Help me understand neuroscience, I'm sure that will be easy
July 18, 2023 2:50 PM Subscribe
Help an interested layperson: what is the scientific view of the role of amyloid beta in Alzheimer's disease? Books, articles, whatever - I would love to learn more.
.... I mean, obviously this is a big big question, and I'm not a scientist. This question is partly prompted by reading about the apparent success of donanemab in clinical trials. I'm in the UK and there have been a lot of big splashy news items about this (and it does sound like a breakthrough). But I understand there is some debate about the role of amyloid in Alzheimer's, and whether targeting it specifically will help clinically. And - I'm not sure where to start with my reading.
Could you help me out? I'm interested in learning more about what is actually happening in the brain when people have Alzheimer's. But I'm having a hard time hitting the sweet spot of in-depth enough vs. understandable as a layperson.
.... I mean, obviously this is a big big question, and I'm not a scientist. This question is partly prompted by reading about the apparent success of donanemab in clinical trials. I'm in the UK and there have been a lot of big splashy news items about this (and it does sound like a breakthrough). But I understand there is some debate about the role of amyloid in Alzheimer's, and whether targeting it specifically will help clinically. And - I'm not sure where to start with my reading.
Could you help me out? I'm interested in learning more about what is actually happening in the brain when people have Alzheimer's. But I'm having a hard time hitting the sweet spot of in-depth enough vs. understandable as a layperson.
I read The Fragile Brain: The strange, hopeful science of dementia by Kathleen Taylor a couple of years ago. It was recommended to me by my father, who has dementia, and who is on the clinical trial of lecanemab. I found it understandable from a lay person's point of view. It is on the fence, leaning negative, about the amyloid hypothesis, as far as I recall. It's from 2016, however, so will be interested to hear what is recommended that is more up to date, as will my father.
posted by paduasoy at 3:04 PM on July 18, 2023
posted by paduasoy at 3:04 PM on July 18, 2023
I'd really caution against reading articles from even a year or two ago without a generous helping of salt. The very recent, and frankly rather surprising, successful trials of e.g. lecanemab & donanemab have really changed the picture.
posted by kickingtheground at 3:05 PM on July 18, 2023 [2 favorites]
posted by kickingtheground at 3:05 PM on July 18, 2023 [2 favorites]
By far the best guide in my opinion, and not by any means coincidentally among the most skeptical, is Derek Lowe at In the Pipeline, and he happens to have devoted today's column to donenamab:
I wrote earlier this year about donenamab, the anti-amyloid antibody developed by Eli Lilly that they’re hoping to get approved by the FDA. At the time, I said that we all really need to see more clinical data than the Lilly press release had in it at the time, and now that day has arrived. So what’s the verdict?posted by jamjam at 4:06 PM on July 18, 2023 [2 favorites]
Unfortunately, these numbers do not get rid of my doubts. The clinical trial was able to demonstrate a slowing of disease progression, but it’s still not possible to say if that reaches a level that any nonspecialist observer would be able to notice outside of a controlled clinical trial. Just to be clear, by “nonspecialist observers”, I mean family members and acquaintances: would they be able to tell that a person was taking donanemab or not?
It’s still not clear, based on the changes in the rating scales, if they would, and that’s using the rating scale difference after 76 weeks of treatment. It’s important to remember that both the patients getting the antibody and the control patients getting placebo IVs deteriorated steadily over this whole period - it’s a painful and horrible fact that we don’t know of anything that keeps Alzheimer’s patients from deteriorating steadily. At best, donanemab might slow this down a bit, but I have to say that this might also depend on which rating scale you use. The ADCAS-iADL scale shows the greatest effect, albeit with the widest variance, but others (such as the MMSE) show what may be less slowing of the disease progression (ranging down to imperceptible levels), although to be fair, the error bars overlap. And no, we don’t know which of these scales is the best marker for real-world effects, nor what to what degree deterioration in them is likely to be noticed by non-clinicians.
[…]
Backing up from aducanemab and friends a bit....
Amyloid has long been considered the hallmark protein of Alzheimer's disease. Back in 1906, a woman named Auguste Deter died of sepsis, after about five years of progressive confusion and paranoia. She had been institutionalized in a psychiatric hospital, where neurology resident Dr. Alois Alzheimer became interested in her care. Eventually the cost became too much for her husband, at which time Dr. A offered to fund her care himself, provided he could examine her brain on autopsy -- a curious and kind of unethical response to the cost of long-term care!
Anyway, when Dr. A ultimately stained Frau Deter's brain with silver, it lit up with what he called amyloid plaques and neurofibrillary tangles. These are considered the hallmark findings of Alzheimer's disease (AD, which ironically were also Frau Deter's initials...) and are presumed to be the causative agent* -- smut "clogging up" the normal synaptic processes, if you will. For the last 100+ years, the main research efforts in AD have been to find a way to vacuum up that amyloid and get rid of it. When I was a medical student, lo these many years, beta-secretase inhibitors, which were supposed to stop amyloid plaque from forming in the first place, were the exciting new trials. Unfortunately none of them panned out.
Which makes it all the more impressive that lecanemab and donanemab actually do seem to work. Unlike aducanemab, which only met its fake-out biomarker endpoint and its clinical endpoint, both of these drugs do seem to slow (???) the progression of disease. It's important to note that they do NOT reverse changes, or even stop progression entirely. But they do seem to slow progression by several months. And while the risk of brain bleeds is still there (this was the biggest issue with aducanemab -- it didn't work AND it killed people!), 6-8 months of functional independence may be meaningful to some. Both trials were 18 months long, which is where the press reports of 27-35% benefit comes from. Lecanemab is currently in open-label extension, and I presume they will do the same with donanemab.
With regard to the "would anyone notice" point -- it's a fair one, for sure. The two trials used different scales for their primary (clinical) endpoint, with different minimal clinically important differences (MCID), essentially the minimum meaningful change between time 1 and time 2. For lecanemab, there was a 0.45 point difference on a MCID of 1-2, and for donanemab, there was a 2.92 point difference on a MCID of 5-9. That's the glass-half-empty way to look at it.
It's kind of wild to think that all this is ultimately built on the brain of a 19th century German seamstress who happened to carry an unlucky gene. I work in the related field of Parkinson's disease, where we are maybe like 25 years behind AD researchers in our understanding of the disease process. These two drugs bring me some hope that we might be able to accelerate our own anti-synuclein therapies, using the lessons learned from our cognitive neurology friends.
* This is somewhat controversial, as it's possible that amyloid is just a bystander. That seems less of a tenable hypothesis in light of data that vacuuming up the amyloid, as demonstrated in CLARITY-AD (NEJM, open-access) and TRAILBLAZER-ALZ-2 (JAMA, probably paywalled), leads to actual clinical slowing.
posted by basalganglia at 5:03 PM on July 18, 2023 [14 favorites]
Amyloid has long been considered the hallmark protein of Alzheimer's disease. Back in 1906, a woman named Auguste Deter died of sepsis, after about five years of progressive confusion and paranoia. She had been institutionalized in a psychiatric hospital, where neurology resident Dr. Alois Alzheimer became interested in her care. Eventually the cost became too much for her husband, at which time Dr. A offered to fund her care himself, provided he could examine her brain on autopsy -- a curious and kind of unethical response to the cost of long-term care!
Anyway, when Dr. A ultimately stained Frau Deter's brain with silver, it lit up with what he called amyloid plaques and neurofibrillary tangles. These are considered the hallmark findings of Alzheimer's disease (AD, which ironically were also Frau Deter's initials...) and are presumed to be the causative agent* -- smut "clogging up" the normal synaptic processes, if you will. For the last 100+ years, the main research efforts in AD have been to find a way to vacuum up that amyloid and get rid of it. When I was a medical student, lo these many years, beta-secretase inhibitors, which were supposed to stop amyloid plaque from forming in the first place, were the exciting new trials. Unfortunately none of them panned out.
Which makes it all the more impressive that lecanemab and donanemab actually do seem to work. Unlike aducanemab, which only met its fake-out biomarker endpoint and its clinical endpoint, both of these drugs do seem to slow (???) the progression of disease. It's important to note that they do NOT reverse changes, or even stop progression entirely. But they do seem to slow progression by several months. And while the risk of brain bleeds is still there (this was the biggest issue with aducanemab -- it didn't work AND it killed people!), 6-8 months of functional independence may be meaningful to some. Both trials were 18 months long, which is where the press reports of 27-35% benefit comes from. Lecanemab is currently in open-label extension, and I presume they will do the same with donanemab.
With regard to the "would anyone notice" point -- it's a fair one, for sure. The two trials used different scales for their primary (clinical) endpoint, with different minimal clinically important differences (MCID), essentially the minimum meaningful change between time 1 and time 2. For lecanemab, there was a 0.45 point difference on a MCID of 1-2, and for donanemab, there was a 2.92 point difference on a MCID of 5-9. That's the glass-half-empty way to look at it.
It's kind of wild to think that all this is ultimately built on the brain of a 19th century German seamstress who happened to carry an unlucky gene. I work in the related field of Parkinson's disease, where we are maybe like 25 years behind AD researchers in our understanding of the disease process. These two drugs bring me some hope that we might be able to accelerate our own anti-synuclein therapies, using the lessons learned from our cognitive neurology friends.
* This is somewhat controversial, as it's possible that amyloid is just a bystander. That seems less of a tenable hypothesis in light of data that vacuuming up the amyloid, as demonstrated in CLARITY-AD (NEJM, open-access) and TRAILBLAZER-ALZ-2 (JAMA, probably paywalled), leads to actual clinical slowing.
posted by basalganglia at 5:03 PM on July 18, 2023 [14 favorites]
Here is the summary of a systematic review on amyloid beta testing.
And here is a link to the full review. If you read the background and discussion sections, both will discuss AB both generally and in the context of this study. There will be more references in those sections that could provide additional background.
Cautionary note: disregard all the bits between background and discussion, like study methods and results - these are lengthy, technical, extremely detailed sections that are adjacent to your question.
posted by lulu68 at 5:40 PM on July 18, 2023
And here is a link to the full review. If you read the background and discussion sections, both will discuss AB both generally and in the context of this study. There will be more references in those sections that could provide additional background.
Cautionary note: disregard all the bits between background and discussion, like study methods and results - these are lengthy, technical, extremely detailed sections that are adjacent to your question.
posted by lulu68 at 5:40 PM on July 18, 2023
The theory goes, first your brain starts to accumulate amyloid plaques in the extra cellular spaces around your neurons; this leads to neuroinflammation as non-neuronal cells nearby (microglia) attempt to rid the brain of the amyloid, but can’t; meanwhile, the amyloid accumulation has also triggered the spreading of neurofibrillary tangles made of phosphorylated tau protein, inside neurons. The amyloid and the tau are in effect prions, self-propagating proteins which, if they are misfolded, cause others to misfold, and then in these bad conformations, they aggregate. In the end, this aggregation kills neurons, and your brain begins to shrink, most notably first in the hippocampus, but then all over.
Things I do not understand yet. I believe tau is a protein that provides structure to microtubules neurons, used for transporting stuff around the cell, but what is amyloid for? What starts the misfolding & accumulation in the first place? We know certain genes cause it to start younger on average, some before middle age. I don’t know of a lifestyle marker that correlates with onset. This is puzzling because many have claimed relationships between lifestyle factors and dementia risk. Why are drugs which are incredibly effective at clearing amyloid only somewhat effective at saving the person? Most importantly, what will we see when the people who now begin taking these drugs have been on them for ten years?
posted by eirias at 7:33 PM on July 18, 2023 [1 favorite]
Things I do not understand yet. I believe tau is a protein that provides structure to microtubules neurons, used for transporting stuff around the cell, but what is amyloid for? What starts the misfolding & accumulation in the first place? We know certain genes cause it to start younger on average, some before middle age. I don’t know of a lifestyle marker that correlates with onset. This is puzzling because many have claimed relationships between lifestyle factors and dementia risk. Why are drugs which are incredibly effective at clearing amyloid only somewhat effective at saving the person? Most importantly, what will we see when the people who now begin taking these drugs have been on them for ten years?
posted by eirias at 7:33 PM on July 18, 2023 [1 favorite]
I'm a big fan or Robert Sapolsky, neurobiologist at Stanford. His 1st year course videos for Human Behavioral Biology are online and recommended. Not specific to your interest in amyloid beta and Alzheimer's disease, but an excellent intro to neurobiology
posted by theora55 at 9:58 PM on July 18, 2023 [1 favorite]
posted by theora55 at 9:58 PM on July 18, 2023 [1 favorite]
Best answer: Hello from the tail end of the Alzheimer’s Association International Conference! I am writing/wrote this before and after watching a set of presentations on results from a bunch of the clinical trials, both successful (lecanemab, donanemab) and unsuccessful. I was just watching a Q&A where clinicians and researchers were directly discussing this question, the exact role of amyloid beta in the devlopment of Alzheimer’s disease, in the context of the newer trial results. Answer: it’s uncertain!
I’m not an AD researcher or science communicator person by trade so I don’t want to say anything that could be claimed as the latest Science Facts on the possible root cause of Alzheimer’s disease. I am just a layperson who has seen a ton of AD talks for my job. I don’t think I’m actually going to have much specific substance to add to this thread but given that I have spent the past few days listening to the people who know the most about it presenting their latest work about this exact topic I feel compelled to post. Amyloid plaques in the brain are a hallmark of the disease, but AD researchers are still very deep in the process of determining what the actual cause of the disease is and amyloid’s exact role in it.
Right now, in July 2023, we now have drugs that can reduce amyloid in the brain as measured by amyloid PET imaging, and improve CSF- and blood-based biomarker measures (as measured by the most well-established measurement methods we have right now). In trials or some experimental drugs, the improvement of amyloid measures did not come with improved cognitive measures. Results from multiple trials (each!) of the new drugs lecanemab and donanemab showed both amyloid improvement and cognitive improvement. (I’m not going to mention aducanumab at the moment.) It’s not a huge amount of “time saved” in terms of disease progression but it’s still VERY early right now and all of these clinical trial datasets are going to be hugely valuable in the upcoming years in helping elucidate what happens when amyloid gets reduced (specifically at the point in the individuals’ disease courses when they entered the trial). Based on the results there’s a good chance that outcomes could be improved by targeting amyloid earlier in the disease course before it can accumulate further and cause more damage. But the actual causality is still under active (very active!!! so active!!!!) discussion.
By posting here I just want to try to express how much the current research is like stepping into a running river of information that is constantly flowing. Everyone has their own niche and is studying it in extreme detail. Tomorrow is the last day of this particular conference and in the next week or two all the researchers will go home and take back what they got from the massive amount of presentations that they saw in their particular niche and start to use it to build on their own group’s work. In general I kind of just want to tell anyone reading this to be VERY careful to avoid interpreting anything from more than a couple years ago as established fact. There is so much motivation and funding for figuring out and treating this disease and research is moving really fast in every single niche - investigation of new measures and how useful they are for AD, updating diagnostic criteria to refine what is even considered to be a positive AD diagnosis (uh please don’t tell my boss I missed that one…), developments in technology and analysis, examinations of genetic factors, investigations of heterogeneity of disease development speed and severity, investigations of various risk factors and protective factors, trying to tease apart the order of the changes that happen that we know about within the “normal” disease course. I’m generalizing and leaving out a heck of a lot.
So much of the research I’m seeing focuses on trying to figure out what’s going on and why. The clinical trials that get us to the “so how can we fix it” part are a relatively small percentage of the work presented but they provide a ton of info on whether some of these hypotheses make sense and where prior results might fit into the big picture. And the trials take a relatively long time before the results start coming out, so they were all designed and started with the information and technology available at that point. The latest clinical trial news is just the tip of the iceberg in terms of the research work going on, and all that research work that is unrelated or less-immediately related to amyloid is also concurrently leading to drug trials for other potential targets. Targeting tau is most likely the next big pharmaceutical goal. The anti-amyloid drugs did best in people who were earlier in the disease so if trying them in earlier or preclinical AD works even better it will definitely shift the current thinking about timing of which detectable changes happen when as AD develops and progresses.
All that said, I did some searching and found this 2023 summary of a review article from 2021 (PDF of summary), which is getting a little up there in age (I wouldn’t have thought so but today I heard someone describe a 2021 publication as “a few years old by now” - haha??). The first and last authors are people affiliated with Eisai so are obviously heavily involved in and invested in the recent successes (donanemab is Lilly and lecanemab is Eisai/Biogen). But I confirmed with an Actual Researcher that it’s a good journal and there are other big AD names on the author list and the things I’m more familiar with in that summary mostly check out with what I’ve seen recently and over the past few days so I’m hoping the areas I’m less familiar with are also decent.
I was just informed by my actual-researcher partner that Alzforum is a good public facing research resource that actual researchers post actual information to.
There’s also a good chance that the Alzhemer’s Association will put out a nice summary write up of this year’s conference highlights in the next week or two which I would personally tend to trust, while being aware that they are also Very Excited about things that are leading to treatments.
Generally if you dig in looking for other sources for the current understanding of AD disease processes, you’ll reeeally want to make sure that its references are recent, probably within the last year, peer reviewed, and from reputable journals.
Sorry I said a lot and maybe was not particularly helpful about your question! But I hope I was able to give a little context on why it’s not an easy answer!
posted by freesocker at 4:21 PM on July 19, 2023 [7 favorites]
I’m not an AD researcher or science communicator person by trade so I don’t want to say anything that could be claimed as the latest Science Facts on the possible root cause of Alzheimer’s disease. I am just a layperson who has seen a ton of AD talks for my job. I don’t think I’m actually going to have much specific substance to add to this thread but given that I have spent the past few days listening to the people who know the most about it presenting their latest work about this exact topic I feel compelled to post. Amyloid plaques in the brain are a hallmark of the disease, but AD researchers are still very deep in the process of determining what the actual cause of the disease is and amyloid’s exact role in it.
Right now, in July 2023, we now have drugs that can reduce amyloid in the brain as measured by amyloid PET imaging, and improve CSF- and blood-based biomarker measures (as measured by the most well-established measurement methods we have right now). In trials or some experimental drugs, the improvement of amyloid measures did not come with improved cognitive measures. Results from multiple trials (each!) of the new drugs lecanemab and donanemab showed both amyloid improvement and cognitive improvement. (I’m not going to mention aducanumab at the moment.) It’s not a huge amount of “time saved” in terms of disease progression but it’s still VERY early right now and all of these clinical trial datasets are going to be hugely valuable in the upcoming years in helping elucidate what happens when amyloid gets reduced (specifically at the point in the individuals’ disease courses when they entered the trial). Based on the results there’s a good chance that outcomes could be improved by targeting amyloid earlier in the disease course before it can accumulate further and cause more damage. But the actual causality is still under active (very active!!! so active!!!!) discussion.
By posting here I just want to try to express how much the current research is like stepping into a running river of information that is constantly flowing. Everyone has their own niche and is studying it in extreme detail. Tomorrow is the last day of this particular conference and in the next week or two all the researchers will go home and take back what they got from the massive amount of presentations that they saw in their particular niche and start to use it to build on their own group’s work. In general I kind of just want to tell anyone reading this to be VERY careful to avoid interpreting anything from more than a couple years ago as established fact. There is so much motivation and funding for figuring out and treating this disease and research is moving really fast in every single niche - investigation of new measures and how useful they are for AD, updating diagnostic criteria to refine what is even considered to be a positive AD diagnosis (uh please don’t tell my boss I missed that one…), developments in technology and analysis, examinations of genetic factors, investigations of heterogeneity of disease development speed and severity, investigations of various risk factors and protective factors, trying to tease apart the order of the changes that happen that we know about within the “normal” disease course. I’m generalizing and leaving out a heck of a lot.
So much of the research I’m seeing focuses on trying to figure out what’s going on and why. The clinical trials that get us to the “so how can we fix it” part are a relatively small percentage of the work presented but they provide a ton of info on whether some of these hypotheses make sense and where prior results might fit into the big picture. And the trials take a relatively long time before the results start coming out, so they were all designed and started with the information and technology available at that point. The latest clinical trial news is just the tip of the iceberg in terms of the research work going on, and all that research work that is unrelated or less-immediately related to amyloid is also concurrently leading to drug trials for other potential targets. Targeting tau is most likely the next big pharmaceutical goal. The anti-amyloid drugs did best in people who were earlier in the disease so if trying them in earlier or preclinical AD works even better it will definitely shift the current thinking about timing of which detectable changes happen when as AD develops and progresses.
All that said, I did some searching and found this 2023 summary of a review article from 2021 (PDF of summary), which is getting a little up there in age (I wouldn’t have thought so but today I heard someone describe a 2021 publication as “a few years old by now” - haha??). The first and last authors are people affiliated with Eisai so are obviously heavily involved in and invested in the recent successes (donanemab is Lilly and lecanemab is Eisai/Biogen). But I confirmed with an Actual Researcher that it’s a good journal and there are other big AD names on the author list and the things I’m more familiar with in that summary mostly check out with what I’ve seen recently and over the past few days so I’m hoping the areas I’m less familiar with are also decent.
I was just informed by my actual-researcher partner that Alzforum is a good public facing research resource that actual researchers post actual information to.
There’s also a good chance that the Alzhemer’s Association will put out a nice summary write up of this year’s conference highlights in the next week or two which I would personally tend to trust, while being aware that they are also Very Excited about things that are leading to treatments.
Generally if you dig in looking for other sources for the current understanding of AD disease processes, you’ll reeeally want to make sure that its references are recent, probably within the last year, peer reviewed, and from reputable journals.
Sorry I said a lot and maybe was not particularly helpful about your question! But I hope I was able to give a little context on why it’s not an easy answer!
posted by freesocker at 4:21 PM on July 19, 2023 [7 favorites]
Results from multiple trials (each!) of the new drugs lecanemab and donanemab showed both amyloid improvement and cognitive improvement
So far as I've read, the best any of these drugs has managed is a mild slowing of the progression of cognitive decline compared to placebo.
While "doing better than if you hadn't taken the drug" might be considered an "improvement" to some, it's important to use precise language.
The average patient doesn't improve on these drugs; they *might* get worse slightly more slowly.
You mention you are at a conference, so perhaps my data is old.
posted by soylent00FF00 at 6:32 PM on July 23, 2023 [2 favorites]
So far as I've read, the best any of these drugs has managed is a mild slowing of the progression of cognitive decline compared to placebo.
While "doing better than if you hadn't taken the drug" might be considered an "improvement" to some, it's important to use precise language.
The average patient doesn't improve on these drugs; they *might* get worse slightly more slowly.
You mention you are at a conference, so perhaps my data is old.
posted by soylent00FF00 at 6:32 PM on July 23, 2023 [2 favorites]
These drugs are great at eliminating amyloid but do next to nothing against the disease. One fellow I know (a doctor but not a dementia expert) says "maybe amyloid is the tombstone of a dead neuron". In which case, removing amyloid doesn't solve anything.
The Alzheimer's Association is strongly advocating use of these drugs for some reason. I suggest taking anything coming out of AA with a grain of salt.
posted by neuron at 4:34 PM on July 24, 2023 [1 favorite]
The Alzheimer's Association is strongly advocating use of these drugs for some reason. I suggest taking anything coming out of AA with a grain of salt.
posted by neuron at 4:34 PM on July 24, 2023 [1 favorite]
the best any of these drugs has managed is a mild slowing of the progression of cognitive decline compared to placebo
yes this is correct, sorry my language was imprecise! It is not a lot on its face, but as far as I know it’s a relatively big result compared to other treatment trials.
posted by freesocker at 8:08 PM on August 3, 2023
yes this is correct, sorry my language was imprecise! It is not a lot on its face, but as far as I know it’s a relatively big result compared to other treatment trials.
posted by freesocker at 8:08 PM on August 3, 2023
You are not logged in, either login or create an account to post comments
posted by rockindata at 2:52 PM on July 18, 2023