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How Not to Study a Disease: The Story of Alzheimer's
An authority on Alzheimer's disease offers a history of past failures and a roadmap that points us in a new direction in our journey to a cure.
For decades, some of our best and brightest medical scientists have dedicated themselves to finding a cure for Alzheimer's disease. What happened? Where is the cure? The biggest breakthroughs occurred twenty-five years ago, with little progress since. In How Not to Study a Disease , neurobiologist Karl Herrup explains why the Alzheimer's discoveries of the 1990s didn't bear fruit and maps a direction for future research. Herrup describes the research, explains what's taking so long, and offers an approach for resetting future research.
Herrup offers a unique insider's perspective, describing the red flags that science ignored in the rush to find a cure. He is unsparing in calling out the stubbornness, greed, and bad advice that has hamstrung the field, but his final message is a largely optimistic one. Herrup presents a new and sweeping vision of the field that includes a redefinition of the disease and a fresh conceptualization of aging and dementia that asks us to imagine the brain as a series of interconnected "neighborhoods." He calls for changes in virtually every aspect of the Alzheimer's disease research effort, from the drug development process, to the mechanisms of support for basic research, to the often-overlooked role of the scientific media, and more. With How Not to Study a Disease , Herrup provides a roadmap that points us in a new direction in our journey to a cure for Alzheimer's.
For decades, some of our best and brightest medical scientists have dedicated themselves to finding a cure for Alzheimer's disease. What happened? Where is the cure? The biggest breakthroughs occurred twenty-five years ago, with little progress since. In How Not to Study a Disease , neurobiologist Karl Herrup explains why the Alzheimer's discoveries of the 1990s didn't bear fruit and maps a direction for future research. Herrup describes the research, explains what's taking so long, and offers an approach for resetting future research.
Herrup offers a unique insider's perspective, describing the red flags that science ignored in the rush to find a cure. He is unsparing in calling out the stubbornness, greed, and bad advice that has hamstrung the field, but his final message is a largely optimistic one. Herrup presents a new and sweeping vision of the field that includes a redefinition of the disease and a fresh conceptualization of aging and dementia that asks us to imagine the brain as a series of interconnected "neighborhoods." He calls for changes in virtually every aspect of the Alzheimer's disease research effort, from the drug development process, to the mechanisms of support for basic research, to the often-overlooked role of the scientific media, and more. With How Not to Study a Disease , Herrup provides a roadmap that points us in a new direction in our journey to a cure for Alzheimer's.
272 pages, Hardcover
Published October 5, 2021
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Displaying 1 - 17 of 17 reviews
December 14, 2021
"For reasons that we partially understand, women are nearly twice as likely as men to develop Alzheimer’s disease. At 45 years of age, a woman’s lifetime risk of Alzheimer’s disease is about 20 percent; the risk for a 45-year-old man is about 10 percent. By age 65, the lifetime risk for both sexes increases slightly, but the twofold elevated risk just for being female is still found."
"A study was conducted in Scotland, where researchers tracked down people who had taken a nationwide IQ test in the 1940s and found that higher scores on the IQ test were correlated with a reduced risk of Alzheimer’s disease."
"Although there are features of our lives and life choices that are correlated with Alzheimer’s disease, to date only the aggressive lowering of blood pressure has been shown to actually block the disease."
"aging is not one highly regulated process but rather the biological consequences of selecting for a virtual cornucopia of genes that help us when we’re young."
"You live longer if you eat less. For those of us who really love to eat, this is a frightening thought. And if you’re hoping that for some reason this logic is faulty, it’s not. Restricting the number of calories eaten works to slow aging, it works well, and it works in every organism that’s been examined from yeast to mammals."
"The higher levels of blood insulin also lead to high levels of brain insulin, and the high levels of brain insulin drive our neurons to become insulin resistant. This is a huge problem because when neurons become insulin resistant, they get their signals crossed and trigger their oncogene-induced senescence program."
Still from The Wind Will Carry Us (Abbas Kiarostami, 1999)
October 23, 2021
Prof. Herrup provides important insights on how different perspectives can be integrated to our current strategies to find a cure for Alzheimer’s disease.
For researchers, I’m sure you’ll find great ideas in here, regardless of the role you perceive for amyloid-β in the disease course. Even from amyloid-related perspectives (part of my own research interests involve it), there is much more to it than focusing solely on the neuron, for example. Regarding other perspectives, we get a good panorama of the alternative (or maybe inclusive) models that emerged and faded over the years. He proposes a novel holistic model, with somewhat (intentional, according to him) unclear boundaries between different types of dementia + that a solely-clinical definition of AD is adopted.
For non-researchers, this can give you an idea of what the scientific field behind this terrible disease looks like, in an accessible language. Despite many brilliant and skilled researchers devoting their lives to it and recent increases in funding, Karl argues the disease’s extraordinary complexity (maybe unmatched in Medicine, he stresses) might require unprecedented complexity in the ways it is studied.
A great read and a long way to go still.
For researchers, I’m sure you’ll find great ideas in here, regardless of the role you perceive for amyloid-β in the disease course. Even from amyloid-related perspectives (part of my own research interests involve it), there is much more to it than focusing solely on the neuron, for example. Regarding other perspectives, we get a good panorama of the alternative (or maybe inclusive) models that emerged and faded over the years. He proposes a novel holistic model, with somewhat (intentional, according to him) unclear boundaries between different types of dementia + that a solely-clinical definition of AD is adopted.
For non-researchers, this can give you an idea of what the scientific field behind this terrible disease looks like, in an accessible language. Despite many brilliant and skilled researchers devoting their lives to it and recent increases in funding, Karl argues the disease’s extraordinary complexity (maybe unmatched in Medicine, he stresses) might require unprecedented complexity in the ways it is studied.
A great read and a long way to go still.
May 21, 2024
Very opinionated. Not incorrect, just aggressive in presentation.
May 3, 2026
How Not to Study a Disease : The Story of Alzheimer’s by Karl Herrup (2021) is an interesting book that describes how research into Alzheimer’s Disease has floundered and what should be done about it. Herrup is a Professor of Neurobiology. The book is an excellent companion to the book Doctored by Charles Pillar. Herrup expresses concerns about the dominant hypothesis for Alzheimer’s Disease (AD). This is the hypothesis that Amyloid Beta (AB) causes AD.
In the first part of the book Alzheimer’s is described from a layperson’s view, from a physicians view and from a scientists view. In the layperson’s view the personal toll that Alzheimer’s takes is first described. The huge cost of AD is also outlined.
In the physicians view Amyloid beta and tau tangles were first detected. Here Herrup also introduces conceptual models where plaques and tangles cause dementia, one where something else causes plaques, tangle and dementia and also a model where dementia causes, as a side effect, plaques and tangles. Herrup emphasizes that the causality may not be that way it is generally assumed to be.
In the scientists view the role of genetics, the role of inflammation, the role of fats in the brain, the role of vesicles and their transport of waste out of brain cells are all described. However, in 1995 a discovery was announced that led some Alzheimer’s researchers to believe that Alzheimer’s would be cured within the next 5 years. It was the discovery of Amyloid Beta. Knowledge of some kind of deposits goes back as far as ‘miliar deposits’ that Alois Alzheimer found in the first case described. Interestingly Alzheimer’s disease appears to only appear in humans. Once the Amyloid Beta hypothesis was made scientists managed to create a similar disease in mice and then cure it. A cure for humans was thought to be next.
Alas, over 30 years later, this hasn’t been the case.
In Part Two of the book Herrup goes into the problems with the AB hypothesis. Many people have substantial deposits but don’t develop AD. Also some people with AD don’t appear to have large deposits. Other possible causes are introduced such as myelin degradation in the brain. Also reactions to insulin may have an impact.
In the Third Part of the book the way funding for old age research and pharmaceutical research in the US is described and how this has impacted research into AD. The National Institutes of Health (NIH), The National Institute on Aging (NIA) and their turn toward AD is outlined. Herrup also writes about how the National Institute for Neurological Disorders and Stroke (NINDS) should be more involved in research into AD.
In the Fourth Part of the book Herrup writes about what should be done in future. He starts by pointing out the role of aging in general and how it is likely that AD is very much tied up with the biology of aging. He also describes how the institutions that fund research should be altered to better research AD and to not get fixated on one explanation.
How Not to Study a Disease is an excellent book about the problems with the study of Alzheimer’s Disease from the perspective of a scientist who has worked in the field. Herrup does a good job of convincing the reader that Amyloid Beta deposits are unlikely to be the driver of Alzheimer’s. He shows how a reasonable correlation may not cause the disease. This, and the failure to make progress in the past 30 years give a strong indication that other approaches are needed.
In the first part of the book Alzheimer’s is described from a layperson’s view, from a physicians view and from a scientists view. In the layperson’s view the personal toll that Alzheimer’s takes is first described. The huge cost of AD is also outlined.
In the physicians view Amyloid beta and tau tangles were first detected. Here Herrup also introduces conceptual models where plaques and tangles cause dementia, one where something else causes plaques, tangle and dementia and also a model where dementia causes, as a side effect, plaques and tangles. Herrup emphasizes that the causality may not be that way it is generally assumed to be.
In the scientists view the role of genetics, the role of inflammation, the role of fats in the brain, the role of vesicles and their transport of waste out of brain cells are all described. However, in 1995 a discovery was announced that led some Alzheimer’s researchers to believe that Alzheimer’s would be cured within the next 5 years. It was the discovery of Amyloid Beta. Knowledge of some kind of deposits goes back as far as ‘miliar deposits’ that Alois Alzheimer found in the first case described. Interestingly Alzheimer’s disease appears to only appear in humans. Once the Amyloid Beta hypothesis was made scientists managed to create a similar disease in mice and then cure it. A cure for humans was thought to be next.
Alas, over 30 years later, this hasn’t been the case.
In Part Two of the book Herrup goes into the problems with the AB hypothesis. Many people have substantial deposits but don’t develop AD. Also some people with AD don’t appear to have large deposits. Other possible causes are introduced such as myelin degradation in the brain. Also reactions to insulin may have an impact.
In the Third Part of the book the way funding for old age research and pharmaceutical research in the US is described and how this has impacted research into AD. The National Institutes of Health (NIH), The National Institute on Aging (NIA) and their turn toward AD is outlined. Herrup also writes about how the National Institute for Neurological Disorders and Stroke (NINDS) should be more involved in research into AD.
In the Fourth Part of the book Herrup writes about what should be done in future. He starts by pointing out the role of aging in general and how it is likely that AD is very much tied up with the biology of aging. He also describes how the institutions that fund research should be altered to better research AD and to not get fixated on one explanation.
How Not to Study a Disease is an excellent book about the problems with the study of Alzheimer’s Disease from the perspective of a scientist who has worked in the field. Herrup does a good job of convincing the reader that Amyloid Beta deposits are unlikely to be the driver of Alzheimer’s. He shows how a reasonable correlation may not cause the disease. This, and the failure to make progress in the past 30 years give a strong indication that other approaches are needed.
April 29, 2025
very interesting read for neuroscience book club! As a scientist I have worked at many places with AD projects, never really been involved in them myself, so it was really interesting to hear about the politics and overt ignorance of data by this community. I didn't realize such a majority of NIA funding went to AD, and while I was able to understand why pharma companies make the decisions they do, I didn't appreciate the long-ranging effects. I'm curious to know how this book was received by this community and what, if anything, has changed since.
July 18, 2022
In “How not to study a disease”, neurobiologist Prof Karl Herrup discusses how research into Alzheimer’s disease has been hindered by unfortunate research policy and practice. The trouble started with the definition of Alzheimer's disease as a form of dementia characterised by plaques in the brain without firm evidence that the plaques were relevant for the aetiology of the clinical presentation. Subsequently, the field became obsessed with the hypothesis that Alzheimer's disease is caused by amyloid plaques, ignored or explained away the evidence against this hypothesis, and did not pursue other promising ideas. The focus on amyloid was driven initially by promising genetic results and superficially encouraging treatments in rodent models. However, the single-minded focus on amyloid was also politically motivated. The newly founded NIH Institute of Aging had to find a suitable research target that could garner public interest. In turn, the pharmaceutical industry preferred to run questionable phase-two trials rather than admit failure to stakeholders.
The author also presents an alternative approach for research that could push the field of Alzheimer's disease research forward. That would entail diversifying the research portfolio to investigate processes like oxidative stress, the insulin pathway, and inflammation in typical ageing and AD. He also provides recommendations for a better institutional organisation to counteract the skew towards the amyloid hypothesis currently dominating the field.
Even though I work on the opposite of the lifespan, I found the book highly interesting. Research is portrayed as a rational enterprise focused on scientific progress. I liked that this book highlighted the unseen forces that influence research in the pursuit of a different agenda. I also liked the comprehensive yet accessible explanations of the neurobiology of AD. I highly recommend this book to anyone working in research on human diseases or disorders.
The author also presents an alternative approach for research that could push the field of Alzheimer's disease research forward. That would entail diversifying the research portfolio to investigate processes like oxidative stress, the insulin pathway, and inflammation in typical ageing and AD. He also provides recommendations for a better institutional organisation to counteract the skew towards the amyloid hypothesis currently dominating the field.
Even though I work on the opposite of the lifespan, I found the book highly interesting. Research is portrayed as a rational enterprise focused on scientific progress. I liked that this book highlighted the unseen forces that influence research in the pursuit of a different agenda. I also liked the comprehensive yet accessible explanations of the neurobiology of AD. I highly recommend this book to anyone working in research on human diseases or disorders.
June 9, 2025
I am a researcher with a special interest and background in preclinical drug development for AD (non-amyloid therapies for interested readers :p ). We read this for a neuroscience book club I run and I loved it. Fantastically detailed, process oriented and informative. I wish I had read it the summer before I started my postdoc. Note: most members of my book club are interested members of the general public, and the book was generally well liked and regarded as accessible. I won't go into all my thoughts here, but in case you're interested in the murder-mystery of the amyloid hypothesis, here is a juicy summary from the book.
The heady amyloid years:
• A team at UCSD gets access to amyloid plaques (via blood vessels that feed the brain, which might not be exactly the same type of plaques, but people thought at the time that the plaques only happened in AD, so it seemed reasonable), and figure out the amino acid sequence of it
• Down syndrome brain was loaded with amyloid, and amino acid sequence showed it to be very similar to the AD plaques imaged by the UCSD team. Down syndrome is caused by an extra copy of chromosome 21, and the gene for the main plaque protein (amyloid-beta peptides) mapped to that chromosome!
• Precursor protein for amyloid-beta peptides is tracked down, looks like a cell surface receptor protein that sticks into the cell membrane. They called it amyloid precursor protein (APP).
• In the 1990s, geneticists found that in familial, early-onset AD, mutations appeared very near where the amyloid-beta peptide gene is found on chromosome 21, and led to increased production of APP. Two more mutations were identified, presenilin 1 (chromosome 14) and presenilin 2 (chromosome 1), which are both associated with gamma-secretase, an enzyme that cuts APP. The presenilin mutations cut amyloid-beta peptides out of APP in a way that made the amyloid-beta peptides more prone to aggregation (a longer 42 amino acid form vs a shorter 40 amino acid form)
• Human beings are the only species that get amyloid plaques and associated dementia, for reasons not yet clear, even though most species have the APP gene as well as the two secretases that cleave it into amyloid-beta. So transgenic mice were created to carry the human version of the APP gene with mutations present in familial early-onset AD. Elan pharmaceuticals developed a vaccine using artificially synthesized amyloid-beta to train the immune system to recognize and clear amyloid-beta, which worked super well in mice to prevent and actually clear already formed plaques. But in human trials, the vaccine caused life-threatening side effects. Later, we did find a way to clear plaques (passive immunization, but that didn’t help either).
Thus the amyloid cascade idea was formed. Because of the genetics of early-onset AD, plaques became the main focus of the field. The idea that amyloid-beta plaques caused AD was so strong that in future trials, amyloid-beta in CSF was often used as an outcome measure in the absence of cognitive measures. Alternative hypotheses, like that the beta- and gamma- secretases that cleave APP into amyloid-beta also regulate myelin thickness, and so it is possible that the presenilin mutations are linked to familiar AD not because of their role in amyloid-beta cleavage, but because of myelin, are relegated to the fringe.
Oh shoot, it might not be amyloid after all
• Plaque location doesn’t correlate well with cognitive dysfunction
• 25-30% of elderly people with normal cognition have a density of amyloid plaques in their brain that is similar to AD brains. Almost everyone has some, even kids. PiB staining in living brains using PET starting in 2002 started to make this clear. Having amyloid deposits in the brain increases risk of developing AD by 3-4 fold over the next few years, but it seems like our brains can function pretty well in the presence of a lot of plaques. Author doesn’t discuss cognitive reserve.
• 15% of people clinically diagnosed with AD don’t have significant plaque formation
• It turns out there’s a long delay between the appearance of plaques and the start of dementia, suggesting a third factor might be causing both. Alternatively, it’s possible the brain has enough redundant pathways to work around plaques up to a certain threshold of plaque density.
• Mice with human versions of mutated APP show plaque build up, but very few other health problems. They do normal species-typical behaviors, and only develop subtle cognitive deficits, if at all. We had trouble replicating the cognitive deficits in our own lab during my research. These mouse models often lack tau tangles, neuronal death, synapse loss, and other hallmark features. Yet they were used as the main model of AD.
• When mouse AD models do get cognitive deficits, they’re not very AD-like. Also, they don’t degenerate over time.
• PiB staining showed that early and late onset AD had pretty different patterns of plaque deposition in humans, not clear they’re actually the same disease since plaques are pretty non-specific pathology in the first place
All this actually shows the mouse and human data align well. Mice can have a lot of amyloid-beta plaques, and not have cognitive symptoms, just like humans.
The heady amyloid years:
• A team at UCSD gets access to amyloid plaques (via blood vessels that feed the brain, which might not be exactly the same type of plaques, but people thought at the time that the plaques only happened in AD, so it seemed reasonable), and figure out the amino acid sequence of it
• Down syndrome brain was loaded with amyloid, and amino acid sequence showed it to be very similar to the AD plaques imaged by the UCSD team. Down syndrome is caused by an extra copy of chromosome 21, and the gene for the main plaque protein (amyloid-beta peptides) mapped to that chromosome!
• Precursor protein for amyloid-beta peptides is tracked down, looks like a cell surface receptor protein that sticks into the cell membrane. They called it amyloid precursor protein (APP).
• In the 1990s, geneticists found that in familial, early-onset AD, mutations appeared very near where the amyloid-beta peptide gene is found on chromosome 21, and led to increased production of APP. Two more mutations were identified, presenilin 1 (chromosome 14) and presenilin 2 (chromosome 1), which are both associated with gamma-secretase, an enzyme that cuts APP. The presenilin mutations cut amyloid-beta peptides out of APP in a way that made the amyloid-beta peptides more prone to aggregation (a longer 42 amino acid form vs a shorter 40 amino acid form)
• Human beings are the only species that get amyloid plaques and associated dementia, for reasons not yet clear, even though most species have the APP gene as well as the two secretases that cleave it into amyloid-beta. So transgenic mice were created to carry the human version of the APP gene with mutations present in familial early-onset AD. Elan pharmaceuticals developed a vaccine using artificially synthesized amyloid-beta to train the immune system to recognize and clear amyloid-beta, which worked super well in mice to prevent and actually clear already formed plaques. But in human trials, the vaccine caused life-threatening side effects. Later, we did find a way to clear plaques (passive immunization, but that didn’t help either).
Thus the amyloid cascade idea was formed. Because of the genetics of early-onset AD, plaques became the main focus of the field. The idea that amyloid-beta plaques caused AD was so strong that in future trials, amyloid-beta in CSF was often used as an outcome measure in the absence of cognitive measures. Alternative hypotheses, like that the beta- and gamma- secretases that cleave APP into amyloid-beta also regulate myelin thickness, and so it is possible that the presenilin mutations are linked to familiar AD not because of their role in amyloid-beta cleavage, but because of myelin, are relegated to the fringe.
Oh shoot, it might not be amyloid after all
• Plaque location doesn’t correlate well with cognitive dysfunction
• 25-30% of elderly people with normal cognition have a density of amyloid plaques in their brain that is similar to AD brains. Almost everyone has some, even kids. PiB staining in living brains using PET starting in 2002 started to make this clear. Having amyloid deposits in the brain increases risk of developing AD by 3-4 fold over the next few years, but it seems like our brains can function pretty well in the presence of a lot of plaques. Author doesn’t discuss cognitive reserve.
• 15% of people clinically diagnosed with AD don’t have significant plaque formation
• It turns out there’s a long delay between the appearance of plaques and the start of dementia, suggesting a third factor might be causing both. Alternatively, it’s possible the brain has enough redundant pathways to work around plaques up to a certain threshold of plaque density.
• Mice with human versions of mutated APP show plaque build up, but very few other health problems. They do normal species-typical behaviors, and only develop subtle cognitive deficits, if at all. We had trouble replicating the cognitive deficits in our own lab during my research. These mouse models often lack tau tangles, neuronal death, synapse loss, and other hallmark features. Yet they were used as the main model of AD.
• When mouse AD models do get cognitive deficits, they’re not very AD-like. Also, they don’t degenerate over time.
• PiB staining showed that early and late onset AD had pretty different patterns of plaque deposition in humans, not clear they’re actually the same disease since plaques are pretty non-specific pathology in the first place
All this actually shows the mouse and human data align well. Mice can have a lot of amyloid-beta plaques, and not have cognitive symptoms, just like humans.
January 28, 2024
I found this book interesting, but somewhat inconsistent.
In essence, the author disagrees with the amyloid hypothesis of Alzheimer's disease. He does not deny that the presence of amyloid plaques in the brain increases the probability that the person has or will develop Alzheimer's disease. I agree with that.
He also describes the almost vicious disagreements between the amyloid people and the tau people, representing two of the best known camps in the Alzheimer's research world. Having heard some of these disputes, I can attest that much of this is true. So, again, I was nodding along with the author as he develops his theme.
He then develops the thesis that for 30 years or so, biological and medical research aiming to cure Alzheimer's by removing amyloid or preventing its buildup, has failed to deliver an effective drug. Well... that was true when the book was published, but lecanemab, an anti-amyloid antibody given intravenously, did show an effect on cognitive measures and is now an approved drug. Still, I agree with the author's position that mechanisms other than the pure amyloid-cascade hypothesis should be pursued.
Where I started to disconnect was the chapter where he proposes alternative approaches. What this seems to come down to is the statement that senile dementia is a disease of aging, and that we should study "aging". That sounds good, but it's not exactly clear what biological mechanisms this would involve. The author then uses a theoretical model of "neuronal neighborhoods" and "neuronal cities" to describe how cells in the central nervous system interact with each other, and uses that concept to describe how future drugs might work. The problem I had with that is that while the author used actual experimental data and results to expound on his problem with the amyloid cascade hypothesis, he resorted to very vague and theoretical concepts to describe what he thinks is a better approach. So this thinking felt a little lopsided to me.
His prescription for doing better research in Alzheimer's was not particularly original : more money for basic research (and preferably for non-amyloid research), changing the way the pharmaceutical industry works, etcetera.
In essence, the author disagrees with the amyloid hypothesis of Alzheimer's disease. He does not deny that the presence of amyloid plaques in the brain increases the probability that the person has or will develop Alzheimer's disease. I agree with that.
He also describes the almost vicious disagreements between the amyloid people and the tau people, representing two of the best known camps in the Alzheimer's research world. Having heard some of these disputes, I can attest that much of this is true. So, again, I was nodding along with the author as he develops his theme.
He then develops the thesis that for 30 years or so, biological and medical research aiming to cure Alzheimer's by removing amyloid or preventing its buildup, has failed to deliver an effective drug. Well... that was true when the book was published, but lecanemab, an anti-amyloid antibody given intravenously, did show an effect on cognitive measures and is now an approved drug. Still, I agree with the author's position that mechanisms other than the pure amyloid-cascade hypothesis should be pursued.
Where I started to disconnect was the chapter where he proposes alternative approaches. What this seems to come down to is the statement that senile dementia is a disease of aging, and that we should study "aging". That sounds good, but it's not exactly clear what biological mechanisms this would involve. The author then uses a theoretical model of "neuronal neighborhoods" and "neuronal cities" to describe how cells in the central nervous system interact with each other, and uses that concept to describe how future drugs might work. The problem I had with that is that while the author used actual experimental data and results to expound on his problem with the amyloid cascade hypothesis, he resorted to very vague and theoretical concepts to describe what he thinks is a better approach. So this thinking felt a little lopsided to me.
His prescription for doing better research in Alzheimer's was not particularly original : more money for basic research (and preferably for non-amyloid research), changing the way the pharmaceutical industry works, etcetera.
July 1, 2026
from Gemini
美國神經生物學家卡爾·赫魯普（Karl Herrup）所著的《**How Not to Study a Disease: The Story of Alzheimer's**》（暫譯：如何不要研究一種疾病：阿茲海默症的故事）是一部針對現代醫學界與科學界發出的深刻反思與強烈警鐘。
作者以內部專家的視角，剖析了為何過去 25 年來，人類在阿茲海默症（Alzheimer's disease）的藥物研發上投入數十億美元，卻幾乎毫無建樹。以下是本書的重點、精華與核心觀點整理：
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## 核心重點（The Core Insights）
### 1. 陷入「澱粉樣蛋白」的學術陷阱 (The Amyloid Trap)
過去幾十年來，阿茲海默症的研究與藥物開發幾乎完全被「澱粉樣蛋白級聯假說」（Amyloid cascade hypothesis）所壟斷。科學界盲目地相信：只要清除大腦中的澱粉樣蛋白斑塊，就能治癒失智症。Herrup 嚴厲批判這種「隧道視野」，指出這種過度簡化的生物學假設，導致了無數次臨床試驗的失敗，並排擠了其他可能的研究方向。
### 2. 科學界與醫療產業的結構性沉痾
作者毫不留情地揭露了阻礙解藥誕生的非科學因素：
* **固執與貪婪：** 藥廠的利益驅動與追求名利的學術文化。
* **學術壟斷：** 審查機制對主流假說的盲目擁護，導致反對聲音或創新觀點拿不到研究經費。
* **媒體推波助瀾：** 科學媒體缺乏批判性思考，盲目誇大未能證實的「醫學突破」。
### 3. 重新定義阿茲海默症與老化
Herrup 呼籲我們必須放棄「生物還原論」（Biological reductionism），不該把阿茲海默症視為單一蛋白質出錯的結果。他主張我們應該重新概念化「老化」與「失智症」的關係，重視大腦發炎、血管健康以及人體系統性退化在其中扮演的角色。
### 4. 提出全新的「鄰里模型」（The Neighborhood Model）
作為未來研究的藍圖，作者提出將大腦想像成一系列相互連接的「社區 / 鄰里」。這種整體性的視角強調大腦局部神經網絡的互動，甚至涵蓋了睡眠、社會不平等、孤獨感等公共衛生與社會因素對大腦健康的深遠影響。
---
## 本書精華（Key Summary）
這本書既是一部阿茲海默症研究的「失敗史」**，也是一份寫給未來的**「希望藍圖」。
它告訴我們，科學研究最致命的錯誤不是「找不到答案」，而是「數十年來都在死胡同裡問著錯誤的問題」。Herrup 從藥物開發流程、基礎研究的資金分配，到公共衛生政策，提出了全面性的改革呼籲。他最終傳遞的訊息是樂觀的：只要我們有勇氣承認過去的錯誤，打破單一理論的僵局，走向更宏觀、跨學科的整體大腦健康研究，尋找解藥的旅程仍然充滿希望。
---
## 經典佳句與核心觀點（Quotes & Golden Nuggets）
> **"If you're not studying amyloid, you're not studying Alzheimer's."**
> 「如果你不研究澱粉樣蛋白，你就不算在研究阿茲海默症。」
> *(註：這是作者分享其學術生涯中常聽到的一句行內名言，精準諷刺了整個研究領域如何被單一且僵化的理論所綁架。)*
> **「我們必須停止將大腦視為一台只要替換故障零件就能修好的機器，而應該將其視為一個複雜的生態系統或相互關聯的『鄰里』（Neighborhoods）。」**
> *(提倡從微觀的單一蛋白分子，轉向宏觀的系統性大腦健康)*
> **「在爭相尋找解藥的熱潮中，科學界忽視了無數的危險信號（Red flags）。」**
> *(提醒科學家與社會大眾，面對重大疾病時，必須保持批判性思考，不應被利益與盲目的樂觀蒙蔽。)*
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### 💡 總結
如果你對現代醫學史、科學哲學，或是阿茲海默症的未來發展感興趣，這本書提供了一個非常犀利且具批判性的「內部吹哨者」觀點，它教導我們如何在科學中保持清醒，**「如何不要用錯誤的方式去研究一種疾病」**。
美國神經生物學家卡爾·赫魯普（Karl Herrup）所著的《**How Not to Study a Disease: The Story of Alzheimer's**》（暫譯：如何不要研究一種疾病：阿茲海默症的故事）是一部針對現代醫學界與科學界發出的深刻反思與強烈警鐘。
作者以內部專家的視角，剖析了為何過去 25 年來，人類在阿茲海默症（Alzheimer's disease）的藥物研發上投入數十億美元，卻幾乎毫無建樹。以下是本書的重點、精華與核心觀點整理：
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## 核心重點（The Core Insights）
### 1. 陷入「澱粉樣蛋白」的學術陷阱 (The Amyloid Trap)
過去幾十年來，阿茲海默症的研究與藥物開發幾乎完全被「澱粉樣蛋白級聯假說」（Amyloid cascade hypothesis）所壟斷。科學界盲目地相信：只要清除大腦中的澱粉樣蛋白斑塊，就能治癒失智症。Herrup 嚴厲批判這種「隧道視野」，指出這種過度簡化的生物學假設，導致了無數次臨床試驗的失敗，並排擠了其他可能的研究方向。
### 2. 科學界與醫療產業的結構性沉痾
作者毫不留情地揭露了阻礙解藥誕生的非科學因素：
* **固執與貪婪：** 藥廠的利益驅動與追求名利的學術文化。
* **學術壟斷：** 審查機制對主流假說的盲目擁護，導致反對聲音或創新觀點拿不到研究經費。
* **媒體推波助瀾：** 科學媒體缺乏批判性思考，盲目誇大未能證實的「醫學突破」。
### 3. 重新定義阿茲海默症與老化
Herrup 呼籲我們必須放棄「生物還原論」（Biological reductionism），不該把阿茲海默症視為單一蛋白質出錯的結果。他主張我們應該重新概念化「老化」與「失智症」的關係，重視大腦發炎、血管健康以及人體系統性退化在其中扮演的角色。
### 4. 提出全新的「鄰里模型」（The Neighborhood Model）
作為未來研究的藍圖，作者提出將大腦想像成一系列相互連接的「社區 / 鄰里」。這種整體性的視角強調大腦局部神經網絡的互動，甚至涵蓋了睡眠、社會不平等、孤獨感等公共衛生與社會因素對大腦健康的深遠影響。
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## 本書精華（Key Summary）
這本書既是一部阿茲海默症研究的「失敗史」**，也是一份寫給未來的**「希望藍圖」。
它告訴我們，科學研究最致命的錯誤不是「找不到答案」，而是「數十年來都在死胡同裡問著錯誤的問題」。Herrup 從藥物開發流程、基礎研究的資金分配，到公共衛生政策，提出了全面性的改革呼籲。他最終傳遞的訊息是樂觀的：只要我們有勇氣承認過去的錯誤，打破單一理論的僵局，走向更宏觀、跨學科的整體大腦健康研究，尋找解藥的旅程仍然充滿希望。
---
## 經典佳句與核心觀點（Quotes & Golden Nuggets）
> **"If you're not studying amyloid, you're not studying Alzheimer's."**
> 「如果你不研究澱粉樣蛋白，你就不算在研究阿茲海默症。」
> *(註：這是作者分享其學術生涯中常聽到的一句行內名言，精準諷刺了整個研究領域如何被單一且僵化的理論所綁架。)*
> **「我們必須停止將大腦視為一台只要替換故障零件就能修好的機器，而應該將其視為一個複雜的生態系統或相互關聯的『鄰里』（Neighborhoods）。」**
> *(提倡從微觀的單一蛋白分子，轉向宏觀的系統性大腦健康)*
> **「在爭相尋找解藥的熱潮中，科學界忽視了無數的危險信號（Red flags）。」**
> *(提醒科學家與社會大眾，面對重大疾病時，必須保持批判性思考，不應被利益與盲目的樂觀蒙蔽。)*
---
### 💡 總結
如果你對現代醫學史、科學哲學，或是阿茲海默症的未來發展感興趣，這本書提供了一個非常犀利且具批判性的「內部吹哨者」觀點，它教導我們如何在科學中保持清醒，**「如何不要用錯誤的方式去研究一種疾病」**。
April 29, 2025
Outstanding
In this volume, Karl Herrup, a respected researcher on the biology and biochemistry of Alzheimer’s disease, makes the case that the amyloid theory of Alzheimer’s — the presence of plaques in the brain — is incorrect and needs to be replaced with new avenues of research.
Despite early successes in mouse studies, which showed that plaque-eliminating vaccines were successful in reversing memory impairments, these results have never been replicated in decades of human trials.
Equally troubling, the presence or absence of plaques in the brain is only partially correlated with the presence or absence of Alzheimer’s disease. While plaque deposits increase substantially the risk of developing Alzheimer’s, 30 percent of those with plaque deposits remain cognitively healthy. Conversely, 15% of those without plaque deposits develop the clinical symptoms of Alzheimer’s.
Herrup posits an alternative theory — that multiple age-related changes affecting networks of brain cells — many of them inflammatory in character — may cause Alzheimer’s disease and other dementias. To his credit, Herrup agrees that plaque formation may indicate an as yet undetermined causal factor, and should continue to be studied along with other hypotheses.
Herrup makes a compelling case for opening alternative lines of research into the causes of Alzheimer’s disease. After decades of fruitless research on the amyloid theory, additional hypotheses should be examined.
In this volume, Karl Herrup, a respected researcher on the biology and biochemistry of Alzheimer’s disease, makes the case that the amyloid theory of Alzheimer’s — the presence of plaques in the brain — is incorrect and needs to be replaced with new avenues of research.
Despite early successes in mouse studies, which showed that plaque-eliminating vaccines were successful in reversing memory impairments, these results have never been replicated in decades of human trials.
Equally troubling, the presence or absence of plaques in the brain is only partially correlated with the presence or absence of Alzheimer’s disease. While plaque deposits increase substantially the risk of developing Alzheimer’s, 30 percent of those with plaque deposits remain cognitively healthy. Conversely, 15% of those without plaque deposits develop the clinical symptoms of Alzheimer’s.
Herrup posits an alternative theory — that multiple age-related changes affecting networks of brain cells — many of them inflammatory in character — may cause Alzheimer’s disease and other dementias. To his credit, Herrup agrees that plaque formation may indicate an as yet undetermined causal factor, and should continue to be studied along with other hypotheses.
Herrup makes a compelling case for opening alternative lines of research into the causes of Alzheimer’s disease. After decades of fruitless research on the amyloid theory, additional hypotheses should be examined.
July 18, 2026
Neuroscientist here! Although I don't study Alzheimer's Disease (AD), one of the reasons I've shied away from that corner of research is that it always felt very political. The amyloid hypothesis, which claims that amyloid beta aggregation is the driving force of AD, has dominated the field for as long as I can remember. Herrup has a controversial idea here, but he makes a strong logical case: amyloid is not THE central player, maybe not even A central player, in the aging-associated dementia that we call Alzheimer's disease. As someone who has been deeply disappointed and perplexed by the lack of efficacy of amyloid- clearing drugs, I appreciate his historical account of the three great "inflationary events" that expanded the definition of AD and conflated it so thoroughly with amyloid. And indeed, each of these events was motivated just as much by politics as by science. After reading this book, I am persuaded that the field needs to expand its approach to make progress -- we need to admit that it is possible, even advisable, to study AD without studying amyloid.
April 22, 2022
As someone who has significant interest in Alzheimer's for multiple reasons, I found this book enlightening. The author is an active Alzheimer's investigator for the University of Pittsburgh and makes clear his disagreement that Alzheimer's Disease be defined solely by the existence of amyloid plaques. He makes his case that this may be the main reason why a cure has not been forthcoming even after decades of research. I think the key line in the book is "Son, if you're not studying amyloid you're not studying Alzheimer's". This has been the response when alternative hypothesis are presented.
Given the failure of every pharmacological treatment to date, this book presents a reasonable explanation as to why. The author also details his own hypothesis, which in some ways is similar to what Dr Dale Bredesen has been suggesting. Hopefully, things are changing, but it seems we've lost valuable time.
Given the failure of every pharmacological treatment to date, this book presents a reasonable explanation as to why. The author also details his own hypothesis, which in some ways is similar to what Dr Dale Bredesen has been suggesting. Hopefully, things are changing, but it seems we've lost valuable time.
May 7, 2023
Bizim labın çalıştığı alana girme için iyiydi. neuro ve neuro degeneration çalışmak isteyen herkes okuyabilir. Alzheimer ile ilgili genel okuyucu için de gayet anlaşılabilir. Kafam dolu olduğu için yada labda okuduğumuz makalelere benzediği için yavaş okudum, ama belki daha akıcı okunabiliyodur. 8/10
March 10, 2022
Gives a great overview of why clinical research on finding a treatment for Alzheimer's has been stalled for the last twenty years and why a paradigm shift - away from the Amyloid cascade hypothesis - is strongly needed.
August 17, 2026
This book is more valuable as a peek into the socio-political side of science than as a detailed guide to the problems of Alzheimer's research. Interesting read, but the author is just as hung up on his pet hypothesis as the researchers he's criticising.
May 9, 2025
Very much worth reading & adopting his ideas.
April 24, 2026
This is an excellent book. It is highly readable but also technical, getting into a lot of science on cell structures, proteins and brain functions. But that is OK!
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