This is a fascinating example of how our understanding of Alzheimer’s disease is evolving beyond a single “amyloid versus tau” framework. The connection between lipid metabolism, lipoprotein biology, vascular health, and neurodegeneration is particularly compelling as the brain is extraordinarily dependent on tightly regulated lipid transport and homeostasis.
As a physician-scientist, I find the possibility of targeting upstream metabolic pathways especially interesting. But the key question is whether improving a lipid-related biomarker or modifying a mechanistic pathway ultimately translates into slower cognitive decline or reduced dementia incidence. In Alzheimer’s research, biological plausibility is an important starting point, but clinical outcomes are the real test.
What I find most promising is the broader movement toward understanding Alzheimer’s as a multifactorial disease involving interactions among amyloid, tau, lipid metabolism, vascular biology, inflammation, and aging. This may eventually allow us to identify distinct biological subtypes and match interventions to the pathways that are actually driving disease in each individual.
The future of Alzheimer’s treatment may therefore be less about finding one universal cure and more about understanding which biological levers matter most for each person’s disease, and intervening early enough to change the trajectory.
The great psychotherapist Irwin Yalom described himself as "love's executioner," because he often had to help his patients see that their infatuations were based on illusions. Lately I've come to think of you as "hope's executioner," because of the clear way you explain that treatments that have been described elsewhere as breakthroughs are in fact far from proven. Your posts often leave me disappointed, but also appreciative--glad to have come across an Alzheimer's researcher who explains things so clearly and with such intellectual integrity.
I would be curious to hear your views about the research concerning the Shingles vaccine's benefits in preventing dementia. Reports of the studies done in Wales and elsewhere made it seem beneficial beyond dispute, but more recently I've heard that the same observational trials were done in England and showed no effect.
Anyway, thank you for sharing your findings and reflections with interested readers on this platform.
Thank you for your reply, and for sharing your post about shingles. My concern about this arose from reading this recent Substack post by a writer I'm unfamiliar with. He's reporting on a study that evidently has not yet been published, but if his account is accurate, it seems to cast serious doubt on the idea that the shingles vaccine may be protective against dementia. I hope you'll revisit the subject at some point! Thank you again.
Let me take a look. But a post that starts by "the truth" puts me off. Science is about trials, misses, and correction. And who decides what the "truth" is?
I didn't even notice that, but now that you mention it, the entire post is suffused with a kind of swagger that seems inappropriate in discussions of complex and unresolved scientific questions. That said, when the study he cites is published, your readers will welcome your thoughts about the data from England. Thank you again for doing so much to shed light on the daunting questions surrounding aging and cognitive health.
Great article, Hussein. Curious whether SPINOZA has built that kind of phenotyping into its enrollment criteria explicitly, or whether it's relying on APOE status and p-tau217 alone to define the target group.
This is a fascinating example of how our understanding of Alzheimer’s disease is evolving beyond a single “amyloid versus tau” framework. The connection between lipid metabolism, lipoprotein biology, vascular health, and neurodegeneration is particularly compelling as the brain is extraordinarily dependent on tightly regulated lipid transport and homeostasis.
As a physician-scientist, I find the possibility of targeting upstream metabolic pathways especially interesting. But the key question is whether improving a lipid-related biomarker or modifying a mechanistic pathway ultimately translates into slower cognitive decline or reduced dementia incidence. In Alzheimer’s research, biological plausibility is an important starting point, but clinical outcomes are the real test.
What I find most promising is the broader movement toward understanding Alzheimer’s as a multifactorial disease involving interactions among amyloid, tau, lipid metabolism, vascular biology, inflammation, and aging. This may eventually allow us to identify distinct biological subtypes and match interventions to the pathways that are actually driving disease in each individual.
The future of Alzheimer’s treatment may therefore be less about finding one universal cure and more about understanding which biological levers matter most for each person’s disease, and intervening early enough to change the trajectory.
Thank you!
The great psychotherapist Irwin Yalom described himself as "love's executioner," because he often had to help his patients see that their infatuations were based on illusions. Lately I've come to think of you as "hope's executioner," because of the clear way you explain that treatments that have been described elsewhere as breakthroughs are in fact far from proven. Your posts often leave me disappointed, but also appreciative--glad to have come across an Alzheimer's researcher who explains things so clearly and with such intellectual integrity.
I would be curious to hear your views about the research concerning the Shingles vaccine's benefits in preventing dementia. Reports of the studies done in Wales and elsewhere made it seem beneficial beyond dispute, but more recently I've heard that the same observational trials were done in England and showed no effect.
Anyway, thank you for sharing your findings and reflections with interested readers on this platform.
Thank you Brian! I much appreciate your kind note. On Shingles: https://substack.com/@husseinyassine1/note/p-181008898?r=5ha6ys&utm_medium=ios&utm_source=notes-share-action
Thank you for your reply, and for sharing your post about shingles. My concern about this arose from reading this recent Substack post by a writer I'm unfamiliar with. He's reporting on a study that evidently has not yet been published, but if his account is accurate, it seems to cast serious doubt on the idea that the shingles vaccine may be protective against dementia. I hope you'll revisit the subject at some point! Thank you again.
https://alasdairmunro.substack.com/p/the-truth-about-the-shingles-vaccine?utm_campaign=posts-open-in-app&triedRedirect=true
Let me take a look. But a post that starts by "the truth" puts me off. Science is about trials, misses, and correction. And who decides what the "truth" is?
I didn't even notice that, but now that you mention it, the entire post is suffused with a kind of swagger that seems inappropriate in discussions of complex and unresolved scientific questions. That said, when the study he cites is published, your readers will welcome your thoughts about the data from England. Thank you again for doing so much to shed light on the daunting questions surrounding aging and cognitive health.
Great article, Hussein. Curious whether SPINOZA has built that kind of phenotyping into its enrollment criteria explicitly, or whether it's relying on APOE status and p-tau217 alone to define the target group.
PTau217 and GFAP.