Judes Poirier - Academia.edu (original) (raw)

Papers by Judes Poirier

Research paper thumbnail of Association of a Total Cholesterol Polygenic Score with Cholesterol Levels and Pathological Biomarkers across the Alzheimer’s Disease Spectrum

Genes

Midlife hypercholesterolemia is a well-known risk factor for sporadic Alzheimer’s disease (AD), a... more Midlife hypercholesterolemia is a well-known risk factor for sporadic Alzheimer’s disease (AD), and like AD, it is highly influenced by genetics with heritability estimates of 32–63%. We thus hypothesized that genetics underlying peripheral blood total cholesterol (TC) levels could influence the risk of developing AD. We created a weighted polygenic score (TC-PGS) using summary data from a meta-analysis of TC genome-wide association studies for evaluation in three independent AD-related cohorts spanning pre-clinical, clinical, and pathophysiologically proved AD. APOE-ε4 variant was purposely included in the analysis as it represents an already well-established genetic risk factor for both AD and circulating TC. We could vastly improve the performance of the score when considering p-value thresholds for inclusion in the score, sex, and statin use. This optimized score (p-value threshold of 1 × 10−6 for inclusion in the score) explained 18.2% of the variance in TC levels in statin fre...

Research paper thumbnail of Apolipoprotein B is a novel marker for early tau pathology in Alzheimer's disease

Alzheimer's & Dementia

INTRODUCTION We examine the role of brain apolipoprotein B (apoB) as a putative marker of early t... more INTRODUCTION We examine the role of brain apolipoprotein B (apoB) as a putative marker of early tau pathology and cognitive decline. METHODS Cerebrospinal fluid (CSF) samples from cognitively normal and Alzheimer's disease (AD) participants were collected to measure protein levels of apoB and AD biomarkers amyloid beta (Aβ), t-tau and p-tau, as well as synaptic markers GAP43, SYNAPTOTAGMIN-1, synaptosome associated protein 25 (SNAP-25), and NEUROGRANIN. CSF apoB levels were contrasted with positron emission tomography (PET) scan measures of Aβ (18F-NAV4694) and Tau (flortaucipir) along with cognitive assessment alterations over 6 to 8 years. RESULTS CSF apoB levels were elevated in AD participants and correlated with t-tau, p-tau, and the four synaptic markers in pre-symptomatic individuals. In the latter, CSF apoB levels correlated with PET flortaucipir-binding in entorhinal, parahippocampal, and fusiform regions. Baseline CSF apoB levels were associated with longitudinal visuospatial cognitive decline. DISCUSSION CSF apoB markedly associates with early tau dysregulation in asymptomatic subjects and identifies at-risk individuals predisposed to develop visuospatial cognitive decline over time.

Research paper thumbnail of Herpes Simplex Virus Type 1 in the Brain, Apolipoprotein E Genotype and Alzheimer’s Disease

McGill Journal of Medicine

The ε4 allele of apolipoprotein E (apoE) is an important risk factor for Alzheimer's disease ... more The ε4 allele of apolipoprotein E (apoE) is an important risk factor for Alzheimer's disease (AD), however, it is not required nor sufficient to cause the disease on its own. Herpes viruses cause acute and chronic diseases of the central nervous system and have been implicated in AD. Using a sensitive polymerase chain reaction method, latent herpes simplex virus type 1 (HSV-1) has been detected from five different brain regions (hippocampus, frontal cortex, occipital cortex, cerebellum and striatum) of neuropathologically confirmed AD and control tissue. HSV-1 positivity was then correlated with AD, presence of the virus in specific brain regions, and apoE genotype. The results confirm that the ε4 allele of apoE is a risk factor for AD, while HSV-1 alone is not. This held true for all five brain regions examined. Furthermore, no synergy between the two factors could be found when any one of the brain regions was examined individually or when the data were pooled. These findings ...

Research paper thumbnail of Open Science Datasets from PREVENT-AD, a Longitudinal Cohort of Pre-symptomatic Alzheimer’s Disease

ABSTRACTTo move Alzheimer Disease (AD) research forward it is essential to collect data from larg... more ABSTRACTTo move Alzheimer Disease (AD) research forward it is essential to collect data from large cohorts, but also make such data available to the global research community. We describe the creation of an open science dataset from the PREVENT-AD (PResymptomatic EValuation of Experimental or Novel Treatments for AD) cohort, composed of cognitively unimpaired older individuals with a parental or multiple-sibling history of AD. From 2011 to 2017, 386 participants were enrolled (mean age 63 years old ± 5) for sustained investigation among whom 349 have retrospectively agreed to share their data openly. Repositories are findable through the unified interface of the Canadian Open Neuroscience Platform (https://portal.conp.ca/) and contain up to five years of longitudinal imaging data, cerebral fluid biochemistry, neurosensory capacities, cognitive, genetic, and medical information. Imaging data can be accessed openly at https://openpreventad.loris.ca while most of the other information,...

Research paper thumbnail of Amyloid and tau pathology associations with personality traits, neuropsychiatric symptoms and cognitive lifestyle in the preclinical phases of sporadic and autosomal dominant Alzheimer’s disease

Biological Psychiatry

BACKGROUND: Major prevention trials for Alzheimer's disease (AD) are now focusing on multidomain ... more BACKGROUND: Major prevention trials for Alzheimer's disease (AD) are now focusing on multidomain lifestyle interventions. However, the exact combination of behavioral factors related to AD pathology remains unclear. In 2 cohorts of cognitively unimpaired individuals at risk of AD, we examined which combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle (years of education or lifetime cognitive activity) related to the pathological hallmarks of AD, amyloid-b, and tau deposits. METHODS: A total of 115 older adults with a parental or multiple-sibling family history of sporadic AD (PREVENT-AD [PRe-symptomatic EValuation of Experimental or Novel Treatments for AD] cohort) underwent amyloid and tau positron emission tomography and answered several questionnaires related to behavioral attributes. Separately, we studied 117 mutation carriers from the DIAN (Dominant Inherited Alzheimer Network) study group cohort with amyloid positron emission tomography and behavioral data. Using partial least squares analysis, we identified latent variables relating amyloid or tau pathology with combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle. RESULTS: In PREVENT-AD, lower neuroticism, neuropsychiatric burden, and higher education were associated with less amyloid deposition (p = .014). Lower neuroticism and neuropsychiatric features, along with higher measures of openness and extraversion, were related to less tau deposition (p = .006). In DIAN, lower neuropsychiatric burden and higher education were also associated with less amyloid (p = .005). The combination of these factors accounted for up to 14% of AD pathology. CONCLUSIONS: In the preclinical phase of both sporadic and autosomal dominant AD, multiple behavioral features were associated with AD pathology. These results may suggest potential pathways by which multidomain interventions might help delay AD onset or progression.

Research paper thumbnail of Genetic and Environmental Factors Are Differentially Related to Aβ Burden in the Presymptomatic Phase of Autosomal Dominant and Sporadic Alzheimer’s Disease

Alzheimer's & Dementia

Genetic and environmental factors are differentially related to Aβ burden in the presymptomatic p... more Genetic and environmental factors are differentially related to Aβ burden in the presymptomatic phase of autosomal dominant and sporadic Alzheimer's disease Participants and Methods Summary and conclusions Our results suggest that, as it is the case in ADAD, a parental EYO index might help to predict Aβ accumulation in asymptomatic individuals at risk of sAD. 6,7 This might have important implications for the characterization of the preclinical phase of sAD and the recruitment of prevention/clinical trials. While APOE4 is highly associated with Aβ burden in people at risk of sAD, it has no impact in ADAD. By contrast, environmental factors, approximated here using years of education, could affect biomarker progression in both variants of the disease. Furthermore, education seems able to counteract the deleterious effect of APOE4 on Aβ burden in asymptomatic individuals with a PH of sAD. 8 These results suggest the existence of reserve mechanisms, not only in individuals at risk of sAD , but also in individuals carrying aggressive ADAD variants.

Research paper thumbnail of Nsaids for Ad Prevention? Naproxen Enters the CNS Without Apparent Effect on CSF Immune Markers

Alzheimer's & Dementia

Background: The locus coeruleus (LC) is the initial site of Alzheimer’s disease (AD) neuropatholo... more Background: The locus coeruleus (LC) is the initial site of Alzheimer’s disease (AD) neuropathology with hyperphosphorylated Tau appearing in early adulthood, with severe neurodegeneration in AD. Loss of norepinephrine (NE) from LC contributes to AD pathobiology in experimental models, which can be rescued by increasing NE transmission. To test whether increased NE signaling in humans could be useful to treat AD pathogenesis, we repurposed atomoxetine (ATX), an FDA-approved NE transporter inhibitor, in a phase II trial for MCI. We hypothesized that ATX is safe and well tolerated, achieves target engagement, and reduces CNS inflammation.Methods: In a single-center double-blind crossover trial, we randomized MCI patients with prodromal AD to ATX/placebo and placebo/ATX arms. Assessments were collected at baseline, 6(crossover) and 12-months (completer). Target engagement was assessed by HPLC measures of NE and metabolites. Prespecified primary outcomes were CSF levels of IL1a and Thymus-Expressed Chemokine (TECK). Secondary/exploratory outcomes included CSF AD biomarkers, a panel of 92 inflammation-related analytes (O-link), and others. Results: 39 participants were enrolled, with dropout rates 5.1% (2/39) for ATX and 2.7% (1/37) for placebo phases. Baseline demographic and clinical measures were similar across arms. There were no significant differences in adverse events. ATX increased plasma and CSF NE and reduced DHPG (p<0.0001), demonstrating target engagement. ATX reduced CSF Tau by 6% (CI: 1.5-10.3%, p1⁄40.02), with no effect on Ab42. CSF IL-1a and TECK were not measurable in most samples; however, ATX treatment showed a trend for decreased CSF IL1a detectability (odds ratio 2.7; CI: 0.8-8.9, p1⁄40.10), suggesting reduced inflammation, with no effect on TECK (p>0.4). Among exploratory inflammation-related biomarkers (without adjusting for multiple testing), ATX treatment reduced CSF CDCP1, CD244 and TWEAK, and increased OPG (p<0.05). ATX treatment was also associated with increased BDNF and reduced triglycerides in plasma. Conclusions: ATX treatment was safe, well tolerated, and robustly achieved target engagement. While ATX had no significant effect on preselected inflammation biomarkers, ATX significantly reduced CSF Tau and several pro-inflammatory markers (CDCP1, CD244 and TWEAK). Further study of ATX is warranted for repurposing the drug to slow AD progression.

Research paper thumbnail of CDK5RAP2 Gene and Tau Pathophysiology in Late-Onset Sporadic Alzheimer’s Disease

Alzheimer's & Dementia

that results in increased amyloid beta levels. Results:We will report our results and discuss how... more that results in increased amyloid beta levels. Results:We will report our results and discuss how they relate to the relationship between these mutations and both chemokine and amyloid beta levels in mammalian cell lines. Conclusions: This work will allow us to examine the role that amyloid beta plays in the activation of pro-inflammatory responses by the chemokine receptors CCBP2 and CCLR2 and their respective mutants. This work could lead to a means of regulating amyloid beta production and expression which could lead to novel therapeutic solutions.

Research paper thumbnail of Isoprenoids and tau pathology in sporadic Alzheimer's disease

Research paper thumbnail of Multiple cholinergic markers are unexpectedly not altered in the rat dentate gyrus following entorhinal cortex lesions

The Journal of Neuroscience

We thank Dr. Paul Clarke for his helpful comments and critical reading of the manuscript. Annie B... more We thank Dr. Paul Clarke for his helpful comments and critical reading of the manuscript. Annie Baccichet and Doris Dea are acknowledged for their technical support in performing lesions of the entorhinal cortex. This work was supported by grants from the Medical Research Council of Canada (R.Q., J.P.). R.Q. and J.P. are, respectively, holders of "Chercheur-Boursier" of the "Fends de ia Recherche en Sante du Qu6bec" (FRSQ) and an MRCC scholarship. LA. is the holder of a studentshio from the Alzheimer Societv of Canada.

Research paper thumbnail of Brain properties predict proximity to symptom onset in sporadic Alzheimer's disease

Brain : a journal of neurology, Jan 23, 2018

Alzheimer's disease is preceded by a lengthy 'preclinical' stage spanning many years,... more Alzheimer's disease is preceded by a lengthy 'preclinical' stage spanning many years, during which subtle brain changes occur in the absence of overt cognitive symptoms. Predicting when the onset of disease symptoms will occur is an unsolved challenge in individuals with sporadic Alzheimer's disease. In individuals with autosomal dominant genetic Alzheimer's disease, the age of symptom onset is similar across generations, allowing the prediction of individual onset times with some accuracy. We extend this concept to persons with a parental history of sporadic Alzheimer's disease to test whether an individual's symptom onset age can be informed by the onset age of their affected parent, and whether this estimated onset age can be predicted using only MRI. Structural and functional MRIs were acquired from 255 ageing cognitively healthy subjects with a parental history of sporadic Alzheimer's disease from the PREVENT-AD cohort. Years to estimated symptom...

Research paper thumbnail of Proximity to Parental Symptom Onset and Amyloid-β Burden in Sporadic Alzheimer Disease

JAMA neurology, Jan 26, 2018

Alzheimer disease (AD) develops during several decades. Presymptomatic individuals might be the b... more Alzheimer disease (AD) develops during several decades. Presymptomatic individuals might be the best candidates for clinical trials, but their identification is challenging because they have no symptoms. To assess whether a sporadic parental estimated years to symptom onset calculation could be used to identify information about amyloid-β (Aβ) levels in asymptomatic individuals with a parental history of AD dementia. This cohort study analyzed Aβ1-42 in cerebrospinal fluid (CSF) specimens from 101 cognitively normal individuals who had a lumbar puncture as part of the Presymptomatic Evaluation of Novel or Experimental Treatments for Alzheimer Disease (PREVENT-AD) cohort from September 1, 2011, through November 30, 2016 (374 participants were enrolled in the cohort during this period). The study estimated each participant's proximity to his/her parent's symptom onset by subtracting the index relative's onset age from his/her current age. The association between proximity ...

Research paper thumbnail of {"__content__"=>" \nvariant mitigates Alzheimer disease pathophysiology in vivo and postmortem.", "i"=>{"__content__"=>"CYP2C19"}}

Neurology. Genetics, 2018

To verify whetherpolymorphisms are associated with amyloid-β (Aβ) pathology across the spectrum o... more To verify whetherpolymorphisms are associated with amyloid-β (Aβ) pathology across the spectrum of clinical Alzheimer disease using in vivo and postmortem data from 2 independent cohorts. A candidate-gene approach tested the association between 5 genes (28 single nucleotide polymorphisms) and Aβ load measured in vivo by the global [F]florbetapir PET standardized uptake value ratio (SUVR) in 338 Alzheimer's Disease Neuroimaging Initiative participants. Significant results were then tested using plasma Aβ and CSF Aβ and Aβ/phosphorylated tau (Aβ/p-tau) ratio in the same cohort. The significant association was also generalized to postmortem Aβ load measurement in the Rush Religious Orders Study/Memory and Aging Project cohorts. In addition, global cognition was used as a phenotype in the analysis in both cohorts. Analysis of Aβ PET identified a variant in thegene (rs4388808;= 0.0006), in which carriers of the minor allele (MA) had a lower global SUVR. A voxel-wise analysis revealed...

Research paper thumbnail of Regionally specific changes in the hippocampal circuitry accompany progression of cerebrospinal fluid biomarkers in preclinical Alzheimer's disease

Human brain mapping, 2018

Neuropathological and in vivo brain imaging studies agree that the cornu ammonis 1 and subiculum ... more Neuropathological and in vivo brain imaging studies agree that the cornu ammonis 1 and subiculum subfields of the hippocampus are most vulnerable to atrophy in the prodromal phases of Alzheimer's disease (AD). However, there has been limited investigation of the structural integrity of the components of the hippocampal circuit, including subfields and extra-hippocampal white matter structure, in relation to the progression of well-accepted cerebrospinal fluid (CSF) biomarkers of AD, amyloid-β 1-42 (Aβ) and total-tau (tau). We investigated these relationships in 88 aging asymptomatic individuals with a parental or multiple-sibling familial history of AD. Apolipoprotein (APOE) ɛ4 risk allele carriers were identified, and all participants underwent cognitive testing, structural magnetic resonance imaging, and lumbar puncture for CSF assays of tau, phosphorylated-tau (p-tau) and Aβ. Individuals with a reduction in CSF Aβ levels (an indicator of amyloid accretion into neuritic plaque...

Research paper thumbnail of Apolipoprotein E knockout mice display procedural deficits in the Morris water maze: analysis of learning strategies in three versions of the task

Neuroscience

öApolipoprotein E knockout (apoEKO) mice have been shown to be impaired in the spatial Morris wat... more öApolipoprotein E knockout (apoEKO) mice have been shown to be impaired in the spatial Morris water maze (MWM). However, several groups failed to replicate this ¢nding. One reason for this inconsistency may stem from variations in the experimental protocols and environment between laboratories. In the present study, we have tested if age and variations in protocol implementation that speci¢cally a¡ect salience of the visual extramaze cues in£uence performance and navigational strategies in the MWM. We tested three-and 12-month-old apoEKO and wild type mice in three versions of the MWM di¡ering on the availability of visual extramaze cues: (1) salient cues, (2) di¡use cues, and (3) absence of cues. Our results show that the presence of salient cues enhances acquisition performance of wild type, but not apoEKO mice in the MWM. This e¡ect was restricted to the acquisition phase since apoEKO mice reached a level of performance that was comparable to that of controls toward the end of the task. No signi¢cant di¡erences were detected between apoEKO and controls in either the di¡use cues or absence of cues paradigms. Thigmotaxic tendencies were observed in apoEKO mice and correlated high latency scores. Thigmotaxis may have interfered with the initial ability to engage in a pro¢cient navigational strategy. These ¢ndings suggest that, in contrast to what has been proposed in the past, apoEKO mice appear not to be impaired in spatial memory per se but are de¢cient in a procedural component of the MWM. Furthermore, the procedural de¢cit and corresponding thigmotaxic tendencies of apoEKO mice appeared to increase with age. Taken together, these ¢ndings con¢rm our hypothesis that age and variations in experimental protocols can in£uence MWM performances.

Research paper thumbnail of Odor identification as a biomarker of preclinical AD in older adults at risk

Neurology

Objective:To assess odor identification (OI) as an indicator of presymptomatic Alzheimer disease ... more Objective:To assess odor identification (OI) as an indicator of presymptomatic Alzheimer disease (AD) pathogenesis in cognitively normal aging individuals at increased risk of AD dementia.Methods:In 274 members of the PREVENT-AD cohort of healthy aging persons with a parental or multiple-sibling history of AD dementia, we assessed the cross-sectional association of OI with potential indicators of presymptomatic AD. Some 101 participants donated CSF, thus enabling assessment of AD pathology with the biomarkers total tau (t-tau), phospho-tau (P181-tau), and their ratios with β-amyloid (Aβ1-42). Adjusted analyses considered age, cognition, APOE ε4 status, education, and sex as covariates. We measured OI using the University of Pennsylvania Smell Identification Test and cognitive performance using the Repeatable Battery for Assessment of Neuropsychological Status. Standard kits provided assays of the AD biomarkers. Analyses used robust-fit linear regression models.Results:Reduced OI was...

Research paper thumbnail of Familiarity deficits in cognitively normal aging individuals with APOE ε4: A follow-up investigation of medial temporal lobe structural correlates

Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring

Research paper thumbnail of Selective familiarity deficits in otherwise cognitively intact aging individuals with genetic risk for Alzheimer's disease

Alzheimer's & dementia (Amsterdam, Netherlands), 2016

Familiarity has been associated with integrity of the rhinal cortex. Thus, impairment in familiar... more Familiarity has been associated with integrity of the rhinal cortex. Thus, impairment in familiarity is expected in very early stages of Alzheimer's disease (AD). The apolipoprotein E (APOE) ε4 allele is a major risk factor for AD. Here, we investigated the effect of the APOE ε4 status on familiarity in cognitively normal aging individuals. Eighty-one individuals aged between 55 and 80 years, 21 carriers and 60 noncarriers, were used in these analyses. A cognitive evaluation was performed on all participants to document the absence of objective cognitive deficits. The effect of APOE ε4 status on familiarity was tested using independent sample t test and an analysis of covariance controlling for age, gender, and education. The groups did not differ in term of age, education, and male/female ratio. APOE ε4 carriers showed a significant reduction in familiarity. No other cognitive deficit was observed in the group of ε4 carriers, relative to noncarriers. APOE ε4 is associated with ...

Research paper thumbnail of BDNF Val66Met Polymorphism Interacts with Sleep Consolidation to Predict Ability to Create New Declarative Memories

The Journal of neuroscience : the official journal of the Society for Neuroscience, Aug 10, 2016

It is hypothesized that a fundamental function of sleep is to restore an individual's day-to-... more It is hypothesized that a fundamental function of sleep is to restore an individual's day-to-day ability to learn and to constantly adapt to a changing environment through brain plasticity. Brain-derived neurotrophic factor (BDNF) is among the key regulators that shape brain plasticity. However, advancing age and carrying the BDNF Met allele were both identified as factors that potentially reduce BDNF secretion, brain plasticity, and memory. Here, we investigated the moderating role of BDNF polymorphism on sleep and next-morning learning ability in 107 nondemented individuals who were between 55 and 84 years of age. All subjects were tested with 1 night of in-laboratory polysomnography followed by a cognitive evaluation the next morning. We found that in subjects carrying the BDNF Val66Val polymorphism, consolidated sleep was associated with significantly better performance on hippocampus-dependent episodic memory tasks the next morning (β-values from 0.290 to 0.434, p ≤ 0.01). ...

Research paper thumbnail of Brain Lipoprotein Metabolism and Its Relation to Neurodegenerative Disease

Critical Reviews in Neurobiology, 1999

Lipoproteins are macromolecular complexes composed of lipids and proteins. The role of these comp... more Lipoproteins are macromolecular complexes composed of lipids and proteins. The role of these complexes is to provide cells of the organism with lipids to be used as a source of energy, building blocks for biomembrane synthesis, and lipophilic molecules (e.g., steroid hormones and vitamin E) for other physiological purposes, such as cell signaling and antioxidative mechanisms. Lipoproteins also promote the cellular efflux of cholesterol for its disposal into bile. Thus, lipoproteins play an important role in the maintenance of lipid homeostasis throughout the organism. Accordingly, lipoprotein particles have been found circulating in blood, lymph, and interstitial fluid. Despite the existence of the blood-brain barrier, lipoprotein particles have been shown to be also present in the cerebrospinal fluid (CSF). Although a portion of their protein components may filter through the barrier from the vascular compartment, experimental evidence indicates that these particles originate from the nervous tissue. The other protein components include apolipoproteins E, J, and D, and these have been shown to be synthesized by cells within the central nervous system (CNS). Furthermore, it was shown that lipoprotein particles can be isolated from the conditioned medium of astrocytic cultures. The differences in size, structure, and composition of in vitro assembled particles compared with those isolated from the CSF suggest that the particles are modified following their secretion in vivo. This is supported by observations that lipoprotein-modifying enzymes and transfer proteins are also present within CNS tissue and CSF. The fate of CSF lipoproteins is unclear but is probably related to the turnover and clearance of lipids from the CNS or, alternatively, the particles may be recaptured and recycled back into the CNS tissue. The presence of several cell surface receptors for apoE-containing lipoproteins on ependymal cells, as well as on neurons and glial cells, supports this notion and suggests that the isolated brain possesses its own system to maintain local lipid homeostasis. This is further exemplified by the salvage and recycling of lipids shown to occur following a lesion in order to allow surviving neurons to sprout and reestablish lost synapses. Not much is currently known about lipoprotein metabolism in neurodegenerative diseases, but lipid alterations have been repeatedly reported in Alzheimer brains in which neuronal loss and deafferentation are major features. Although the mechanism underlying the link between the epsilon4 allele of the apolipoprotein E gene and Alzheimer&#39;s disease is presently unclear, it may well be postulated that it is related to disturbances in brain lipoprotein metabolism.

Research paper thumbnail of Association of a Total Cholesterol Polygenic Score with Cholesterol Levels and Pathological Biomarkers across the Alzheimer’s Disease Spectrum

Genes

Midlife hypercholesterolemia is a well-known risk factor for sporadic Alzheimer’s disease (AD), a... more Midlife hypercholesterolemia is a well-known risk factor for sporadic Alzheimer’s disease (AD), and like AD, it is highly influenced by genetics with heritability estimates of 32–63%. We thus hypothesized that genetics underlying peripheral blood total cholesterol (TC) levels could influence the risk of developing AD. We created a weighted polygenic score (TC-PGS) using summary data from a meta-analysis of TC genome-wide association studies for evaluation in three independent AD-related cohorts spanning pre-clinical, clinical, and pathophysiologically proved AD. APOE-ε4 variant was purposely included in the analysis as it represents an already well-established genetic risk factor for both AD and circulating TC. We could vastly improve the performance of the score when considering p-value thresholds for inclusion in the score, sex, and statin use. This optimized score (p-value threshold of 1 × 10−6 for inclusion in the score) explained 18.2% of the variance in TC levels in statin fre...

Research paper thumbnail of Apolipoprotein B is a novel marker for early tau pathology in Alzheimer's disease

Alzheimer's & Dementia

INTRODUCTION We examine the role of brain apolipoprotein B (apoB) as a putative marker of early t... more INTRODUCTION We examine the role of brain apolipoprotein B (apoB) as a putative marker of early tau pathology and cognitive decline. METHODS Cerebrospinal fluid (CSF) samples from cognitively normal and Alzheimer's disease (AD) participants were collected to measure protein levels of apoB and AD biomarkers amyloid beta (Aβ), t-tau and p-tau, as well as synaptic markers GAP43, SYNAPTOTAGMIN-1, synaptosome associated protein 25 (SNAP-25), and NEUROGRANIN. CSF apoB levels were contrasted with positron emission tomography (PET) scan measures of Aβ (18F-NAV4694) and Tau (flortaucipir) along with cognitive assessment alterations over 6 to 8 years. RESULTS CSF apoB levels were elevated in AD participants and correlated with t-tau, p-tau, and the four synaptic markers in pre-symptomatic individuals. In the latter, CSF apoB levels correlated with PET flortaucipir-binding in entorhinal, parahippocampal, and fusiform regions. Baseline CSF apoB levels were associated with longitudinal visuospatial cognitive decline. DISCUSSION CSF apoB markedly associates with early tau dysregulation in asymptomatic subjects and identifies at-risk individuals predisposed to develop visuospatial cognitive decline over time.

Research paper thumbnail of Herpes Simplex Virus Type 1 in the Brain, Apolipoprotein E Genotype and Alzheimer’s Disease

McGill Journal of Medicine

The ε4 allele of apolipoprotein E (apoE) is an important risk factor for Alzheimer's disease ... more The ε4 allele of apolipoprotein E (apoE) is an important risk factor for Alzheimer's disease (AD), however, it is not required nor sufficient to cause the disease on its own. Herpes viruses cause acute and chronic diseases of the central nervous system and have been implicated in AD. Using a sensitive polymerase chain reaction method, latent herpes simplex virus type 1 (HSV-1) has been detected from five different brain regions (hippocampus, frontal cortex, occipital cortex, cerebellum and striatum) of neuropathologically confirmed AD and control tissue. HSV-1 positivity was then correlated with AD, presence of the virus in specific brain regions, and apoE genotype. The results confirm that the ε4 allele of apoE is a risk factor for AD, while HSV-1 alone is not. This held true for all five brain regions examined. Furthermore, no synergy between the two factors could be found when any one of the brain regions was examined individually or when the data were pooled. These findings ...

Research paper thumbnail of Open Science Datasets from PREVENT-AD, a Longitudinal Cohort of Pre-symptomatic Alzheimer’s Disease

ABSTRACTTo move Alzheimer Disease (AD) research forward it is essential to collect data from larg... more ABSTRACTTo move Alzheimer Disease (AD) research forward it is essential to collect data from large cohorts, but also make such data available to the global research community. We describe the creation of an open science dataset from the PREVENT-AD (PResymptomatic EValuation of Experimental or Novel Treatments for AD) cohort, composed of cognitively unimpaired older individuals with a parental or multiple-sibling history of AD. From 2011 to 2017, 386 participants were enrolled (mean age 63 years old ± 5) for sustained investigation among whom 349 have retrospectively agreed to share their data openly. Repositories are findable through the unified interface of the Canadian Open Neuroscience Platform (https://portal.conp.ca/) and contain up to five years of longitudinal imaging data, cerebral fluid biochemistry, neurosensory capacities, cognitive, genetic, and medical information. Imaging data can be accessed openly at https://openpreventad.loris.ca while most of the other information,...

Research paper thumbnail of Amyloid and tau pathology associations with personality traits, neuropsychiatric symptoms and cognitive lifestyle in the preclinical phases of sporadic and autosomal dominant Alzheimer’s disease

Biological Psychiatry

BACKGROUND: Major prevention trials for Alzheimer's disease (AD) are now focusing on multidomain ... more BACKGROUND: Major prevention trials for Alzheimer's disease (AD) are now focusing on multidomain lifestyle interventions. However, the exact combination of behavioral factors related to AD pathology remains unclear. In 2 cohorts of cognitively unimpaired individuals at risk of AD, we examined which combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle (years of education or lifetime cognitive activity) related to the pathological hallmarks of AD, amyloid-b, and tau deposits. METHODS: A total of 115 older adults with a parental or multiple-sibling family history of sporadic AD (PREVENT-AD [PRe-symptomatic EValuation of Experimental or Novel Treatments for AD] cohort) underwent amyloid and tau positron emission tomography and answered several questionnaires related to behavioral attributes. Separately, we studied 117 mutation carriers from the DIAN (Dominant Inherited Alzheimer Network) study group cohort with amyloid positron emission tomography and behavioral data. Using partial least squares analysis, we identified latent variables relating amyloid or tau pathology with combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle. RESULTS: In PREVENT-AD, lower neuroticism, neuropsychiatric burden, and higher education were associated with less amyloid deposition (p = .014). Lower neuroticism and neuropsychiatric features, along with higher measures of openness and extraversion, were related to less tau deposition (p = .006). In DIAN, lower neuropsychiatric burden and higher education were also associated with less amyloid (p = .005). The combination of these factors accounted for up to 14% of AD pathology. CONCLUSIONS: In the preclinical phase of both sporadic and autosomal dominant AD, multiple behavioral features were associated with AD pathology. These results may suggest potential pathways by which multidomain interventions might help delay AD onset or progression.

Research paper thumbnail of Genetic and Environmental Factors Are Differentially Related to Aβ Burden in the Presymptomatic Phase of Autosomal Dominant and Sporadic Alzheimer’s Disease

Alzheimer's & Dementia

Genetic and environmental factors are differentially related to Aβ burden in the presymptomatic p... more Genetic and environmental factors are differentially related to Aβ burden in the presymptomatic phase of autosomal dominant and sporadic Alzheimer's disease Participants and Methods Summary and conclusions Our results suggest that, as it is the case in ADAD, a parental EYO index might help to predict Aβ accumulation in asymptomatic individuals at risk of sAD. 6,7 This might have important implications for the characterization of the preclinical phase of sAD and the recruitment of prevention/clinical trials. While APOE4 is highly associated with Aβ burden in people at risk of sAD, it has no impact in ADAD. By contrast, environmental factors, approximated here using years of education, could affect biomarker progression in both variants of the disease. Furthermore, education seems able to counteract the deleterious effect of APOE4 on Aβ burden in asymptomatic individuals with a PH of sAD. 8 These results suggest the existence of reserve mechanisms, not only in individuals at risk of sAD , but also in individuals carrying aggressive ADAD variants.

Research paper thumbnail of Nsaids for Ad Prevention? Naproxen Enters the CNS Without Apparent Effect on CSF Immune Markers

Alzheimer's & Dementia

Background: The locus coeruleus (LC) is the initial site of Alzheimer’s disease (AD) neuropatholo... more Background: The locus coeruleus (LC) is the initial site of Alzheimer’s disease (AD) neuropathology with hyperphosphorylated Tau appearing in early adulthood, with severe neurodegeneration in AD. Loss of norepinephrine (NE) from LC contributes to AD pathobiology in experimental models, which can be rescued by increasing NE transmission. To test whether increased NE signaling in humans could be useful to treat AD pathogenesis, we repurposed atomoxetine (ATX), an FDA-approved NE transporter inhibitor, in a phase II trial for MCI. We hypothesized that ATX is safe and well tolerated, achieves target engagement, and reduces CNS inflammation.Methods: In a single-center double-blind crossover trial, we randomized MCI patients with prodromal AD to ATX/placebo and placebo/ATX arms. Assessments were collected at baseline, 6(crossover) and 12-months (completer). Target engagement was assessed by HPLC measures of NE and metabolites. Prespecified primary outcomes were CSF levels of IL1a and Thymus-Expressed Chemokine (TECK). Secondary/exploratory outcomes included CSF AD biomarkers, a panel of 92 inflammation-related analytes (O-link), and others. Results: 39 participants were enrolled, with dropout rates 5.1% (2/39) for ATX and 2.7% (1/37) for placebo phases. Baseline demographic and clinical measures were similar across arms. There were no significant differences in adverse events. ATX increased plasma and CSF NE and reduced DHPG (p<0.0001), demonstrating target engagement. ATX reduced CSF Tau by 6% (CI: 1.5-10.3%, p1⁄40.02), with no effect on Ab42. CSF IL-1a and TECK were not measurable in most samples; however, ATX treatment showed a trend for decreased CSF IL1a detectability (odds ratio 2.7; CI: 0.8-8.9, p1⁄40.10), suggesting reduced inflammation, with no effect on TECK (p>0.4). Among exploratory inflammation-related biomarkers (without adjusting for multiple testing), ATX treatment reduced CSF CDCP1, CD244 and TWEAK, and increased OPG (p<0.05). ATX treatment was also associated with increased BDNF and reduced triglycerides in plasma. Conclusions: ATX treatment was safe, well tolerated, and robustly achieved target engagement. While ATX had no significant effect on preselected inflammation biomarkers, ATX significantly reduced CSF Tau and several pro-inflammatory markers (CDCP1, CD244 and TWEAK). Further study of ATX is warranted for repurposing the drug to slow AD progression.

Research paper thumbnail of CDK5RAP2 Gene and Tau Pathophysiology in Late-Onset Sporadic Alzheimer’s Disease

Alzheimer's & Dementia

that results in increased amyloid beta levels. Results:We will report our results and discuss how... more that results in increased amyloid beta levels. Results:We will report our results and discuss how they relate to the relationship between these mutations and both chemokine and amyloid beta levels in mammalian cell lines. Conclusions: This work will allow us to examine the role that amyloid beta plays in the activation of pro-inflammatory responses by the chemokine receptors CCBP2 and CCLR2 and their respective mutants. This work could lead to a means of regulating amyloid beta production and expression which could lead to novel therapeutic solutions.

Research paper thumbnail of Isoprenoids and tau pathology in sporadic Alzheimer's disease

Research paper thumbnail of Multiple cholinergic markers are unexpectedly not altered in the rat dentate gyrus following entorhinal cortex lesions

The Journal of Neuroscience

We thank Dr. Paul Clarke for his helpful comments and critical reading of the manuscript. Annie B... more We thank Dr. Paul Clarke for his helpful comments and critical reading of the manuscript. Annie Baccichet and Doris Dea are acknowledged for their technical support in performing lesions of the entorhinal cortex. This work was supported by grants from the Medical Research Council of Canada (R.Q., J.P.). R.Q. and J.P. are, respectively, holders of "Chercheur-Boursier" of the "Fends de ia Recherche en Sante du Qu6bec" (FRSQ) and an MRCC scholarship. LA. is the holder of a studentshio from the Alzheimer Societv of Canada.

Research paper thumbnail of Brain properties predict proximity to symptom onset in sporadic Alzheimer's disease

Brain : a journal of neurology, Jan 23, 2018

Alzheimer's disease is preceded by a lengthy 'preclinical' stage spanning many years,... more Alzheimer's disease is preceded by a lengthy 'preclinical' stage spanning many years, during which subtle brain changes occur in the absence of overt cognitive symptoms. Predicting when the onset of disease symptoms will occur is an unsolved challenge in individuals with sporadic Alzheimer's disease. In individuals with autosomal dominant genetic Alzheimer's disease, the age of symptom onset is similar across generations, allowing the prediction of individual onset times with some accuracy. We extend this concept to persons with a parental history of sporadic Alzheimer's disease to test whether an individual's symptom onset age can be informed by the onset age of their affected parent, and whether this estimated onset age can be predicted using only MRI. Structural and functional MRIs were acquired from 255 ageing cognitively healthy subjects with a parental history of sporadic Alzheimer's disease from the PREVENT-AD cohort. Years to estimated symptom...

Research paper thumbnail of Proximity to Parental Symptom Onset and Amyloid-β Burden in Sporadic Alzheimer Disease

JAMA neurology, Jan 26, 2018

Alzheimer disease (AD) develops during several decades. Presymptomatic individuals might be the b... more Alzheimer disease (AD) develops during several decades. Presymptomatic individuals might be the best candidates for clinical trials, but their identification is challenging because they have no symptoms. To assess whether a sporadic parental estimated years to symptom onset calculation could be used to identify information about amyloid-β (Aβ) levels in asymptomatic individuals with a parental history of AD dementia. This cohort study analyzed Aβ1-42 in cerebrospinal fluid (CSF) specimens from 101 cognitively normal individuals who had a lumbar puncture as part of the Presymptomatic Evaluation of Novel or Experimental Treatments for Alzheimer Disease (PREVENT-AD) cohort from September 1, 2011, through November 30, 2016 (374 participants were enrolled in the cohort during this period). The study estimated each participant's proximity to his/her parent's symptom onset by subtracting the index relative's onset age from his/her current age. The association between proximity ...

Research paper thumbnail of {"__content__"=>" \nvariant mitigates Alzheimer disease pathophysiology in vivo and postmortem.", "i"=>{"__content__"=>"CYP2C19"}}

Neurology. Genetics, 2018

To verify whetherpolymorphisms are associated with amyloid-β (Aβ) pathology across the spectrum o... more To verify whetherpolymorphisms are associated with amyloid-β (Aβ) pathology across the spectrum of clinical Alzheimer disease using in vivo and postmortem data from 2 independent cohorts. A candidate-gene approach tested the association between 5 genes (28 single nucleotide polymorphisms) and Aβ load measured in vivo by the global [F]florbetapir PET standardized uptake value ratio (SUVR) in 338 Alzheimer's Disease Neuroimaging Initiative participants. Significant results were then tested using plasma Aβ and CSF Aβ and Aβ/phosphorylated tau (Aβ/p-tau) ratio in the same cohort. The significant association was also generalized to postmortem Aβ load measurement in the Rush Religious Orders Study/Memory and Aging Project cohorts. In addition, global cognition was used as a phenotype in the analysis in both cohorts. Analysis of Aβ PET identified a variant in thegene (rs4388808;= 0.0006), in which carriers of the minor allele (MA) had a lower global SUVR. A voxel-wise analysis revealed...

Research paper thumbnail of Regionally specific changes in the hippocampal circuitry accompany progression of cerebrospinal fluid biomarkers in preclinical Alzheimer's disease

Human brain mapping, 2018

Neuropathological and in vivo brain imaging studies agree that the cornu ammonis 1 and subiculum ... more Neuropathological and in vivo brain imaging studies agree that the cornu ammonis 1 and subiculum subfields of the hippocampus are most vulnerable to atrophy in the prodromal phases of Alzheimer's disease (AD). However, there has been limited investigation of the structural integrity of the components of the hippocampal circuit, including subfields and extra-hippocampal white matter structure, in relation to the progression of well-accepted cerebrospinal fluid (CSF) biomarkers of AD, amyloid-β 1-42 (Aβ) and total-tau (tau). We investigated these relationships in 88 aging asymptomatic individuals with a parental or multiple-sibling familial history of AD. Apolipoprotein (APOE) ɛ4 risk allele carriers were identified, and all participants underwent cognitive testing, structural magnetic resonance imaging, and lumbar puncture for CSF assays of tau, phosphorylated-tau (p-tau) and Aβ. Individuals with a reduction in CSF Aβ levels (an indicator of amyloid accretion into neuritic plaque...

Research paper thumbnail of Apolipoprotein E knockout mice display procedural deficits in the Morris water maze: analysis of learning strategies in three versions of the task

Neuroscience

öApolipoprotein E knockout (apoEKO) mice have been shown to be impaired in the spatial Morris wat... more öApolipoprotein E knockout (apoEKO) mice have been shown to be impaired in the spatial Morris water maze (MWM). However, several groups failed to replicate this ¢nding. One reason for this inconsistency may stem from variations in the experimental protocols and environment between laboratories. In the present study, we have tested if age and variations in protocol implementation that speci¢cally a¡ect salience of the visual extramaze cues in£uence performance and navigational strategies in the MWM. We tested three-and 12-month-old apoEKO and wild type mice in three versions of the MWM di¡ering on the availability of visual extramaze cues: (1) salient cues, (2) di¡use cues, and (3) absence of cues. Our results show that the presence of salient cues enhances acquisition performance of wild type, but not apoEKO mice in the MWM. This e¡ect was restricted to the acquisition phase since apoEKO mice reached a level of performance that was comparable to that of controls toward the end of the task. No signi¢cant di¡erences were detected between apoEKO and controls in either the di¡use cues or absence of cues paradigms. Thigmotaxic tendencies were observed in apoEKO mice and correlated high latency scores. Thigmotaxis may have interfered with the initial ability to engage in a pro¢cient navigational strategy. These ¢ndings suggest that, in contrast to what has been proposed in the past, apoEKO mice appear not to be impaired in spatial memory per se but are de¢cient in a procedural component of the MWM. Furthermore, the procedural de¢cit and corresponding thigmotaxic tendencies of apoEKO mice appeared to increase with age. Taken together, these ¢ndings con¢rm our hypothesis that age and variations in experimental protocols can in£uence MWM performances.

Research paper thumbnail of Odor identification as a biomarker of preclinical AD in older adults at risk

Neurology

Objective:To assess odor identification (OI) as an indicator of presymptomatic Alzheimer disease ... more Objective:To assess odor identification (OI) as an indicator of presymptomatic Alzheimer disease (AD) pathogenesis in cognitively normal aging individuals at increased risk of AD dementia.Methods:In 274 members of the PREVENT-AD cohort of healthy aging persons with a parental or multiple-sibling history of AD dementia, we assessed the cross-sectional association of OI with potential indicators of presymptomatic AD. Some 101 participants donated CSF, thus enabling assessment of AD pathology with the biomarkers total tau (t-tau), phospho-tau (P181-tau), and their ratios with β-amyloid (Aβ1-42). Adjusted analyses considered age, cognition, APOE ε4 status, education, and sex as covariates. We measured OI using the University of Pennsylvania Smell Identification Test and cognitive performance using the Repeatable Battery for Assessment of Neuropsychological Status. Standard kits provided assays of the AD biomarkers. Analyses used robust-fit linear regression models.Results:Reduced OI was...

Research paper thumbnail of Familiarity deficits in cognitively normal aging individuals with APOE ε4: A follow-up investigation of medial temporal lobe structural correlates

Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring

Research paper thumbnail of Selective familiarity deficits in otherwise cognitively intact aging individuals with genetic risk for Alzheimer's disease

Alzheimer's & dementia (Amsterdam, Netherlands), 2016

Familiarity has been associated with integrity of the rhinal cortex. Thus, impairment in familiar... more Familiarity has been associated with integrity of the rhinal cortex. Thus, impairment in familiarity is expected in very early stages of Alzheimer's disease (AD). The apolipoprotein E (APOE) ε4 allele is a major risk factor for AD. Here, we investigated the effect of the APOE ε4 status on familiarity in cognitively normal aging individuals. Eighty-one individuals aged between 55 and 80 years, 21 carriers and 60 noncarriers, were used in these analyses. A cognitive evaluation was performed on all participants to document the absence of objective cognitive deficits. The effect of APOE ε4 status on familiarity was tested using independent sample t test and an analysis of covariance controlling for age, gender, and education. The groups did not differ in term of age, education, and male/female ratio. APOE ε4 carriers showed a significant reduction in familiarity. No other cognitive deficit was observed in the group of ε4 carriers, relative to noncarriers. APOE ε4 is associated with ...

Research paper thumbnail of BDNF Val66Met Polymorphism Interacts with Sleep Consolidation to Predict Ability to Create New Declarative Memories

The Journal of neuroscience : the official journal of the Society for Neuroscience, Aug 10, 2016

It is hypothesized that a fundamental function of sleep is to restore an individual's day-to-... more It is hypothesized that a fundamental function of sleep is to restore an individual's day-to-day ability to learn and to constantly adapt to a changing environment through brain plasticity. Brain-derived neurotrophic factor (BDNF) is among the key regulators that shape brain plasticity. However, advancing age and carrying the BDNF Met allele were both identified as factors that potentially reduce BDNF secretion, brain plasticity, and memory. Here, we investigated the moderating role of BDNF polymorphism on sleep and next-morning learning ability in 107 nondemented individuals who were between 55 and 84 years of age. All subjects were tested with 1 night of in-laboratory polysomnography followed by a cognitive evaluation the next morning. We found that in subjects carrying the BDNF Val66Val polymorphism, consolidated sleep was associated with significantly better performance on hippocampus-dependent episodic memory tasks the next morning (β-values from 0.290 to 0.434, p ≤ 0.01). ...

Research paper thumbnail of Brain Lipoprotein Metabolism and Its Relation to Neurodegenerative Disease

Critical Reviews in Neurobiology, 1999

Lipoproteins are macromolecular complexes composed of lipids and proteins. The role of these comp... more Lipoproteins are macromolecular complexes composed of lipids and proteins. The role of these complexes is to provide cells of the organism with lipids to be used as a source of energy, building blocks for biomembrane synthesis, and lipophilic molecules (e.g., steroid hormones and vitamin E) for other physiological purposes, such as cell signaling and antioxidative mechanisms. Lipoproteins also promote the cellular efflux of cholesterol for its disposal into bile. Thus, lipoproteins play an important role in the maintenance of lipid homeostasis throughout the organism. Accordingly, lipoprotein particles have been found circulating in blood, lymph, and interstitial fluid. Despite the existence of the blood-brain barrier, lipoprotein particles have been shown to be also present in the cerebrospinal fluid (CSF). Although a portion of their protein components may filter through the barrier from the vascular compartment, experimental evidence indicates that these particles originate from the nervous tissue. The other protein components include apolipoproteins E, J, and D, and these have been shown to be synthesized by cells within the central nervous system (CNS). Furthermore, it was shown that lipoprotein particles can be isolated from the conditioned medium of astrocytic cultures. The differences in size, structure, and composition of in vitro assembled particles compared with those isolated from the CSF suggest that the particles are modified following their secretion in vivo. This is supported by observations that lipoprotein-modifying enzymes and transfer proteins are also present within CNS tissue and CSF. The fate of CSF lipoproteins is unclear but is probably related to the turnover and clearance of lipids from the CNS or, alternatively, the particles may be recaptured and recycled back into the CNS tissue. The presence of several cell surface receptors for apoE-containing lipoproteins on ependymal cells, as well as on neurons and glial cells, supports this notion and suggests that the isolated brain possesses its own system to maintain local lipid homeostasis. This is further exemplified by the salvage and recycling of lipids shown to occur following a lesion in order to allow surviving neurons to sprout and reestablish lost synapses. Not much is currently known about lipoprotein metabolism in neurodegenerative diseases, but lipid alterations have been repeatedly reported in Alzheimer brains in which neuronal loss and deafferentation are major features. Although the mechanism underlying the link between the epsilon4 allele of the apolipoprotein E gene and Alzheimer&#39;s disease is presently unclear, it may well be postulated that it is related to disturbances in brain lipoprotein metabolism.