@article{pmid42499147,

title = {Theoretical and practical challenges for capturing reserve and resilience in aging and Alzheimer's disease: A narrative review},

author = {Valentin Ourry and Maude Wagner and Colin Groot and Rory Boyle and Jacob W Vogel and David Bartrés-Faz and Sylvia Villeneuve},

doi = {10.1002/alz.71664},

issn = {1552-5279},

year  = {2026},

date = {2026-07-01},

journal = {Alzheimers Dement},

volume = {22},

number = {7},

pages = {e71664},

abstract = {The concepts of reserve and resilience in aging and Alzheimer's disease (AD) are widely used but their operationalization remains challenging and often lacks conceptual and methodological consistency. In this narrative review, we describe the chronological history of these concepts and then summarize and discuss key theoretical and practical issues, along with proposed solutions and different perspectives, in the context of aging and AD. Theoretical challenges include risk versus protective factors, dynamic brain and cognitive trajectories, overestimation of resilience and inflection points. Practical challenges include proxy measures, study designs, residual approaches, and influential cases. We highlight the need for greater methodological harmonization, improved validation of proxy, and lifespan longitudinal approaches. Addressing these challenges will strengthen interpretability, reproducibility, and causal inference, ultimately facilitating the translation of reserve and resilience research into preventive and therapeutic strategies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid42520805,

title = {Parent-of-origin effects in Alzheimer's liability dissociate neurocognitive and cardiovascular traits in at-risk individuals},

author = {Chloé Savignac and Frédéric St-Onge and Sylvia Villeneuve and AmanPreet Badhwar and Sarah A Gagliano Taliun and Sali Farhan and Maiya Geddes and Yasser Iturria Medina and Judes Poirier and R Nathan Spreng and Danilo Bzdok and },

doi = {10.1016/j.xcrm.2026.102943},

issn = {2666-3791},

year  = {2026},

date = {2026-07-01},

journal = {Cell Rep Med},

pages = {102943},

abstract = {Alzheimer's disease (AD) has a higher prevalence in women than men and is more frequently inherited from mothers than fathers. Yet, while neuroimaging and biomarker studies link maternal family history to stronger AD-related alterations, epidemiological studies suggest that paternal history confers comparable or even greater risk. Here, we leverage the deeply profiled PREVENT-AD cohort to derive three intermediate phenotypes of AD susceptibility. Drawing on nearly 1,000 individual study visits, we quantify how these intermediate phenotypes vary as a function of maternal versus paternal AD lineage. We show that lineage-specific differentiation, including both maternal and paternal biases, is reflected in the brain structure and phenome of adult children of AD patients. Cognitive and cardiovascular risk markers, together with associated genetic variants, show the strongest differentiation along the parental-lineage spectrum of disease susceptibility relative to other correlates of AD burden. Our cross-generational analysis ultimately delineates multidimensional parent-of-origin effects in AD genealogy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41697669,

title = {Sex Differences in P-Tau217, Tau Aggregation, and Cognitive Decline},

author = {Gillian T Coughlan and Valentin Ourry and Diana Townsend and Hannah Klinger and Jane A Brown and Madison Cuppels and Tobey Betthauser and Rebecca Langhough and Karly Cody and Mabel Seto and Colin Birkenbihl and Annie Li and Michelle Farrell and Emma Thibault and Pia Kivisäkk Webb and Steven Arnold and Robert A Rissman and Michael Properzi and Aaron Schultz and Keith Johnson and Oliver Langford and Michael C Donohue and Sylvia Villeneuve and Sterling C Johnson and Hyun-Sik Yang and JoAnn E Manson and Reisa Sperling and Rachel F Buckley and },

doi = {10.1001/jamaneurol.2025.5670},

issn = {2168-6157},

year  = {2026},

date = {2026-04-01},

journal = {JAMA Neurol},

volume = {83},

number = {4},

pages = {369--381},

abstract = {IMPORTANCE: Among individuals with high levels of amyloid-β (Aβ), women exhibit higher insoluble tau burden and accumulation than age-matched men. It remains unclear whether this sex difference is influenced by soluble phosphorylated tau (p-tau), a biomarker that changes early in Alzheimer disease.nnOBJECTIVE: To investigate whether sex and aggregated Aβ synergistically predict plasma phosphorylated tau 217 (p-tau217) levels and whether levels of p-tau217 predict cross-sectional and longitudinal tau aggregation in a sex-specific manner (as measured by positron emission tomography [PET]).nnDESIGN, SETTING, AND PARTICIPANTS: This longitudinal study analyzed data between September 7, 2024, and October 29, 2025, from 1 clinical trial cohort and 4 observational study cohorts including men and women without cognitive impairment who had undergone multiple assessments via tau PET (18F-flortaucipir or 18F-MK-6240) and plasma p-tau217 assay at baseline. Cognitive performance was measured with the Preclinical Alzheimer Cognitive Composite. Data on cognitive performance were available from 3 of the 5 cohorts for a mean of 4.6 years (SD, 3.1 years). Across the 5 cohorts, the mean follow-up for tau PET was 3.6 years (SD, 1.7 years).nnEXPOSURES: Self-reported sex (male or female), tau PET, and p-tau217 assay.nnMAIN OUTCOMES AND MEASURES: The primary analyses used linear and mixed-effects models to assess baseline and longitudinal sex × p-tau217 interactions for 9 tau PET regions. The secondary analyses assessed sex × p-tau217 interactions for cognitive change using the Preclinical Alzheimer Cognitive Composite.nnRESULTS: Across the 5 cohorts, there were a total of 1292 participants (63.6% women; mean age, 70.6 [SD, 6.4] years) with tau PET assessments. Compared with men, women had significantly higher baseline p-tau217 levels at higher aggregated Aβ Centiloid levels (β, -0.21 [95% CI, -0.37 to -0.05], P = .009; highest interaction was found in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease/Longitudinal Evaluation of Amyloid Risk and Neurodegeneration [A4/LEARN] cohort). The sex × p-tau217 interactions at baseline were significant for 1 tau PET region in the Harvard Aging Brain Study (HABS) cohort, for 2 tau PET regions in the A4/LEARN cohort, for 6 tau PET regions in the Wisconsin Registry of Alzheimer's Prevention (WRAP) cohort, and for 4 tau PET regions in the Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD) cohort. Longitudinal interactions were significant for 4 tau PET regions in the A4/LEARN cohort, for 5 tau PET regions in both the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort and the WRAP cohort, and for 2 PET regions in both the HABS cohort and the PREVENT-AD cohort. Compared with men, women displayed greater tau deposition and accumulation at higher p-tau217 levels. Use of a secondary model showed women with higher p-tau217 levels also exhibited faster rates of cognitive decline relative to men in the both the WRAP cohort and the ADNI cohort.nnCONCLUSION AND RELEVANCE: These findings add to growing evidence that women have a differential tau response to Aβ that may emerge at the point of p-tau secretion. These findings have implications for the therapeutics and diagnostics of preclinical Alzheimer disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41646703,

title = {The neural basis of prosocial effort-based decision making in older adults at risk for Alzheimer's disease},

author = {Caitlin S Walker and Garance Barnoin and Mitchell Bennett and Colleen Hughes and Jennifer Tremblay-Mercier and R Nathan Spreng and Judes Poirier and Laurel S Morris and  and Sylvia Villeneuve and Maiya R Geddes},

doi = {10.64898/2026.01.10.26343857},

year  = {2026},

date = {2026-03-01},

journal = {medRxiv},

abstract = {BACKGROUND: Alzheimer's disease is associated with impairments in decision making that undermine autonomy, health behaviors, and quality of life. Effort-based decision making, the process of weighing reward value against effort costs, is particularly disrupted in aging and Alzheimer's disease. However, aging is also characterized by a shift toward socioemotional and prosocial goals, which may preserve motivation and effortful behavior. Understanding prosocial effort-based decision making and its neural substrates in individuals at risk for AD may reveal early alterations in decision making and neural circuits that support healthy aging.nnMETHODS: Fifty-two older adults from the PREVENT-AD cohort (mean age = 68.48, 38 females, 18  carriers) completed an effort-based decision-making task comparing willingness to exert effort for rewards obtained for oneself or for charity. Decision response, response time, and vigor were analyzed using mixed-effects models. Reward-effort relationships were modeled using psychometric functions and compared using random-effects Bayesian model comparison, with parameter estimates from the winning model compared between conditions and between  carriers and non-carriers. Seed-to-voxel resting-state functional connectivity from the ventromedial prefrontal cortex and anterior cingulate cortex examined neural substrates of prosocial effort-based decision making, and ROI-to-ROI connectivity between regions of a frontostriatal reward network was compared between  carriers and non-carriers.nnRESULTS: Participants showed increased acceptance of effort for prosocial compared to selforiented rewards. The relationship between reward and effort in both conditions was best captured by a sigmoid function, with lower motivation for self-oriented compared to prosocial rewards. Across all participants, higher motivation for prosocial compared to self-oriented rewards was associated with resting-state functional connectivity to the ventromedial prefrontal cortex and anterior cingulate cortex.  carriers showed lower overall motivation than non-carriers, but higher vigor when exerting effort for prosocial than self-oriented rewards, along with reduced nucleus accumbens-dorsal anterior cingulate connectivity that was associated with lower motivation for effort.nnCONCLUSIONS: Prosocial incentives may be an effective strategy for motivating effortful behavior in older adults at risk for Alzheimer's disease. Although  carriers show greater aversion to accepting effort for both reward types, they exhibit heightened vigor when working for prosocial compared to self-oriented rewards. Leveraging prosocial motivation and its underlying neural circuitry may therefore represent a promising strategy to sustain goal-directed behavior and decision making, promote physical and cognitive activity, and support emotional and brain health in at-risk aging.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41804764,

title = {Longitudinal association between sleep and Alzheimer's pathology},

author = {Bery Mohammediyan and Andrée-Ann Baril and Alfonso Fajardo Valdez and Frédéric St-Onge and Alexa Pichet Binette and Julie Carrier and Maiya R Geddes and Simon Ducharme and Maxime Montembeault and Jean-Paul Soucy and John Breitner and Judes Poirier and Sylvia Villeneuve and },

doi = {10.1002/alz.71228},

issn = {1552-5279},

year  = {2026},

date = {2026-03-01},

journal = {Alzheimers Dement},

volume = {22},

number = {3},

pages = {e71228},

abstract = {INTRODUCTION: Since sleep disturbance is a modifiable risk factor for Alzheimer's disease (AD), we tested associations between sleep and AD pathology in cognitively unimpaired (CU) persons.nnMETHODS: We included 223 participants from the PREVENT-AD cohort with self-reported measures of sleep, objective actigraphy measures of sleep, and positron emission tomography (PET) scans for AD pathology quantification. Repeated PET scans (mean follow-up: 4.31 ± 0.55 years) were available for 103 participants. We conducted robust linear models (RLM) for cross-sectional analyses and RLMs using the annual change in AD pathology for longitudinal analyses.nnRESULTS: All actigraphy-based sleep variability measures were associated with tau burden (duration: β = 0.121 [95% confidence interval {CI} = 0.010; 0.232], p = 0.034; efficiency: 0.122 [0.010; 0.235], 0.033; fragmentation: 0.115 [0.010; 0.221], 0.033). Greater variability in sleep fragmentation was also associated with amyloid burden (0.074 [0.008; 0.140], 0.028), and variability in sleep efficiency portended amyloid burden and faster accumulation over time (0.075 [0.009; 0.141], 0.026; 0.164 [0.008; 0.320], 0.039; respectively).nnDISCUSSION: Irregularity in sleep patterns is associated with higher pathological burden and faster amyloid accumulation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41916976,

title = {Characterizing spatiotemporal white matter hyperintensity pathophysiology in vivo to disentangle vascular and neurodegenerative contributions},

author = {Olivier Parent and Zaki Alasmar and Sophia Osborne and Aurélie Bussy and Manuela Costantino and Jérémie P Fouquet and Daniela Quesada and Alexandre Pastor-Bernier and Alfonso Fajardo-Valdez and Alexa Pichet-Binette and Ann McQuarrie and Josefina Maranzano and Gabriel A Devenyi and Christopher J Steele and Sylvia Villeneuve and  and  and Mahsa Dadar and M Mallar Chakravarty},

doi = {10.1038/s41467-026-70832-2},

issn = {2041-1723},

year  = {2026},

date = {2026-03-01},

journal = {Nat Commun},

volume = {17},

number = {1},

abstract = {White matter hyperintensities (WMHs) are neuroimaging markers widely interpreted as caused by cerebral small vessel disease, yet emerging evidence suggests that a subset may have a neurodegenerative etiology. Current imaging methods have lacked the specificity to disentangle biological processes underlying WMHs in vivo. Here, we used voxel-level normative modeling and seven microstructural MRI markers with complementary biophysical sensitivities to generate single-subject high-resolution WMH pathophysiology maps in a large cohort (n = 32,526). We calculated data-driven spatial patterns of similar WMHs, revealing distinct periventricular, posterior, and anterior clusters. We identified a reproducible WMH signature linked to dementia and Alzheimer's disease, characterized by a posterior predominance and a pathophysiological pattern indicative of selective fiber degeneration. Posterior WMHs connected cortical regions vulnerable to tau pathology. Our framework helps parsing vascular and neurodegenerative contributions of WMHs in vivo, which could alter the course of treatment strategies and provide nuanced interpretations of research findings.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41234025,

title = {Associations of lifestyle factors with amyloid pathology in persons without dementia},

author = {Julie E Oomens and Stephanie Jb Vos and Nancy N Maserejian and Mercè Boada and Mira Didic and Sebastiaan Engelborghs and Tormod Fladby and Wiesje M van der Flier and Giovanni B Frisoni and Lutz Fröhlich and Kiran Dip Gill and Timo Grimmer and Jakub Hort and Yoshiaki Itoh and Takeshi Iwatsubo and Aleksandra Klimkowicz-Mrowiec and Susan M Landau and Dong Young Lee and Alberto Lleó and Pablo Martinez-Lage and Alexandre de Mendonça and Philipp T Meyer and Piero Parchi and Matteo Pardini and Lucilla Parnetti and Julius Popp and Lorena Rami and Eric M Reiman and Juha O Rinne and Karen M Rodrigue and Pascual Sánchez-Juan and Isabel Santana and Nikolaos Scarmeas and Philip Scheltens and Ingmar Skoog and Reisa A Sperling and Yaakov Stern and Sylvia Villeneuve and Gunhild Waldemar and Jens Wiltfang and Henrik Zetterberg and Daniel Alcolea and Ricardo F Allegri and Daniele Altomare and Randall J Bateman and Simone Baiardi and Ines Baldeiras and Kaj Blennow and Anouk den Braber and Mark A van Buchem and Min Soo Byun and Jiří Cerman and Kewei Chen and Elena Chipi and Gregory S Day and Alexander Drzezga and Laura L Ekblad and Stefan Förster and Juan Fortea and Yvonne Freund-Levi and Lars Frings and Eric Guedj and Christian G Habeck and Ron Handels and Lucrezia Hausner and Sabine Hellwig and Julio F Jiménez-Bonilla and Ane Iriondo Juaristi and Ramesh Kandimalla and Silke Kern and Bjørn-Eivind S Bordewick Kirsebom and Johannes Kornhuber and Nienke Legdeur and Johannes Levin and Wolfgang Maier and Marta Marquié and Shinobu Minatani and Silvia Daniela Morbelli and Barbara Mroczko and Eva Ntanasi and Catarina Resende de Oliveira and Adelina Orellana and Oliver Peters and Sudesh Prabhakar and Inez H Ramakers and Eloy Rodríguez-Rodriguez and Agustín Ruiz and Eckart Rüther and Jayant Sakhardande and Per Selnes and Dina Silva and Hilkka Soininen and Luiza Spiru and Akitoshi Takeda and Charlotte E Teunissen and Betty M Tijms and Lisa Vermunt and Åsa K Wallin and Wietse Wiels and Mary Yannakoulia and Dahyun Yi and Anna Zettergren and  and  and  and  and  and  and Rik Ossenkoppele and Frans Rj Verhey and Pieter Jelle Visser and Willemijn J Jansen},

doi = {10.1177/13872877251379083},

issn = {1875-8908},

year  = {2025},

date = {2025-12-01},

journal = {J Alzheimers Dis},

volume = {108},

number = {3},

pages = {1043--1059},

abstract = {BackgroundThe association between lifestyle factors and Alzheimer's disease (AD) pathophysiology remains incompletely understood.ObjectiveThe aim of this study was to assess the association of alcohol consumption, smoking behavior, sleep quality and physical, cognitive, and social activity with cerebral amyloid pathology.MethodsFor this cross-sectional study, we selected participants from the Amyloid Biomarker Study data pooling initiative. We used generalized estimating equations to assess associations of dichotomized lifestyle measures with amyloid pathology.ResultsWe included 9171 participants with normal cognition (NC) and 2555 participants with mild cognitive impairment (MCI) from the Amyloid Biomarker Study. Of participants with NC, 58% were women, 34% were  ε4 carrier, and 27% had amyloid pathology. Of participants with MCI, 48% were women, 47% were  ε4 carrier, and 57% had amyloid pathology. In NC, cognitively active participants were less likely to have amyloid pathology (OR = 0.77, 95%CI 0.66-0.89, p < 0.001). In MCI, participants who had ever smoked or had sleep problems were less likely to have amyloid pathology (OR = 0.85, 95%CI 0.73-0.99, p = 0.029; OR = 0.62, 95%CI 0.45-0.86, p = 0.004).ConclusionsIn NC, cognitive activity was associated with a lower frequency of amyloid pathology. In MCI, favorable lifestyle behaviors were not associated with a lower frequency of amyloid pathology. The results of the current study contribute to the broader evidence base on lifestyle and AD by further characterizing the role of lifestyle behaviors in AD pathology across different clinical stages.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41434218,

title = {Alzheimer's Imaging Consortium},

author = {Bery Mohammediyan and Sylvia Villeneuve and Béatriz Oliveira and John C S Breitner and Judes Poirier and Erlan Sanchez and Claire André and Géraldine Rauchs and Andree-Ann Baril},

doi = {10.1002/alz70862_110224},

issn = {1552-5279},

year  = {2025},

date = {2025-12-01},

journal = {Alzheimers Dement},

volume = {21 Suppl 8},

number = {Suppl 8},

pages = {e110224},

abstract = {BACKGROUND: We investigated whether insomnia may be associated with changes in cognition over time among older adults at elevated risk of Alzheimer's disease (AD).nnMETHODS: We studied 348 dementia-free older adults (mean age: 65.74 ± 5.57; 72% female) from the PREVENT-AD cohort, all at elevated AD risk due to family history of AD. At baseline, a self-reported insomnia symptoms index was computed based on the Pittsburgh Sleep Quality Index (PSQI). The presence of insomnia symptoms was defined as sleep onset latency >30min ≥3 times/week OR sleep maintenance is difficult ≥3 times/week AND these sleep disturbances interfere with daily life. A subsample of 240 participants also underwent objective sleep assessments (7-day actigraphy). Difficulty with sleep maintenance on actigraphy was defined as ≥3 times/week with a wake after sleep onset >60min or a sleep efficiency <78% (1.5 SD of sample). Cognition was assessed both at baseline and yearly for a total follow-up of 7.15 years on average (SD: 2.40 years), and included measures of immediate and delayed memory, attention, and total score on the Repeatable Battery for Assessment of Cognitive Status (RBANS). First, baseline and longitudinal cognition scores were compared between 3 groups stratified for self-reported insomnia symptoms severity (i.e., 0, ≤1 and 2+ symptoms) using ANCOVAs. The same analyses were performed between 3 groups stratified for objectively defined insomnia symptoms. Finally, cognition scores were compared between 4 groups stratified by the severity of both self-reported and objective insomnia symptoms (i.e., no symptoms, only self-reported symptoms, only objective symptoms or both self-reported and objective symptoms).nnRESULTS: Individuals with ≥2 self-reported insomnia symptoms had higher baseline immediate and delayed memory scores than individuals with ≤1 insomnia symptoms (p = 0.02, Figure 1A; p = 0.02, Figure 1B). Actigraphy-indicating ≥2 insomnia symptoms had higher longitudinal delayed memory scores than individuals with ≤1 insomnia symptom (p = 0.02, Figure 1C). Individuals whose insomnia symptoms were observed only with actigraphy had the greatest longitudinal delayed memory scores (p = 0.01, Figure 1D).nnCONCLUSION: Counterintuitively, in individuals at elevated risk of AD, more self-reported and objective insomnia symptoms were associated with better cognitive scores. This may reflect protective lifestyle factors that improve cognition but also disrupt sleep patterns and sleep satisfaction.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41434164,

title = {Alzheimer's Imaging Consortium},

author = {Alfie Wearn and Christine L Tardif and Ilana R Leppert and Colleen S Hughes and Giulia Baracchini and Judes Poirier and John C S Breitner and Gary R Turner and Sylvia Villeneuve and R Nathan Spreng},

doi = {10.1002/alz70862_110106},

issn = {1552-5279},

year  = {2025},

date = {2025-12-01},

journal = {Alzheimers Dement},

volume = {21 Suppl 8},

number = {Suppl 8},

pages = {e110106},

abstract = {BACKGROUND: The locus coeruleus (LC) is one of the first epicentres of tau pathology in Alzheimer's disease, displaying pathology decades before clinical symptom onset. We investigated whether LC integrity was associated with cortical deposition of amyloid and tau in vivo in asymptomatic, at-risk older adults.nnMETHOD: 208 healthy older adults with first-degree familial history of Alzheimer's disease were included from the PREVENT-AD cohort (mean age 68.4 ± 5.14y, 69% female). 155 subjects were also examined longitudinally over 38.8 ± 14.0 months. Subjects underwent longitudinal 3T MRI: 1mm T1w MPRAGE and Neuromelanin-sensitive brainstem imaging (0.7x0.7x1.8mm). Cortical amyloid and tau were quantified using PET imaging (single timepoint), with 18F-NAV4694 and 18F-flortaucipir tracers, respectively. Regional specific uptake value ratios (SUVR) were calculated for each, relative to cerebellar grey matter. LC was automatically delineated on individual neuromelanin-sensitive brainstem scans by identifying 10 brightest connected voxels within an approximate region of interest and calculating contrast-to-noise relative to a pontine control region (LC). We tested associations between LC and regional amyloid and tau SUVR using robust linear mixed effects models for each region with random intercepts across subjects. Longitudinal change was tested as an interaction term between the PET measure and time. We also tested the dependence of the Tau-LC association on global amyloid pathology at baseline using linear regression. All analyses were corrected for baseline age, sex and education and p-values were FDR-adjusted.nnRESULTS: We observed negative associations between LC integrity and amyloid SUVR across almost all cortical regions (Figure 1). Associations between LC integrity and cortical tau were restricted to temporal lobes, including parahippocampal gyrus, and inferior parietal regions (Figure 1). Associations with both amyloid and tau were particularly strong in the left hemisphere. These associations were observed only at baseline, with no longitudinal effects observed. The relationship between baseline LC integrity and cortical tau was modulated by global amyloid in lateral temporal cortices, particularly along in the left lateral temporal cortex (Figure 2).nnCONCLUSION: LC degeneration was associated with greater expression of key hallmarks of AD pathology in asymptomatic older adults. We support the model that LC is central to the earliest pathophysiological changes of AD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41433899,

title = {Alzheimer's Imaging Consortium},

author = {Yara Yakoub and Ting Qiu and Sylvia Villeneuve and Alexa Pichet Binette},

doi = {10.1002/alz70862_109930},

issn = {1552-5279},

year  = {2025},

date = {2025-12-01},

journal = {Alzheimers Dement},

volume = {21 Suppl 8},

number = {Suppl 8},

pages = {e109930},

abstract = {BACKGROUND: Blood-based biomarkers of AD, especially p-tau217, show high concordance with Aβ-PET load and status. While many studies relied on cross-sectional data, assessing dynamic changes in these assays is important for future clinical use and trial outcomes. We evaluated the longitudinal trajectories of multiple plasma biomarkers and their associations with subsequent changes in Aβ-PET status.nnMETHOD: We used data from the ADNI FNIH consortium consisting of 386 participants (72.7 ± 7.1 years old, 52.3% cognitively unimpaired, 49.7% women) with on average three plasma samples and three Aβ-PET scans collected over 11 years, in which multiple assays were tested (here focussing on 5 p-tau217 and 4 Aβ assays). We first assessed changes over time for each assay in Aβ-PET positive (n = 140, 36.3%) and negative participants. We then focused on progression from Aβ-negativity to Aβ-positivity over follow-up, using cox proportional-hazard models to evaluate if baseline levels and longitudinal (rate of change) of plasma biomarkers were related to subsequent Aβ-positivity (total of 49 progressors).nnRESULT: Across both Aβ-negative and positive groups, all p-tau217 assays, but not the Aβ assays, showed increase over time (Figure 1A-B). In the Aβ-negative subgroup, higher plasma p-tau217 rate of change was associated with increased risk of progression to Aβ-PET positivity (Figure 2A-B), with highest hazard rations (HR) seen with the CN assays (HR = 2.77 and HR = 2.50). Hazard ratios were higher with p-tau217 rates of change compared to baseline values (Figure 2A). With the Aβ assays, higher Aβ pathology at baseline was associated with progression to Aβ-PET positivity (HR from 1.44 -1.65), but no associations or unexpected associations were seen with the rate of change (Figure 2A). Individual slopes between the different groups (Aβ-negative, progressors to Aβ-positive and Aβ-positive) for all assays are displayed in Figure 3 to aid in assay comparisons.nnCONCLUSION: All plasma p-tau217 assays levels changed over time, which was not the case for the Aβ assays. Among Aβ-negative individuals, while baseline plasma p-tau217 and Aβ were associated with progression to Aβ-positivity over 10 years, across all assays, the rate of change in p-tau217 was the measure most strongly predictive of future Aβ-PET positivity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41433743,

title = {Alzheimer's Imaging Consortium},

author = {Ting Qiu and Zhen-Qi Liu and Jonathan Gallego Rudolf and Manon Edde and Alex Valcourt Caron and Yuanchao Zhang and Jean-Paul Soucy and R Nathan Spreng and Alexa Pichet Binette and Maxime Descoteaux and Sylvia Villeneuve},

doi = {10.1002/alz70862_110868},

issn = {1552-5279},

year  = {2025},

date = {2025-12-01},

journal = {Alzheimers Dement},

volume = {21 Suppl 8},

number = {Suppl 8},

pages = {e110868},

abstract = {BACKGROUND: Amyloid-beta (Aβ) and tau pathology in Alzheimer's disease (AD) is commonly associated with disruptions in grey matter integrity, including reduced cortical thickness (CT) and increased cortical mean diffusivity (MD). However, some cross-sectional studies have also reported an increase in CT during the preclinical stage of the disease. Using over 10 years of longitudinal neuroimaging data from the PREVENT-AD cohort, we examined the association between AD pathology (Aβ and tau) and brain structure, measured by CT, free-water corrected MD (MD), and hippocampal volume. We also estimated the longitudinal trajectories of structural changes along the Aβ positivity timeline across the preclinical and prodromal stages of AD.nnMETHOD: We performed partial least square analyses (PLS) separately for Aβ negative (Aβ-) and Aβ positive (Aβ+) groups to identify key brain regions that contributed to pathological-structural associations. We then assessed the cross-sectional and longitudinal associations between AD pathology and structural measures within the PLS-identified regions across all participants. Using the sampled iterative local approximation algorithm, we estimated the time from Aβ+ onset and calculated years from Aβ+ for each MRI scan. These estimates allowed us to track the structural changes relative to Aβ positivity (Figure 1).nnRESULT: We found that higher Aβ deposition was associated with decreased MD and increased CT in the Aβ- group, whereas the Aβ+ group showed opposite associations. Across all participants, associations for MD followed a U-shaped pattern, while CT exhibited an inverse U-shaped relationship with Aβ pathology (Figure 2). These associations were observed in several key AD-related regions, including the entorhinal cortex, fusiform gyrus, and inferior parietal lobule, and middle temporal regions. Longitudinal analyses revealed similar trajectory patterns along the Aβ+ timeline, with these changes emerging several years before Aβ positivity onset (Figure 3).nnCONCLUSION: Our study suggests that brain structural changes in response to Aβ pathology start decades before symptoms and may follow highly nonlinear trajectories. The initial increases in CT and decreases in MD might be related to the space taken by Aβ and/or several other biological processes occurring during the preclinical stage of the disease, such as neuroinflammation, astrocytic and microglia activation, or brain swelling.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41433380,

title = {Alzheimer's Imaging Consortium},

author = {Jonathan Gallego Rudolf and Alex I Wiesman and Sylvain Baillet and Sylvia Villeneuve},

doi = {10.1002/alz70862_110285},

issn = {1552-5279},

year  = {2025},

date = {2025-12-01},

journal = {Alzheimers Dement},

volume = {21 Suppl 8},

number = {Suppl 8},

pages = {e110285},

abstract = {BACKGROUND: Several biomarkers have been proposed for predicting the risk of progression of asymptomatic individuals to mild cognitive impairment (MCI). However, there is the need of characterizing the dynamic change in their accuracy as a function of the time between biomarker collection and MCI diagnosis. In addition, the potential contribution of direct measures of neurophysiological activity for estimating the risk of MCI progression has not been explored in depth.nnMETHOD: We assessed spectral power features from task-free magnetoencephalographic (MEG) recordings, MRI-derived hippocampal volumes, plasma biomarkers, and PET measures of Aβ and tau deposition in a group of cognitively unimpaired older adults with a family history of AD (N = 102). From this sample, 31 individuals developed MCI based on a multidisciplinary consensus who had access to longitudinal neuropsychological assessments but were blind to biomarker information (mean time between biomarkers collection and MCI diagnosis = 4 years; SD = 1.9 years). We benchmarked these biomarkers using a series of logistic regression models to assess the temporal evolution of their accuracy for predicting MCI progression, in combination with clinical information (Figure 1).nnRESULT: Neurophysiological activity features and tau pet provided additional information to the clinical model when acquired up to ∼4 years prior to diagnosis, but their accuracy decreased at larger intervals. In contrast, the accuracy gained by incorporating Aβ PET or plasma biomarkers remained high up to 6 years before diagnosis (Figure 2). These observations were confirmed after running stepwise logistic regression on the model including all biomarkers, highlighting the contribution of age, sex, plasma p-tau217, Aβ and tau PET and neurophysiological activity for predicting MCI progression at different time intervals (Figure 3).nnCONCLUSION: Overall, our results delineate a timeline of the accuracy provided by different biomarkers for predicting progression to MCI. Such findings highlight the dynamic sensitivity of different biomarkers, which is dependent on the time lapse between biomarkers collection and clinical diagnosis. This is particularly relevant for future clinical trials that intend to use biomarkers for screening participants.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41353310,

title = {Longitudinal effects of cerebrovascular reactivity and cerebral pulsatility in cognitively intact older adults with APOE4: links with cognition},

author = {Zacharie Potvin-Jutras and Pierre-Luc Tremblay and Hanieh Mohammadi and Sylvia Villeneuve and R Nathan Spreng and Claudine J Gauthier and },

doi = {10.1007/s11357-025-02036-3},

issn = {2509-2723},

year  = {2025},

date = {2025-12-01},

journal = {Geroscience},

abstract = {The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for Alzheimer's disease (AD) and is linked to poorer cerebrovascular health. Cerebrovascular reactivity (CVR), an indicator of vascular reserve, and cerebral pulsatility (CP), a marker of vascular stiffness, are sensitive biomarkers of early vascular dysfunction associated with aging and AD. However, the relationship between APOE4 status and these cerebrovascular metrics remains unclear. This study investigated whether the APOE genotype influences longitudinal changes in CVR and CP, and their association with cognitive performance in cognitively unimpaired individuals. We utilized the PREVENT-AD cohort, including 101 APOE4 carriers (30 males and 71 females) and 152 non-APOE4 carriers (48 males and 104 females) aged 55 and older. Relative CVR and CP were derived from resting state functional magnetic resonance imaging data, with regional values extracted from cerebral arterial territories. Results indicated significant interactions between APOE4 status and relative CVR in the left middle cerebral artery and left posterior cerebral artery (PCA) territories. APOE4 status disaggregated analyses revealed that APOE4 carriers uniquely presented a significant decline in relative CVR within the left PCA. Furthermore, sex-specific effects were identified, with female APOE4 carriers having lower relative CVR in the right anterior cerebral artery territory compared to female non-carriers. Importantly, higher relative CVR was positively associated with better cognitive performance in APOE4 carriers. No significant effects of APOE4 status on CP were found. Together, these findings suggest that relative CVR may be an important early measure of cerebrovascular health and cognition in cognitively intact APOE4 carriers.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41282725,

title = {Quantifying brain atrophy in Frontotemporal Dementia: a head-to-head comparison of neuroimaging techniques},

author = {Amelie Metz and Roqaie Moqadam and Yashar Zeighami and D Louis Collins and Sylvia Villeneuve and Mahsa Dadar},

doi = {10.1101/2025.10.28.25339007},

year  = {2025},

date = {2025-11-01},

journal = {medRxiv},

abstract = {Frontotemporal Dementia (FTD) is a neurodegenerative disorder characterized by extensive atrophy in the frontal and temporal lobes of the brain as well as high cerebrovascular burden. While anatomical Magnetic Resonance Imaging (MRI) is well established for quantifying brain atrophy in FTD, the variability in (pre-)processing methods limits the generalizability and comparability of findings. This study systematically compared the robustness and sensitivity of multiple widely used neuroimaging metrics, namely Deformation-Based Morphometry (DBM), Voxel-Based Morphometry (VBM), Cortical Thickness (CT), and segmentation-based grey matter Volumes, in detecting atrophy across FTD subtypes. We processed 732 T1-weighted MRI scans from 156 participants with FTD and 139 healthy controls from the Frontotemporal Lobar Degeneration Neuroimaging Initiative using our in-house pipeline PELICAN (Dadar et al., 2025) for volumetric measures and FreeSurfer version 7 (Fischl, 2012) for CT and grey matter segmentations. Visual quality control using consistent quality control images at each step of the pipelines revealed significantly higher failure rates for CT (38.52%) and FreeSurfer segmentations (23.63%) relative to PELICAN's volumetric measures (2.04% DBM, 3.05% VBM). Failure rates differed between FTD subtypes and were related to pathological burden. Particularly for FreeSurfer, errors occurred predominantly in regions with high prevalence of atrophy and White Matter Hyperintensities. In PELICAN, the addition of a FTD-specific template as an intermediate step during nonlinear registration decreased the failure rates in this step in the FTD population. We then applied linear regression models to assess each metric's sensitivity in detecting cross-sectional differences between FTD groups controls as well as linear mixed-effects models to determine which method is most sensitive to longitudinal anatomical changes. While CT yielded effect sizes comparable to VBM and DBM when analyzing the same subset of successfully processed scans, VBM and DBM demonstrated enhanced power to detect effects due to lower failure rates and higher participant retention in the full sample. Overall, we demonstrate that image processing methodology and pipeline selection profoundly influences effect sizes and statistical power to detect meaningful between-group differences or longitudinal changes. Volumetric measures (DBM and VBM) yielded sufficiently robust pipeline outcomes to maintain adequate statistical power for capturing atrophy patterns after quality control procedures.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40952756,

title = {Plasma Phosphorylated Tau 217 to Identify Preclinical Alzheimer Disease},

author = {Gemma Salvadó and Shorena Janelidze and Divya Bali and Anna Orduña Dolado and Joseph Therriault and Wagner S Brum and Alexa Pichet Binette and Erik Stomrud and Niklas Mattsson-Carlgren and Sebastian Palmqvist and Emma M Coomans and Charlotte E Teunissen and Wiesje M van der Flier and Nesrine Rahmouni and Tammie L S Benzinger and Juan Domingo Gispert and Kaj Blennow and Vincent Doré and Azadeh Feizpour and Christopher C Rowe and Daniel Alcolea and Juan Fortea and Sylvia Villeneuve and Sterling C Johnson and Pedro Rosa-Neto and Ronald C Petersen and Clifford R Jack and Suzanne E Schindler and Marc Suárez-Calvet and Rik Ossenkoppele and Oskar Hansson and },

doi = {10.1001/jamaneurol.2025.3217},

issn = {2168-6157},

year  = {2025},

date = {2025-11-01},

journal = {JAMA Neurol},

volume = {82},

number = {11},

pages = {1122--1134},

abstract = {IMPORTANCE: Advances in Alzheimer disease (AD) have shifted research focus to earlier disease stages, necessitating more scalable approaches to identify cognitively unimpaired individuals with amyloid β (Aβ) pathology.nnOBJECTIVE: To assess the utility of plasma phosphorylated tau 217 (p-tau217) for classifying Aβ status in cognitively unimpaired individuals, both as a stand-alone test and in a 2-step approach where positive plasma results were confirmed using a second modality (Aβ positron emission tomography [PET] or cerebrospinal fluid [CSF]).nnDESIGN, SETTING, AND PARTICIPANTS: This cross-sectional cohort study used data collected between June 2009 and March 2024. We included 2916 cognitively unimpaired participants from 12 international independent observational cohorts in the US, Europe, Australia, and Canada with available plasma p-tau217 levels and CSF or PET Aβ biomarkers. Performance comparisons between mass spectrometry and immunoassay-based p-tau217 measurements were also performed (n = 964).nnEXPOSURES: Plasma p-tau217 levels measured by immunoassay.nnMAIN OUTCOME AND MEASURES: Aβ status, determined by CSF or Aβ PET biomarkers.nnRESULTS: Participants had a mean (SD) age of 66.9 (9.9) years; 971 (33.3%) were Aβ positive by either CSF or PET, 1667 (57.2%) were women, and 1108 (38.1%) carried at least 1 APOE ε4 allele. As a stand-alone test, plasma p-tau217 achieved a positive predictive value (PPV) of 79% (95% CI, 74-84) and an overall accuracy of 81% (95% CI, 80-82). In a 2-step workflow, the PPV and accuracy significantly increased to 91% (95% CI, 86-95). While this approach required screening of 677 individuals with plasma p-tau217 to identify 100 Aβ-positive individuals, compared to 536 participants when using PET alone, it reduced the need for PET testing to 124. Immunoassays demonstrated comparable PPVs to mass spectrometry (80% [95% CI, 74-86] vs 85% [95% CI, 81-90]; P = .12) but significantly lower overall accuracy (82% [95% CI, 79-84]% vs 88 [95% CI, 86-90]; P < .001) and true Aβ-positive detection rate (49% [95% CI, 43-55] vs 69% [95% CI, 64-75]; P < .001).nnCONCLUSIONS AND RELEVANCE: The findings highlight the potential of plasma p-tau217 as a stand-alone test-or when used in a sequential 2-step approach alongside PET or CSF testing-as a cost-effective, scalable, and minimally burdensome strategy for identifying preclinical AD. Tailored screening workflows that incorporate p-tau217 can improve efficiency in participant selection for preclinical AD trials and, in the future, help guide access to disease-modifying treatments.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41188354,

title = {Longitudinal functional connectivity during rest and task is differentially related to Alzheimer's pathology and episodic memory in older adults},

author = {Larissa Fischer and Jenna N Adams and Eóin N Molloy and Jennifer Tremblay-Mercier and Jordana Remz and Alexa Pichet Binette and M Natasha Rajah and Sylvia Villeneuve and Anne Maass and },

doi = {10.1038/s41598-025-21596-0},

issn = {2045-2322},

year  = {2025},

date = {2025-11-01},

journal = {Sci Rep},

volume = {15},

number = {1},

pages = {38499},

abstract = {Changes in functional connectivity (FC) strength involving the medial temporal lobe (MTL) and posteromedial cortex (PMC) are related to early Alzheimer's pathology and alterations in episodic memory performance in cognitively unimpaired older adults, but their dynamics remain unclear. We examined how longitudinal changes in FC involving MTL and PMC during resting-state, episodic memory encoding, and retrieval relate to subsequent amyloid- and tau-PET burden, longitudinal episodic memory performance, and the APOE4 genotype in 152 cognitively unimpaired older adults from the PREVENT-AD cohort. We found APOE4- and fMRI paradigm-dependent associations of change in FC strength with pathology burden and change in episodic memory performance. Decreasing FC over time, or "hypoconnectivity", within PMC during rest in APOE4 carriers and during retrieval in APOE4 non-carriers was related to more amyloid and tau, respectively. Conversely, increasing FC over time, or "hyperconnectivity", within MTL during encoding in APOE4 carriers and between MTL and PMC during retrieval independent of APOE4 status was related to more tau. Further, increasing FC between MTL and PMC during rest, unlike during encoding, was beneficial for episodic memory. Our study highlights that pathology-related episodic memory network changes manifest differently during rest and task and have differential implications for episodic memory trajectories.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41144662,

title = {Quantitative MRI of the hippocampus reveals microstructural trajectories of aging and Alzheimer's disease pathology},

author = {Alfie Wearn and Christine L Tardif and Ilana R Leppert and Giulia Baracchini and Colleen Hughes and Jennifer Tremblay-Mercier and John Breitner and Judes Poirier and Sylvia Villeneuve and Boris C Bernhardt and Gary R Turner and R Nathan Spreng and },

doi = {10.1073/pnas.2502674122},

issn = {1091-6490},

year  = {2025},

date = {2025-11-01},

journal = {Proc Natl Acad Sci U S A},

volume = {122},

number = {44},

pages = {e2502674122},

abstract = {Hippocampal degeneration is a feature of both normal aging and Alzheimer's disease (AD). Prior to macroscopic degeneration, microstructural changes occur such as demyelination, iron deposition, or subtle atrophy, which can be characterized in vivo using MRI. We topographically mapped measures of microstructure and macrostructure across the unfolded surface of the hippocampus in 224 healthy older adults at risk for AD (aged 57 to 87) and 37 younger adults (aged 18 to 37). We describe three spatial regions of unique structural covariance between four parameters sensitive to microstructural tissue properties (R1, MTsat, R2*, PD) and macrostructure (surface thickness), with high convergence with previous spatial segmentations. We demonstrate both cross-sectional and longitudinal associations of microstructure with healthy aging across the lifespan, AD pathological hallmarks, genetic risk, and cognition. These associations had subtle variations across different spatial areas of the hippocampus. We report associations between age and qMRI measures sensitive to macromolecular concentration (R1, MTsat) and paramagnetic susceptibility (R2*), consistent with mechanisms of demyelination and increased iron deposition as key hallmarks of the aging hippocampus and in presymptomatic stages of AD. qMRI measures did not explain more variance in delayed recall than global PET measures, suggesting variation in cognitive performance in aging and incipient AD is influenced by factors beyond hippocampal microstructure. We demonstrate the utility of quantitative MRI to provide greater insight into hippocampal health compared to typical macrostructural measures through "in vivo histology," opening a window to understanding neuropathological mechanisms in the earliest stages of age- and disease-related neurodegeneration.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41020412,

title = {The PREVENT-AD cohort: Accelerating Alzheimer's disease research and treatment in Canada and beyond},

author = {Sylvia Villeneuve and Judes Poirier and John C S Breitner and Jennifer Tremblay-Mercier and Jordana Remz and Jean-Michel Raoult and Yara Yakoub and Jonathan Gallego-Rudolf and Ting Qiu and Alfonso Fajardo Valdez and Bery Mohammediyan and Mohammadali Javanray and Amelie Metz and Safa Sanami and Valentin Ourry and Alfie Wearn and Alexandre Pastor-Bernier and Manon Edde and Julie Gonneaud and Cherie Strikwerda-Brown and Christine L Tardif and Claudine J Gauthier and Maxime Descoteaux and Mahsa Dadar and Étienne Vachon-Presseau and Andrée-Ann Baril and Simon Ducharme and Maxime Montembeault and Maiya R Geddes and Jean-Paul Soucy and Natasha Rajah and Robert Laforce and Christian Bocti and Christos Davatzikos and Lune Bellec and Pedro Rosa-Neto and Sylvain Baillet and Alan C Evans and D Louis Collins and M Mallar Chakravarty and Kaj Blennow and Henrik Zetterberg and R Nathan Spreng and Alexa Pichet Binette and },

doi = {10.1002/alz.70653},

issn = {1552-5279},

year  = {2025},

date = {2025-10-01},

journal = {Alzheimers Dement},

volume = {21},

number = {10},

pages = {e70653},

abstract = {The PResymptomatic EValuation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD) is an investigator-driven study that was created in 2011 and enrolled cognitively normal older adults with a family history of sporadic AD. Participants are deeply phenotyped and have now been followed annually for more than 12 years (median follow-up 8.0 years, SD 3.1). Multimodal magnetic resonance imaging (MRI), genetic, neurosensory, clinical, cerebrospinal fluid, and cognitive data collected until 2017 on 348 participants who agreed to open sharing with the neuroscience community were already available. We now share a new release including 6 years of additional follow-up cognitive data, and additional MRI follow-ups, clinical progression, new longitudinal behavioral and lifestyle measures (questionnaires, actigraphy), longitudinal AD plasma biomarkers, amyloid-beta and tau positron emission tomography (PET), magnetoencephalography, as well as neuroimaging analytic measures from all MRI modalities. We describe the PREVENT-AD study, the data shared with the global research community, as well as the model we created to sustain longitudinal follow-ups while also allowing new innovative data collection. HIGHLIGHTS: The PResymptomatic EValuation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD) is a single-site longitudinal study that started in 2011 with annual follow-up data collection on individuals at risk of Alzheimer's disease who were all cognitively normal at enrolment. All 387 participants were enrolled between 2011 and 2017 and 306 (79%) of these participants were still in the study as of December 2023. While the PREVENT-AD dataset was not originally planned to be shared with the global research community, 348 participants retrospectively consented for their data to be shared with researchers worldwide. The first release of data was in 2019. We now share a second release that includes 6 years of additional follow-up visits, information on clinical progression and novel cognitive, behavioral, genetic, plasma and neuroimaging (amyloid and tau positron emission tomography [PET], magnetoencephalography [MEG], and new magnetic resonance imaging [MRI] sequences) data. It also includes analytic outputs for neuroimaging modalities.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41256144,

title = {Trajectories of plasma biomarkers, amyloid-beta burden and cognitive decline in Alzheimer's disease: A Longitudinal ADNI Study},

author = {Yara Yakoub and Ting Qiu and Clémence Peyrot and Gemma Salvadó and Sylvia Villeneuve and Alexa Pichet Binette},

doi = {10.1101/2025.09.30.25337003},

year  = {2025},

date = {2025-10-01},

journal = {medRxiv},

abstract = {As novel amyloid-β targeted therapies emerge, plasma biomarkers have promising potential to serve as screening tools and as surrogate measures for treatment outcomes. Understanding longitudinal trajectories of these biomarkers and how their changes relate to changes in AD pathology and cognition is needed to help track treatment response and guide patient care. We analyzed data from 394 individuals in the ADNI-FNIH dataset who had plasma biomarkers available across 14 assays, Aβ-PET scans and cognitive assessments over a 10-year period. Plasma p-tau217, regardless of the assay used, had the greatest rate of change over time. This increase was related to concurrent increase in Aβ-PET burden only in individuals with low levels of Aβ. The rate of p-tau217 change, rather than its baseline level, was the strongest predictor of future Aβ-PET positivity. On the other hand, in individuals with elevated levels of Aβ, higher rate of change in p-tau217 was associated with faster cognitive decline. These findings highlight a "dual" role of plasma p-tau217 rate of change, being either predictive of accumulating Aβ pathology at early stages and of cognitive decline at later stages of the AD continuum.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40982102,

title = {Orofacial pain and dementia: a brief narrative review of associations, putative mechanisms, and relevant clinical considerations},

author = {Alberto Herrero Babiloni and Sylvia Villeneuve and Pierre Rainville and Gilles J Lavigne and Cibele Dal Fabbro},

doi = {10.1007/s10266-025-01216-z},

issn = {1618-1255},

year  = {2025},

date = {2025-09-01},

journal = {Odontology},

abstract = {This review examines the possible association between orofacial pain and dementia by synthesizing current findings from clinical, observational, and mechanistic studies. Although chronic pain has been increasingly recognized as a factor linked to cognitive decline, the specific role of orofacial pain, including conditions such as temporomandibular disorders, trigeminal neuralgia, burning mouth syndrome, and primary headaches, remains underexplored. Given the distinct neuroanatomy of the trigeminal system and its close connection to emotional and cognitive processing, orofacial pain may involve unique mechanisms relevant to neurodegeneration. Studies suggesting possible links between orofacial pain conditions and cognitive impairment were identified, highlighting mechanisms such as neuroinflammation, locus coeruleus dysfunction, and central sensitization. Modifiable cofactors, including poor oral health and sleep disturbances, which may influence both pain and dementia risk and are particularly relevant in dental and orofacial clinical practice, were also examined. Pain assessment and management strategies for individuals with dementia were reviewed as well, with emphasis on the need for validated tools and interdisciplinary care models that incorporate dental and orofacial pain specialists. Given the heterogeneous and limited nature of existing studies, this review does not make causal claims but instead conceptually maps the current landscape, identifies critical gaps in the literature, and outlines implications for research and practice. Dentists and orofacial pain providers may be uniquely positioned to recognize pain-related risk factors in cognitively vulnerable patients and implement preventive or therapeutic strategies. Future longitudinal studies and mechanistic investigations are needed to clarify the direction and clinical significance of the orofacial pain-dementia relationship.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}