What’s holding back Alzheimer Disease therapy?
My dad died a few years ago with dementia. The diagnosis was Frontotemporal Lobe Dementia (FTD), based on a psychiatric evaluation and brain imaging. After he died, we had a brain autopsy done, which returned a diagnosis of Alzheimer’s Disease. So which was it? As far as I know, it could be both. But what this little anecdote illustrates is the tension between diagnosis of dementia in a living patient and the use of histopathological diagnostic criteria postmortem.
The New York Review of Books has a review of “How not to study a disease: The story of Alzheimer’s” by Karl Herrup. The review itself is paywalled, but I’ve attached a link to a summary of the book’s premise by the author.
Alzheimer’s disease was first described in 1906, based on a single patient. She was 51 years old. Postmortem histopathology revealed extensive plaques and tangles that Alzheimer and his collaborator concluded likely explained the dementia in this patient. There are two obvious problems with this logic. One is the “post hoc ergo propter hoc” conclusion that the histopathology explained the clinical symptoms, rather than that the histopathology was an epiphenomenon. The other is that the plural of anecdote isn’t data.
Where Herrup says things really ran off the rails was when plaques and tangles were found in the brains of geriatric dementia patients, and the mechanistic extrapolation from a rare form of pre-senile dementia and the much more common dementia seen in individuals of advanced age. What concerns Herrup, and should give all of us pause, is that amyloid plaques are also found in ca. 30% of geriatric brains from people without dementia symptoms.
Disappointingly, drugs that have been show to reduce plaques have had little or no mitigating effect on dementia progression so far. In most cases, these drugs are tested on patients with pre-senile dementia, which may not be representative of most patients. And since there is a paucity of reliable pre-symptomatic markers for dementia, it may be that the drugs need to be administered earlier.
What Herrup argues, however, is that Alzheimer’s research and drug development has been stampeded by orthodoxy into a misplaced focus on amyloid mitigation, when there may be overlooked mechanisms that represent better drug targets. In her New York Review of Books review, Natalie de Souza explains why she thinks Herrup is overstating his criticism, but she does acknowledge the soundness of some of his critique. She notes that genetic research does point strongly to alleles of beta-amlyloid and Tau protein genes in association with Alzheimers. They are clearly important, if not the whole story.
For my part, I’ve mined my genome for the known variants associated with increased risk of Alzheimers, FTD and Parkinson’s Disease, and I don’t have those. But there may well be other alleles of other genes that haven’t yet been flagged. As a geneticist, I think that’s certainly one way to study a disease.
Redefining Alzheimer’s Disease
The New York Review of Books has a review of “How not to study a disease: The story of Alzheimer’s” by Karl Herrup. The review itself is paywalled, but I’ve attached a link to a summary of the book’s premise by the author.
Alzheimer’s disease was first described in 1906, based on a single patient. She was 51 years old. Postmortem histopathology revealed extensive plaques and tangles that Alzheimer and his collaborator concluded likely explained the dementia in this patient. There are two obvious problems with this logic. One is the “post hoc ergo propter hoc” conclusion that the histopathology explained the clinical symptoms, rather than that the histopathology was an epiphenomenon. The other is that the plural of anecdote isn’t data.
Where Herrup says things really ran off the rails was when plaques and tangles were found in the brains of geriatric dementia patients, and the mechanistic extrapolation from a rare form of pre-senile dementia and the much more common dementia seen in individuals of advanced age. What concerns Herrup, and should give all of us pause, is that amyloid plaques are also found in ca. 30% of geriatric brains from people without dementia symptoms.
Disappointingly, drugs that have been show to reduce plaques have had little or no mitigating effect on dementia progression so far. In most cases, these drugs are tested on patients with pre-senile dementia, which may not be representative of most patients. And since there is a paucity of reliable pre-symptomatic markers for dementia, it may be that the drugs need to be administered earlier.
What Herrup argues, however, is that Alzheimer’s research and drug development has been stampeded by orthodoxy into a misplaced focus on amyloid mitigation, when there may be overlooked mechanisms that represent better drug targets. In her New York Review of Books review, Natalie de Souza explains why she thinks Herrup is overstating his criticism, but she does acknowledge the soundness of some of his critique. She notes that genetic research does point strongly to alleles of beta-amlyloid and Tau protein genes in association with Alzheimers. They are clearly important, if not the whole story.
For my part, I’ve mined my genome for the known variants associated with increased risk of Alzheimers, FTD and Parkinson’s Disease, and I don’t have those. But there may well be other alleles of other genes that haven’t yet been flagged. As a geneticist, I think that’s certainly one way to study a disease.
Redefining Alzheimer’s Disease
Joel:
Wow, thank you for teaching me something I could not and did not know. I sometimes wonder where my very fact-oriented brain is going as I lose tract of some things which were always at the tip of my tongue. Like I said one time, I envision a person running down an aisle of file cabinets looking for the right cabinet and drawer which holds the data or thought which was so readily there when younger.
My mother was diagnosed as Alzheimer’s inflicted. She gradually slipped away from us. One day while visiting her alone, I spent 15 minutes teasing her like I used to do when both of us were much younger. One moment which started me was her saying something back to me that I had not heard said by her in quite a while. Years had passed.
“Oh, go on . . . “
For a moment, I knew she was there and had recognized me.
I’ve often read that Alzheimer’s Disease can only be verified by a close examination of the brain post mortem.
There are a lot of different kinds of dementia, with differing symptoms. Mrs Fred’s family has experienced the Lewy-Body form, which is characterized by disturbing hallucinations early on, and is what afflicted Robin Williams.
@Fred,
Yes. My mother-in-law had vascular dementia, which has a very different etiology.
As one who tends to come down with idiopathic maladies, I can relate.
Idiopathic, I suppose, because when a physician says ‘We have to keep testing until we figure out what caused this’ (even after they’ve cured it), I most often decline.
yes, and some people are afflicted with dementia their entire lives. or as a pathologist i used to know told me, there are many ways to injure a brain, but the brain has only a few ways to respond.
I had to see a neurologist back in the late 1980s. He was late for the appointment. He apologized profusely. Someone with Alzheimer’s disease had died and he had the opportunity to attend the autopsy and get samples. Back then, amyloid plaques were still a mystery. Remember, Alzheimer reported the characteristic brain tangle, but it took a while to determine it was a protein and then which protein and its structure. Getting a fresh sample might have revealed a difference between the familiar tangle and its actual in vivo form.
That was over thirty years ago. The idea, which made a lot of sense, was that the tangle of protein itself was the problem. If nothing else, it was characteristic. Coming up with a treatment was a real challenge. No one knew the pathway that created the plaques and whether interfering with it might help. There’s no obvious animal model since it is a slow, progressive brain disease. Since it is a slow, progressive brain disease, any experimental work takes years. Even in such animal models as could be developed, it takes years.
Just the mechanics are daunting. It’s a brain disease, so the relevant tissue is protected by a bony skull. It’s behind a chemical blood brain barrier that limits therapeutic agents among other things. The list goes on. Most of the modern candidates for treating Alzheimer’s disease involve antibodies that tag the plaque for removal by the immune system. That’s a technology that didn’t exist until maybe ten years ago.
Now they finally have drugs that clear out the plaque to some degree, and they don’t seem to do all that much for cognitive function. If you ask me, getting this far is kind of amazing.
The Dark Tangle of Alzheimer’s | Natalie de Souza
NY Review of Books – February
Recent breakthroughs in dementia treatments have been hailed as successes, but after decades of disappointing research it is difficult to be optimistic.