Evidence map›Paper›PMID 41797441›Full record

ArticleAlzheimer's & dementia : the journal of the Alzheimer's Association2026

The neuromodulatory fragility hypothesis of Alzheimer's disease pathogenesis.

Alfie Wearn, Kate M Onuska, Taylor W Schmitz, Gary R Turner, R Nathan Spreng

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Alzheimer's & dementia : the journal of the Alzheimer's Association, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

5 authors.

Alfie WearnDepartment of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
Kate M OnuskaDepartment of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
Taylor W SchmitzDepartment of Physiology & Pharmacology, Western Institute for Neuroscience, Western University, London, Ontario, Canada.
Gary R TurnerDepartment of Psychology, York University, Toronto, Ontario, Canada.
R Nathan SprengDepartment of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.

Funding

Alzheimer's Association AARG-22-927100Fonds de Recherche du Québec - Santé 317644McGill University: Jeanne Timmins Costello Postdoctoral FellowshipNational Institute on Aging AG068563
6 · The paper itself

Abstract

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 factors converge on neuromodulatory subcortical systems to confer AD risk or resilience. Neuromodulatory projection neurons are uniquely fragile due to their large size, sparse myelination, and high basal metabolic demands. We propose that the increased prevalence of AD in older adult populations likely reflects a universal weakness within these projection systems, which is increasingly exposed as cellular transport and maintenance mechanisms deteriorate with age. The key insight of this "neuromodulatory fragility hypothesis" is that neuromodulatory system dysfunction is sufficient to explain both tau hyperphosphorylation and amyloid beta plaque formation, the two pathological hallmarks of AD. We therefore predict that strengthening or preserving the endogenous functions of these systems in midlife represents the most effective strategy for preventing AD.

Indexed as

Alzheimer DiseaseBrainNeuronsAmyloid beta-PeptidesAnimalsHumansRisk Factorstau ProteinsAmyloid beta-Peptidestau ProteinsacetylcholineAlzheimer's diseaseamyloid betadopamineneuroinflammationneuromodulatory subcortical systemsneuronal resilienceneuronal vulnerabilitynoradrenalineorexinpathogenesisrisk factorsserotonintau

Identifiers

PMID41797441
PMCPMC12968472

What Socratic holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.