Research Associate at The Montreal Neurological Institute 🧠 | Studying Alzheimer's disease pathogenesis with neuroimaging | OHBM Communications Committee @ohbm-com.com | He/Him
Alfie Wearn
My hope is that formalising the neuromodulatory fragility hypothesis will raise awareness of the importance of neuromodulatory systems in AD pathogenesis, encouraging more research in this direction.
Read the paper: dx.doi.org/10.1002/alz....
Watch the talk: www.youtube.com/watch?v=WKo4...
The Neuromodulatory Subcortical Systems PIA within @istaart.bsky.social is requesting nominations for the best paper of 2025 on neuromodulatory subcortical systems in Alzheimer's disease!! ISTAART members: promote the work of your colleagues (or yourself) here: alz.surveymonkey.com/r/Publicatio...
The hypothesis also raises questions about cross-species observations:
Locus coeruleus neuromelanin, a potential marker of strain, appears across mammals, but is expressed most strongly in:
a) humans, and
b) toothed whales (e.g. dolphins, porpoises, belugas) 🐬.
As damage accumulates (most likely first in the hardest-to-maintain distal axons) tau misfolds and pre-tangles form.
This destabilises axons, reducing neuromodulatory tone in cortical endpoints.
This disrupts microglial homeostasis and amyloid clearance, promoting plaque formation.
Neuromodulatory neurons are metabolically costly & disproportionately sensitive to energy availability.
As energy availability & cell maintenance falter in older age (amplified by diverse risk factors), the tau-rich web of neuromodulatory axons are the most likely point of early dysfunction.
Based on these ideas, improving neuromodulatory resilience is theoretically the best AD-prevention strategy.
Likewise, tracking neuromodulatory system health may offer a useful way to track individual risk for AD long before symptom onset.
I lay out logical arguments and empirical evidence that point to a neuromodulatory origin of AD pathogenesis.
Critically, neuromodulatory dysfunction is
a) relatively likely to occur, given inherent fragility, and
b) sufficient to explain the emergence of both amyloid and tau pathology
Toothed whales may also be the only other species to naturally develop AD-like pathology…
They also have the largest brains of all non-human mammals...
Comparing neuromodulatory systems between humans, toothed whales and non-human primates may offer opportunities to test the hypothesis.
Neuromodulatory neurons are extremely susceptible to stress. I argue that their fragility is an inherent weak point, the breaking of which directly leads to Alzheimer’s Disease.
I discuss this idea and its implications in a recently published perspective piece:
dx.doi.org/10.1002/alz....
Neuromodulatory neurons are extremely susceptible to stress. I argue that their fragility is an inherent weak point, the breaking of which directly leads to Alzheimer’s Disease.
I discuss this idea and its implications in a recently published perspective piece:
dx.doi.org/10.1002/alz....
Sporadic Alzheimer's disease (AD) is associated with numerous risk factors, yet its precise cause remains unclear. Here, we describe a novel framework for AD pathogenesis, whereby diverse risk factor...
dx.doi.org
Sporadic Alzheimer's disease (AD) is associated with numerous risk factors, yet its precise cause remains unclear. Here, we describe a novel framework for AD pathogenesis, whereby diverse risk factor...
