you. It took some real scientific, organizational and writing skills to pull this article together so well.