@article{pmid41935644,

title = {Human APOB-expressing mice translate molecular phenotypes across the Alzheimer's disease spectrum},

author = {Gabriel Aumont-Rodrigue and Alexandre Poirier and Cynthia Picard and Judes Poirier and },

doi = {10.1016/j.bbi.2026.106575},

issn = {1090-2139},

year  = {2026},

date = {2026-08-01},

journal = {Brain Behav Immun},

volume = {136},

pages = {106575},

abstract = {BACKGROUND: Apolipoprotein B (APOB), a structural component of low-density lipoproteins (LDL), has historically been associated with peripheral lipid transport and cardiovascular disease. Recent studies have revealed a link between APOB and Alzheimer's disease (AD), with increased cerebrospinal fluid (CSF) APOB levels correlating with tau pathology. Although APOB is known to be locally expressed in the brain, albeit at very low levels, its function in the central nervous system and contribution to neurodegenerative processes remains poorly understood. To investigate the effects of chronic APOB overexpression on brain molecular homeostasis, we used a transgenic mouse model expressing human APOB-100 and integrated findings with human cohort data to assess its functional relevance to AD pathology.nnMETHODS: Human APOB transgenic (hAPOB) and wild-type mice were aged to 6 and 12 months. Frontal cortices were analyzed using RNA sequencing and mass spectrometry-based proteomics. Differentially expressed genes and proteins were analyzed via pathway enrichment and cell type deconvolution. Findings were contrasted to post-mortem proteomic alterations observed in brain tissue (ROSMAP) and in the CSF (ADNI).nnRESULTS: hAPOB overexpression in mice induced a robust and persistent upregulation of innate immune genes, particularly those associated with type I interferon responses (Irf7, Ifit1, Oas2), in both young and old transgenic mice. Reduced microglial and endothelial cell signatures were observed through cell type deconvolution, which suggests immune activation without proliferation and possible blood-brain barrier damage. Proteomic analyses showed differentially expressed proteins associated with oxidative stress and dendritic remodeling. Proteins dysregulated in mice-such as CTSD, CRK, and SULT4A1-also showed altered expression in AD human brain and CSF. Remarkably, these proteins are dysregulated in the opposite direction in humans than in mice, unveiling a complex downstream regulation of APOB overexpression.nnCONCLUSION: Chronic hAPOB overexpression drives sustained neuroinflammatory and oxidative responses, potentially mimicking viral-like immune activation in the brain. The proteins dysregulated in hAPOB transgenic mice brains were also dysregulated in humans on opposite side of the APOB level spectrum. Nevertheless, this result shows a consistency across species on hAPOB-driven downstream effects. Some of these proteins were also shown to associate with key features of AD pathology, namely Aβ, Tau and pTau. Our findings support a novel role for APOB in modulating brain immune homeostasis and neurodegenerative processes, offering a mechanistic link between vascular risk and Alzheimer's disease.},

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{pmid42029407,

title = {Locus coeruleus degeneration is associated with cortical tau deposition and cognitive decline in older adults at familial risk of Alzheimer's disease},

author = {Alfie Wearn and Kate M Onuska and Hayley R C Shanks and Rahul Gaurav and Stéphane Lehéricy and Giulia Baracchini and Colleen Hughes and Jennifer Tremblay-Mercier and Sridar Narayanan and John Breitner and Judes Poirier and Taylor W Schmitz and Gary R Turner and R Nathan Spreng and },

doi = {10.1002/alz.71427},

issn = {1552-5279},

year  = {2026},

date = {2026-04-01},

journal = {Alzheimers Dement},

volume = {22},

number = {4},

pages = {e71427},

abstract = {INTRODUCTION: The locus coeruleus (LC) is among the first sites of tau pathology in Alzheimer's disease (AD) and may seed neocortical tau.nnMETHODS: We used longitudinal neuromelanin-sensitive MRI to assess LC integrity in vivo in a cohort of cognitively unimpaired older adults with familial risk of AD in relation to tau and amyloid positron emission tomography (PET) and long-term cognitive trajectories.nnRESULTS: We showed that both LC integrity at baseline and its rate of degeneration over time independently predicted a neocortical pattern of tau deposition. In keeping with the known function of the LC, neuropsychological tests showed that LC integrity at baseline predicted changes in attention. Finally, we found that longitudinal LC degeneration correlated with memory decline in people with elevated neocortical amyloid burden.nnDISCUSSION: Our findings underscore the importance of LC in AD pathogenesis. Longitudinal measurement of LC degeneration may help distinguish trajectories of age-related cognitive decline and early AD.},

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{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{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{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{pmid41040728,

title = {Tracking a decade of structural changes in preclinical and prodromal Alzheimer's disease: insights from amyloid-β pathology},

author = {Ting Qiu and Zhen-Qi Liu and Jonathan Gallego-Rudolf and Manon Edde and Alex Valcourt Caron and Yuanchao Zhang and M Mallar Chakravarty and Jean-Paul Soucy and D Louis Collins and Judes Poirier and John Breitner and Gemma Salvadó and Alexa Pichet Binette and Maxime Descoteaux and Sylvia Villeneuve},

doi = {10.1101/2025.09.25.25336640},

year  = {2025},

date = {2025-09-01},

journal = {medRxiv},

abstract = {Alzheimer's disease (AD) pathology is typically associated with reduced brain volume and cortical thickness, interpreted as neurodegeneration. However, several cross-sectional studies in cognitively unimpaired individuals have paradoxically reported larger brain volume and thicker cortex in the presence of amyloid-β (Aβ), suggesting that Aβ-brain structure associations may not follow a simple linear pattern early in the disease. We leveraged over a decade of longitudinal data from the PREVENT-AD cohort (N=367, mean follow-up 7.17 years, range 0-11.27 years) to investigate how Aβ burden related to both cross-sectional levels and longitudinal changes in brain volume, cortical thickness, and cortical tissue mean diffusivity (MD) derived from free-water corrected diffusion tensor imaging. We examined associations separately in individuals below (Aβ-) and above (Aβ+) the Aβ-positivity threshold, tested for nonlinearity across all participants, and aligned structural trajectories to the estimated years from Aβ-positivity onset. We found that higher Aβ was associated with larger brain volume, higher cortical thickness and lower MD in regions such as the fusiform gyrus, supramarginal gyrus, hippocampal volume, inferior parietal and middle temporal cortex in the Aβ- group. The opposite associations were found in the Aβ+ group. Across all participants, volume and thickness showed an inverse U-shaped relationship with Aβ, while MD followed a U-shaped pattern. Longitudinally, the rate of cortical thickness change showed an inverse U-shaped association with Aβ, whereas Aβ burden was associated with faster volume loss and greater MD increase. When structural measures were aligned to the estimated time of Aβ positivity onset, volume and thickness increased years before the expected Aβ positivity onset and declined thereafter, while MD showed no association with time relative to Aβ positivity onset. Our results help reconcile inconsistencies across prior studies and suggest that brain structural changes related to Aβ pathology start years before Aβ positivity onset and follow nonlinear trajectories. These early structural changes might be due to pathological processes such as neuroinflammatory swelling early in the course of the disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39827219,

title = {Novel synaptic markers predict early tau pathology and cognitive deficit in an asymptomatic population at risk of Alzheimer's disease},

author = {Jiarui Ao and Cynthia Picard and Daniel Auld and Henrik Zetterberg and Ann Brinkmalm and Kaj Blennow and Sylvia Villeneuve and John C S Breitner and Judes Poirier and },

doi = {10.1038/s41380-024-02884-z},

issn = {1476-5578},

year  = {2025},

date = {2025-07-01},

journal = {Mol Psychiatry},

volume = {30},

number = {7},

pages = {2810--2820},

abstract = {Cognitive dysfunction in Alzheimer's disease (AD) correlates closely with pathology in the neuronal microtubule-associated protein tau. Tau pathology may spread via neural synapses. In a population of cognitively unimpaired elderly at elevated risk of AD, we investigated four cerebrospinal (CSF) markers of synaptic dysfunction and degeneration. Three of these (SYT1, SNAP25, and ADAM23) are derived from pre-synaptic structures, while ADAM22 reflects post-synaptic changes. All four markers correlated strongly with tau protein measures. In statistical models, SYT1 accounted for more than half the total variance in both total- and P(181)-tau levels. Observed correlations with CSF levels of Alzheimer amyloid-β (Aβ42) were somewhat weaker. In longitudinal data, baseline levels of ADAM22 and ADAM23 robustly predicted increase over time in both total- and P-tau. CSF SYT1 levels also correlated with PET image uptake of tau and (at a trend level) Aβ in areas of interest for early AD pathology. CSF SYT1 and SNAP25 levels correlated inversely with a global psychometric score and several of its domain subscales. In quantitative trait loci analyses, all four synaptic markers were associated with at least one AD genetic risk locus. Upon "staging" participants by their evidence of amyloid and tau pathology (A/T/N framework), the CSF synaptic markers were unexpectedly reduced in participants with CSF evidence of amyloid but not tau pathology. They were clearly elevated, however, in the CSF of persons with indications of both tau and amyloid pathology. These observations provide evidence for clear pre-synaptic degeneration in cognitively unimpaired persons with biomarker evidence of early AD pathology.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40203224,

title = {Amyloid and Tau Pathology in Cognitively Unimpaired Individuals With a Parental History of Alzheimer Disease: Role of Sex and Parent's Sex},

author = {Valentin Ourry and Alfonso Fajardo-Valdez and Jean-Paul Soucy and Judes Poirier and John C S Breitner and Sylvia Villeneuve and },

doi = {10.1212/WNL.0000000000213507},

issn = {1526-632X},

year  = {2025},

date = {2025-05-01},

journal = {Neurology},

volume = {104},

number = {9},

pages = {e213507},

abstract = {BACKGROUND AND OBJECTIVES: Female sex and a parental history of Alzheimer disease (AD), especially maternal, confer increased risk of AD. Associations between sex, or affected AD parent's sex, and biomarkers of AD are less clear. We examined whether sex or affected AD parent's sex influences (1) β-amyloid (Aβ) and tau burden/accumulation, (2) the association between Aβ and tau burden, and (3) brain and cognitive resilience to Aβ and tau burden.nnMETHODS: The sample included 243 participants from the Presymptomatic Evaluation of Experimental or Novel Treatments for AD cohort in Canada. All participants with [18F]-NAV4694 and [18F]-AV1451 PET and MRI were included. We examined (1) sex or affected AD parent's sex differences on regional Aβ and tau burden/accumulation; (2) 2-way interactions between sex, or affected AD parent's sex, and Aβ on tau burden; and (3) 3-way interactions between time, sex or affected AD parent's sex, and Aβ or tau deposition on hippocampal volume (brain resilience) and cognition (cognitive resilience) over time.nnRESULTS: Participants (69.4% female) were aged 68.3 ± 5.1 years at their first PET scans. All were cognitively unimpaired at baseline. Longitudinal cognitive data were available for 242 participants (follow-up, 6.72 ± 2.38 years), including 238 (6.53 ± 2.48 years of follow-up) with MRI follow-ups and 115 (4.4 ± 0.6 years of follow-up) with PET follow-ups, and 71 developed mild cognitive impairment. Women showed greater tau deposition (standardized β = 0.13 ± 0.3) and showed a stronger association between global Aβ and tau deposition than men (standardized β = 0.79 ± 0.1). Individuals with an affected AD father showed stronger association between global Aβ and tau deposition than those with an affected AD mother (standardized β = 0.65 ± 0.1). Women showed less Aβ-associated hippocampal atrophy over time (standardized β = 0.24 ± 0.1).nnDISCUSSION: Women and, surprisingly, individuals with a paternal history of AD seemed more vulnerable to the Aβ-related spread of tau, whereas women showed greater brain resilience to Aβ. Understanding sex-specific risk and resilience could allow more clinical trial precision and personalization. A major limitation included the reduced sample for the affected AD parent's sex analyses.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39961166,

title = {Exploring morphological and microstructural signatures across the Alzheimer's spectrum and risk factors},

author = {Aurélie Bussy and Raihaan Patel and Olivier Parent and Alyssa Salaciak and Saashi A Bedford and Sarah Farzin and Stephanie Tullo and Cynthia Picard and Sylvia Villeneuve and Judes Poirier and John Cs Breitner and Gabriel A Devenyi and  and Christine L Tardif and M Mallar Chakravarty},

doi = {10.1016/j.neurobiolaging.2025.01.011},

issn = {1558-1497},

year  = {2025},

date = {2025-05-01},

journal = {Neurobiol Aging},

volume = {149},

pages = {1--18},

abstract = {Neural alterations, including myelin degeneration and inflammation-related iron burden, may accompany early Alzheimer's disease (AD) pathophysiology. This study aims to identify multi-modal signatures associated with MRI-derived atrophy and quantitative MRI (qMRI) measures of myelin and iron in a unique dataset of 158 participants across the AD spectrum, including those without cognitive impairment, at familial risk for AD, with mild cognitive impairment, and with AD dementia. Our results revealed a brain pattern with decreased cortical thickness, indicating increased neuronal death, and compromised hippocampal integrity due to reduced myelin content. This pattern was associated with lifestyle factors such as smoking, high blood pressure, high cholesterol, and anxiety, as well as older age, AD progression, and APOE-ɛ4 carrier status. These findings underscore the value of qMRI metrics as a non-invasive tool, offering sensitivity to lifestyle-related modifiable risk factors and medical history, even in preclinical stages of AD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40015754,

title = {Protocol for an intergenerational randomized controlled trial to enhance physical activity in older adults at risk for Alzheimer's disease},

author = {Caitlin S Walker and Adrián E Noriega de la Colina and Linda Li and Carolynn Boulanger and Nagashree Thovinakere and Alix Noly-Gandon and Garance Barnoin and Mitchell Bennett and Jillian Caplan and Laurence Côté and Sarah Elbaz and Shania Fock Ka Bao and Ryan Kara and Nicolas Lavoie and Maggie Nguyen and Franciska Otaner and Helen Pallett-Wiesel and Johanie Victoria Piché and Andreanne Powers and Sofia Ricciardelli and Kayla Williams and Christine Déry and Jennifer Tremblay-Mercier and Judes Poirier and Sylvia Villeneuve and Arthur F Kramer and Maiya R Geddes and },

doi = {10.1016/j.tjpad.2024.100039},

issn = {2426-0266},

year  = {2025},

date = {2025-03-01},

journal = {J Prev Alzheimers Dis},

volume = {12},

number = {3},

pages = {100039},

abstract = {BACKGROUND: Physical inactivity is one of the most important modifiable risk factors for Alzheimer's disease in North America. Despite this, most older adults are physically inactive. It is currently unknown how to successfully motivate physical activity behavior in older adults at risk for Alzheimer's disease, and this knowledge is crucial for early and effective disease prevention. Prior research has shown that intergenerational social engagement and prosocial behaviours can enhance the health and well-being of older adults.nnOBJECTIVES: This manuscript describes the design of a randomized controlled trial that will test the efficacy of a behavioral intervention to enhance physical activity in older adults at risk for Alzheimer's disease.nnDESIGN/SETTING: This is a single-blinded, two-arm stratified randomized controlled trial that incorporates a hybrid efficacy and implementation design. Participants are randomized to an intervention or control condition in a 1:1 ratio and are stratified by a multimodal Alzheimer's disease risk score. All study visits are conducted remotely through videoconferencing.nnPARTICIPANTS: The study aims to recruit 60 older adults with a first-degree family history of Alzheimer's disease from the PREVENT-AD cohort and 30 younger adults who are paired with older adults in the intervention condition.nnINTERVENTION: Older participants in the intervention group will be paired with younger study partners and receive positive, daily messages over four weeks using a novel technology platform. The daily messages combine intergenerational social engagement (growing a virtual garden with a younger study partner) and prosocial goals (donations to charity after reaching step count goals).nnMEASUREMENTS: The primary outcome is change in step count compared to baseline measured using a wrist-worn triaxial accelerometer. Secondary outcomes include time spent physically active, mood, generativity, loneliness, and cognition. Target mechanisms (social support and generativity) of physical activity engagement will be examined. Ease of use, acceptability, and feasibility of the technology as well as barriers and facilitators of participation will be assessed.nnCONCLUSIONS: This research will advance our understanding of mechanisms and individual differences underlying successful physical activity engagement in older adults who are at risk for Alzheimer's disease. This knowledge will contribute to strategies for promoting health behaviours that can prevent the risk of Alzheimer's disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40008832,

title = {Plasma p-tau217 identifies cognitively normal older adults who will develop cognitive impairment in a 10-year window},

author = {Yara Yakoub and Fernando Gonzalez-Ortiz and Nicholas J Ashton and Christine Déry and Cherie Strikwerda-Brown and Frédéric St-Onge and Valentin Ourry and Michael Schöll and Maiya R Geddes and Simon Ducharme and Maxime Montembeault and Pedro Rosa-Neto and Jean-Paul Soucy and John C S Breitner and Henrik Zetterberg and Kaj Blennow and Judes Poirier and Sylvia Villeneuve and },

doi = {10.1002/alz.14537},

issn = {1552-5279},

year  = {2025},

date = {2025-02-01},

journal = {Alzheimers Dement},

volume = {21},

number = {2},

pages = {e14537},

abstract = {INTRODUCTION: We assessed the prognostic accuracy of plasma p-tau217 in predicting the progression to mild cognitive impairment (MCI) in cognitively unimpaired (CU) individuals over a mean follow-up of 5.65 years after plasma collection (range 1.01-10.47).nnMETHODS: We included 215 participants from the PREVENT-AD cohort with plasma Aβ and p-tau217, 159 with cerebrospinal fluid (CSF) Aβ and p-tau217, and 155 with F-NAV4694 and F-flortaucipir PET scans. MCI progression was determined by multidisciplinary consensus among memory experts blind to biomarker and genetic information.nnRESULTS: Cox proportional hazard models indicated a greater progression rate in A+T+ and A-T+ compared to A-T- individuals (HR = 7.81 [95% CI = 3.92 to 15.59] and HR = 4.25 [1.60-11.31] respectively). Similar results were found with CSF (HR = 3.63 [1.72-7.70]) and PET (HR = 9.30 [3.67-23.55]).nnDISCUSSION: Plasma p-tau217 is a prognostic marker for identifying individuals who will develop cognitive impairment within ten years.nnHIGHLIGHTS: Elevated plasma p-tau217 levels in CU individuals indicate future clinical progression. Adding plasma Aβ status to p-tau markers did not improve the prediction to MCI. All individuals with abnormal tau PET measured in a temporal meta-ROI progressed to MCI.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39788739,

title = {Precuneus Activity during Retrieval Is Positively Associated with Amyloid Burden in Cognitively Normal Older 4 Carriers},

author = {Larissa Fischer and Eóin N Molloy and Alexa Pichet Binette and Niklas Vockert and Jonas Marquardt and Andrea Pacha Pilar and Michael C Kreissl and Jordana Remz and Jennifer Tremblay-Mercier and Judes Poirier and Maria Natasha Rajah and Sylvia Villeneuve and  and Anne Maass},

doi = {10.1523/JNEUROSCI.1408-24.2024},

issn = {1529-2401},

year  = {2025},

date = {2025-02-01},

journal = {J Neurosci},

volume = {45},

number = {6},

abstract = {The precuneus is a site of early amyloid-beta (Aβ) accumulation. Previous cross-sectional studies reported increased precuneus fMRI activity in older adults with mild cognitive deficits or elevated Aβ. However, longitudinal studies in early Alzheimer's disease (AD) are lacking and the relationship to the Apolipoprotein-E () genotype is unclear. Investigating the PREVENT-AD dataset, we assessed how baseline and longitudinal precuneus activity during successful memory retrieval relates to future Aβ and tau burden and change in memory performance. We further studied the moderation by 4 genotype. We included 165 older adults (age, 62.8 ± 4.4 years; 113 female; 66 4 carriers) who were cognitively normal at baseline with a family history of AD. All participants performed task-fMRI at baseline and underwent F-flortaucipir-PET and F-NAV4694-Aβ-PET on average 5 years later. We found that higher baseline activity and greater longitudinal increase in precuneus activity were associated with higher Aβ burden in 4 carriers but not noncarriers. We observed no effects of precuneus activity on tau burden. Finally, 4 noncarriers with low baseline precuneus activity exhibited better longitudinal performance in an independent memory test compared with (1) noncarriers with higher baseline activity and (2) 4 carriers. Our findings suggest that higher task-related precuneus activity during memory retrieval at baseline and over time are associated with greater Aβ burden in cognitively normal 4 carriers. Our results further indicate that the absence of "hyperactivation" and the absence of the 4 allele is related with better future cognitive outcomes in cognitively normal older adults at risk for AD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39395793,

title = {Apolipoprotein B gene expression and regulation in relation to Alzheimer's disease pathophysiology},

author = {Gabriel Aumont-Rodrigue and Cynthia Picard and Anne Labonté and Judes Poirier},

doi = {10.1016/j.jlr.2024.100667},

issn = {1539-7262},

year  = {2024},

date = {2024-11-01},

journal = {J Lipid Res},

volume = {65},

number = {11},

pages = {100667},

abstract = {Apolipoprotein B (APOB), a receptor-binding protein present in cholesterol-rich lipoproteins, has been implicated in Alzheimer's disease (AD). High levels of APOB-containing low-density lipoproteins (LDL) are linked to the pathogenesis of both early-onset familial and late-onset sporadic AD. Rare coding mutations in the APOB gene are associated with familial AD, suggesting a role for APOB-bound lipoproteins in the central nervous system. This research explores APOB gene regulation across the AD spectrum using four cohorts: BRAINEAC (elderly control brains), DBCBB (controls, AD brains), ROSMAP (controls, MCI, AD brains), and ADNI (control, MCI, AD clinical subjects). APOB protein levels, measured via mass spectrometry and ELISA, positively correlated with AD pathology indices and cognition, while APOB mRNA levels showed negative correlations. Brain APOB protein levels are also correlated with cortical Aβ levels. A common coding variant in the APOB gene locus affected its expression but didn't impact AD risk or brain cholesterol concentrations, except for 24-S-hydroxycholesterol. Polymorphisms in the CYP27A1 gene, notably rs4674344, were associated with APOB protein levels. A negative correlation was observed between brain APOB gene expression and AD biomarker levels. CSF APOB correlated with Tau pathology in presymptomatic subjects, while cortical APOB was strongly associated with cortical Aβ deposition in late-stage AD. The study discusses the potential link between blood-brain barrier dysfunction and AD symptoms in relation to APOB neurobiology. Overall, APOB's involvement in lipoprotein metabolism appears to influence AD pathology across different stages of the disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39072932,

title = {Osteopontin: A novel marker of pre-symptomatic sporadic Alzheimer's disease},

author = {Marc James Quesnel and Anne Labonté and Cynthia Picard and Daniel C Bowie and Henrik Zetterberg and Kaj Blennow and Ann Brinkmalm and Sylvia Villeneuve and Judes Poirier and  and },

doi = {10.1002/alz.14065},

issn = {1552-5279},

year  = {2024},

date = {2024-09-01},

journal = {Alzheimers Dement},

volume = {20},

number = {9},

pages = {6008--6031},

abstract = {INTRODUCTION: We investigate the role of osteopontin (OPN) in participants with Pre-symptomatic Alzheimer's disease (AD), mild cognitive impairment (MCI), and in AD brains.nnMETHODS: Cerebrospinal fluid (CSF) OPN, AD, and synaptic biomarker levels were measured in 109 cognitively unimpaired (CU), parental-history positive Pre-symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD) participants, and in 167 CU and 399 participants with MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. OPN levels were examined as a function of amyloid beta (Aβ) and tau positivity. Survival analyses investigated the link between OPN and rate of conversion to AD.nnRESULTS: In PREVENT-AD, CSF OPN was positively correlated with synaptic biomarkers. In PREVENT-AD and ADNI, OPN was elevated in CSF Aβ(+)/total tau(+) and CSF Aβ(+)/phosphorylated tau181(+) individuals. In ADNI, OPN was increased in Aβ(+) positron emission tomography (PET) and tau(+) PET individuals, and associated with an accelerated rate of conversion to AD. OPN was elevated in autopsy-confirmed AD brains.nnDISCUSSION: Strong associations between CSF OPN and key markers of AD pathophysiology suggest a significant role for OPN in tau neurobiology, particularly in the early stages of the disease.nnHIGHLIGHTS: In the Pre-symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer's Disease cohort, we discovered that cerebrospinal fluid (CSF) osteopontin (OPN) levels can indicate early synaptic dysfunction, tau deposition, and neuronal loss in cognitively unimpaired elderly with a parental history. CSF OPN is elevated in amyloid beta(+) positron emission tomography (PET) and tau(+) PET individuals. Elevated CSF OPN is associated with an accelerated rate of conversion to Alzheimer's disease (AD). Elevated CSF OPN is associated with an accelerated rate of cognitive decline on the Alzheimer's Disease Assessment Scale-Cognitive subscale 13, Montreal Cognitive Assessment, Mini-Mental State Examination, and Clinical Dementia Rating Scale Sum of Boxes. OPN mRNA and protein levels are significantly upregulated in the frontal cortex of autopsy-confirmed AD brains.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38634644,

title = {Reduced rapid eye movement sleep in late middle-aged and older apolipoprotein E ɛ4 allele carriers},

author = {Claire André and Marie-Ève Martineau-Dussault and Andrée-Ann Baril and Nicola Andrea Marchi and Véronique Daneault and Dominique Lorrain and Carol Hudon and Célyne H Bastien and Dominique Petit and Cynthia Thompson and Judes Poirier and Jacques Montplaisir and Nadia Gosselin and Julie Carrier},

doi = {10.1093/sleep/zsae094},

issn = {1550-9109},

year  = {2024},

date = {2024-07-01},

journal = {Sleep},

volume = {47},

number = {7},

abstract = {STUDY OBJECTIVES: Apolipoprotein E ɛ4 (APOE4) is the strongest genetic risk factor for Alzheimer's disease (AD). In addition, APOE4 carriers may exhibit sleep disturbances, but conflicting results have been reported, such that there is no clear consensus regarding which aspects of sleep are impacted. Our objective was to compare objective sleep architecture between APOE4 carriers and non-carriers, and to investigate the modulating impact of age, sex, cognitive status, and obstructive sleep apnea (OSA).nnMETHODS: A total of 198 dementia-free participants aged >55 years old (mean age: 68.7 ± 8.08 years old, 40.91% women, 41 APOE4 carriers) were recruited in this cross-sectional study. They underwent polysomnography, APOE4 genotyping, and a neuropsychological evaluation. ANCOVAs assessed the effect of APOE4 status on sleep architecture, controlling for age, sex, cognitive status, and the apnea-hypopnea index. Interaction terms were added between APOE4 status and covariates.nnRESULTS: Rapid eye movement (REM) sleep percentage (F = 9.95, p = .002, ηp2 = 0.049) and duration (F = 9.23, p = .003, ηp2 = 0.047) were lower in APOE4 carriers. The results were replicated in a subsample of 112 participants without moderate-to-severe OSA. There were no significant interactions between APOE4 status and age, sex, cognitive status, and OSA in the whole sample.nnCONCLUSIONS: Our results show that APOE4 carriers exhibit lower REM sleep duration, including in cognitively unimpaired individuals, possibly resulting from early neurodegenerative processes in regions involved in REM sleep generation and maintenance.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38830849,

title = {Neuromodulatory subcortical nucleus integrity is associated with white matter microstructure, tauopathy and APOE status},

author = {Alfie Wearn and Stéfanie A Tremblay and Christine L Tardif and Ilana R Leppert and Claudine J Gauthier and Giulia Baracchini and Colleen Hughes and Patrick Hewan and Jennifer Tremblay-Mercier and Pedro Rosa-Neto and Judes Poirier and Sylvia Villeneuve and Taylor W Schmitz and Gary R Turner and R Nathan Spreng and },

doi = {10.1038/s41467-024-48490-z},

issn = {2041-1723},

year  = {2024},

date = {2024-06-01},

journal = {Nat Commun},

volume = {15},

number = {1},

pages = {4706},

abstract = {The neuromodulatory subcortical nuclei within the isodendritic core (IdC) are the earliest sites of tauopathy in Alzheimer's disease (AD). They project broadly throughout the brain's white matter. We investigated the relationship between IdC microstructure and whole-brain white matter microstructure to better understand early neuropathological changes in AD. Using multiparametric quantitative magnetic resonance imaging we observed two covariance patterns between IdC and white matter microstructure in 133 cognitively unimpaired older adults (age 67.9 ± 5.3 years) with familial risk for AD. IdC integrity related to 1) whole-brain neurite density, and 2) neurite orientation dispersion in white matter tracts known to be affected early in AD. Pattern 2 was associated with CSF concentration of phosphorylated-tau, indicating AD specificity. Apolipoprotein-E4 carriers expressed both patterns more strongly than non-carriers. IdC microstructure variation is reflected in white matter, particularly in AD-affected tracts, highlighting an early mechanism of pathological development.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}