Blood-based systems biology biomarkers for next-generation clinical trials in Alzheimer’s disease

Alzheimer's disease (AD)-a complex disease showing multiple pathomechanistic alterations-is triggered by nonlinear dynamic interactions of genetic/epigenetic and environmental risk factors. which, ultimately, converge into a biologically heterogeneous disease. To tackle the burden of AD during early preclinical stages. accessible blood-based biomarkers are currently being developed. Specifically. next-generation clinical trials are expected to integrate positive and negative predictive blood-based biomarkers into study designs to evaluate, at the individual level, target druggability and potential drug resistance mechanisms. In this scenario, systems biology holds promise to accelerate validation and qualification for clinical trial contexts of use-including proof-of-mechanism. patient selection, assessment of treatment efficacy and safety rates and prognostic evaluation. Albeit in their infancy, systems biology-based approaches are poised to identify relevant AD "signatures" through multifactorial and interindividual variability. allowing us to decipher disease pathophysiology and etiology. Hopefully. innovative biomarker-drug codevelopment strategies will be the road ahead towards effective disease-modifying drugs. (C) 2019, AICH - Servier Grou

Plasma amyloid β 40/42 ratio predicts cerebral amyloidosis in cognitively normal individuals at risk for Alzheimer's disease

Introduction: Blood-based biomarkers of pathophysiological brain amyloid β (Aβ) accumulation, particularly for preclinical target and large-scale interventions, are warranted to effectively enrich Alzheimer's disease clinical trials and management. / Methods: We investigated whether plasma concentrations of the Aβ1–40/Aβ1–42 ratio, assessed using the single-molecule array (Simoa) immunoassay, may predict brain Aβ positron emission tomography status in a large-scale longitudinal monocentric cohort (N = 276) of older individuals with subjective memory complaints. We performed a hypothesis-driven investigation followed by a no-a-priori hypothesis study using machine learning. / Results: The receiver operating characteristic curve and machine learning showed a balanced accuracy of 76.5% and 81%, respectively, for the plasma Aβ1–40/Aβ1–42 ratio. The accuracy is not affected by the apolipoprotein E (APOE) ε4 allele, sex, or age. / Discussion: Our results encourage an independent validation cohort study to confirm the indication that the plasma Aβ1–40/Aβ1–42 ratio, assessed via Simoa, may improve future standard of care and clinical trial design

Basal forebrain volume, but not hippocampal volume, is a predictor of global cognitive decline in patients with alzheimer's disease treated with cholinesterase inhibitors

Background: Predicting the progression of cognitive decline in Alzheimer's disease (AD) is important for treatment selection and patient counseling. Structural MRI markers such as hippocampus or basal forebrain volumes might represent useful instruments for the prediction of cognitive decline. The primary objective was to determine the predictive value of hippocampus and basal forebrain volumes for global and domain specific cognitive decline in AD dementia during cholinergic treatment. Methods: We used MRI and cognitive data from 124 patients with the clinical diagnosis of AD dementia, derived from the ADNI-1 cohort, who were on standard of care cholinesterase inhibitor treatment during a follow-up period between 0.4 and 3.1 years. We used linear mixed effects models with cognitive function as outcome to assess the main effects as well as two-way interactions between baseline volumes and time controlling for age, sex, and total intracranial volume. This model accounts for individual variation in follow-up times. Results: Basal forebrain volume, but not hippocampus volume, was a significant predictor of rates of global cognitive decline. Larger volumes were associated with smaller rates of cognitive decline. Left hippocampus volume had a modest association with rates of episodic memory decline. Baseline performance in global cognition and memory was significantly associated with hippocampus and basal forebrain volumes; in addition, basal forebrain volume was associated with baseline performance in executive function. Conclusions: Our findings indicate that in AD dementia patients, basal forebrain volume may be a useful marker to predict subsequent cognitive decline during cholinergic treatment

Plasma amyloid β 40/42 ratio predicts cerebral amyloidosis in cognitively normal individuals at risk for Alzheimer's disease

Introduction: Blood-based biomarkers of pathophysiological brain amyloid β (Aβ) accumulation, particularly for preclinical target and large-scale interventions, are warranted to effectively enrich Alzheimer's disease clinical trials and management. Methods: We investigated whether plasma concentrations of the Aβ1–40/Aβ1–42 ratio, assessed using the single-molecule array (Simoa) immunoassay, may predict brain Aβ positron emission tomography status in a large-scale longitudinal monocentric cohort (N = 276) of older individuals with subjective memory complaints. We performed a hypothesis-driven investigation followed by a no-a-priori hypothesis study using machine learning. Results: The receiver operating characteristic curve and machine learning showed a balanced accuracy of 76.5% and 81%, respectively, for the plasma Aβ1–40/Aβ1–42 ratio. The accuracy is not affected by the apolipoprotein E (APOE)ε4 allele, sex, or age. Discussion: Our results encourage an independent validation cohort study to confirm the indication that the plasma Aβ1–40/Aβ1–42 ratio, assessed via Simoa, may improve future standard of care and clinical trial design

Differential default mode network trajectories in asymptomatic individuals at risk for Alzheimer's disease

Introduction: The longitudinal trajectories of functional brain dynamics and the impact of genetic risk factors in individuals at risk for Alzheimer's disease are poorly understood.Methods: In a large-scale monocentric cohort of 224 amyloid stratified individuals at risk for Alzheimer's disease, default mode network (DMN) resting state functional connectivity (FC) was investigated between two serial time points across 2 years.Results: Widespread DMN FC changes were shown in frontal and posterior areas, as well as in the right hippocampus. There were no cross-sectional differences, however, apolipoprotein E epsilon 4 (APOE epsilon 4) carriers demonstrated slower increase in FC in frontal lobes. There was no impact of individual brain amyloid load status.Discussion: For the first time, we demonstrated that the pleiotropic biological effect of the APOE epsilon 4 allele impacts the dynamic trajectory of the DMN during aging. Dynamic functional biomarkers may become useful surrogate outcomes for the development of preclinical targeted therapeutic interventions. (C) 2019 Published by Elsevier Inc. on behalf of the Alzheimer's Association

Differential default mode network trajectories in asymptomatic individuals at risk for Alzheimer's disease

Introduction:The longitudinal trajectories of functional brain dynamics and the impact of geneticrisk factors in individuals at risk for Alzheimer\u2019s disease are poorly understood.Methods:In a large-scale monocentric cohort of 224 amyloid stratified individuals at risk forAlzheimer\u2019s disease, default mode network (DMN) resting state functional connectivity (FC) wasinvestigated between two serial time points across 2 years.Results:Widespread DMN FC changes were shown in frontal and posterior areas, as well as in theright hippocampus. There were no cross-sectional differences, however, apolipoprotein E\u3b54(APOE\u3b54) carriers demonstrated slower increase in FC in frontal lobes. There was no impact ofindividual brain amyloid load status.Discussion:For the first time, we demonstrated that the pleiotropic biological effect of theAPOE\u3b54allele impacts the dynamic trajectory of the DMN during aging. Dynamic functional biomarkersmay become useful surrogate outcomes for the development of preclinical targeted therapeuticinterventions

Effect of Alzheimer's disease risk and protective factors on cognitive trajectories in subjective memory complainers: An INSIGHT‐preAD study

International audienc

Association of cerebrospinal fluid α-synuclein with total and phospho-tau181 protein concentrations and brain amyloid load in cognitively normal subjective memory complainers stratified by Alzheimer's disease biomarkers

147siIntroduction Several neurodegenerative brain proteinopathies, including Alzheimer's disease (AD), are associated with cerebral deposition of insoluble aggregates of α-synuclein. Previous studies reported a trend toward increased cerebrospinal fluid (CSF) α-synuclein (α-syn) concentrations in AD compared with other neurodegenerative diseases and healthy controls. Methods The pathophysiological role of CSF α-syn in asymptomatic subjects at risk of AD has not been explored. We performed a large-scale cross-sectional observational monocentric study of preclinical individuals at risk for AD (INSIGHT-preAD). Results We found a positive association between CSF α-syn concentrations and brain β-amyloid deposition measures as mean cortical standard uptake value ratios. We demonstrate positive correlations between CSF α-syn and both CSF t-tau and p-tau181 concentrations. Discussion Animal models presented evidence, indicating that α-syn may synergistically and directly induce fibrillization of both tau and β-amyloid. Our data indicate an association of CSF α-syn with AD-related pathophysiological mechanisms, during the preclinical phase of the disease.partially_openopenVergallo A.; Bun R.-S.; Toschi N.; Baldacci F.; Zetterberg H.; Blennow K.; Cavedo E.; Lamari F.; Habert M.-O.; Dubois B.; Floris R.; Garaci F.; Lista S.; Hampel H.; Audrain C.; Auffret A.; Bakardjian H.; Baldacci F.; Batrancourt B.; Benakki I.; Benali H.; Bertin H.; Bertrand A.; Boukadida L.; Cacciamani F.; Causse V.; Cavedo E.; Cherif Touil S.; Chiesa P.A.; Colliot O.; Dalla Barba G.; Depaulis M.; Dos Santos A.; Dubois B.; Dubois M.; Epelbaum S.; Fontaine B.; Francisque H.; Gagliardi G.; Genin A.; Genthon R.; Glasman P.; Gombert F.; Habert M.O.; Hampel H.; Hewa H.; Houot M.; Jungalee N.; Kas A.; Kilani M.; La Corte V.; Le Roy F.; Lehericy S.; Letondor C.; Levy M.; Lista S.; Lowrey M.; Ly J.; Makiese O.; Masetti I.; Mendes A.; Metzinger C.; Michon A.; Mochel F.; Nait Arab R.; Nyasse F.; Perrin C.; Poirier F.; Poisson C.; Potier M.C.; Ratovohery S.; Revillon M.; Rojkova K.; Santos-Andrade K.; Schindler R.; Servera M.C.; Seux L.; Simon V.; Skovronsky D.; Thiebaut M.; Uspenskaya O.; Vlaincu M.; Aguilar L.F.; Babiloni C.; Baldacci F.; Benda N.; Black K.L.; Bokde A.L.W.; Bonuccelli U.; Broich K.; Bun R.S.; Cacciola F.; Castrillo J.; Cavedo E.; Ceravolo R.; Chiesa P.A.; Colliot O.; Coman C.M.; Corvol J.C.; Cuello A.C.; Cummings J.L.; Depypere H.; Dubois B.; Duggento A.; Durrleman S.; Escott-Price V.; Federoff H.; Ferretti M.T.; Fiandaca M.; Frank R.A.; Garaci F.; Genthon R.; George N.; Giorgi F.S.; Graziani M.; Haberkamp M.; Habert M.O.; Hampel H.; Herholz K.; Karran E.; Kim S.H.; Koronyo Y.; Koronyo-Hamaoui M.; Lamari F.; Langevin T.; Lehericy S.; Lista S.; Lorenceau J.; Mapstone M.; Neri C.; Nistico R.; Nyasse-Messene F.; O'Bryant S.E.; Perry G.; Ritchie C.; Rojkova K.; Rossi S.; Santarnecchi E.; Schneider L.S.; Sporns O.; Toschi N.; Verdooner S.R.; Vergallo A.; Villain N.; Welikovitch L.; Woodcock J.; Younesi E.Vergallo, A.; Bun, R. -S.; Toschi, N.; Baldacci, F.; Zetterberg, H.; Blennow, K.; Cavedo, E.; Lamari, F.; Habert, M. -O.; Dubois, B.; Floris, R.; Garaci, F.; Lista, S.; Hampel, H.; Audrain, C.; Auffret, A.; Bakardjian, H.; Baldacci, F.; Batrancourt, B.; Benakki, I.; Benali, H.; Bertin, H.; Bertrand, A.; Boukadida, L.; Cacciamani, F.; Causse, V.; Cavedo, E.; Cherif Touil, S.; Chiesa, P. A.; Colliot, O.; Dalla Barba, G.; Depaulis, M.; Dos Santos, A.; Dubois, B.; Dubois, M.; Epelbaum, S.; Fontaine, B.; Francisque, H.; Gagliardi, G.; Genin, A.; Genthon, R.; Glasman, P.; Gombert, F.; Habert, M. O.; Hampel, H.; Hewa, H.; Houot, M.; Jungalee, N.; Kas, A.; Kilani, M.; La Corte, V.; Le Roy, F.; Lehericy, S.; Letondor, C.; Levy, M.; Lista, S.; Lowrey, M.; Ly, J.; Makiese, O.; Masetti, I.; Mendes, A.; Metzinger, C.; Michon, A.; Mochel, F.; Nait Arab, R.; Nyasse, F.; Perrin, C.; Poirier, F.; Poisson, C.; Potier, M. C.; Ratovohery, S.; Revillon, M.; Rojkova, K.; Santos-Andrade, K.; Schindler, R.; Servera, M. C.; Seux, L.; Simon, V.; Skovronsky, D.; Thiebaut, M.; Uspenskaya, O.; Vlaincu, M.; Aguilar, L. F.; Babiloni, C.; Baldacci, F.; Benda, N.; Black, K. L.; Bokde, A. L. W.; Bonuccelli, U.; Broich, K.; Bun, R. S.; Cacciola, F.; Castrillo, J.; Cavedo, E.; Ceravolo, R.; Chiesa, P. A.; Colliot, O.; Coman, C. M.; Corvol, J. C.; Cuello, A. C.; Cummings, J. L.; Depypere, H.; Dubois, B.; Duggento, A.; Durrleman, S.; Escott-Price, V.; Federoff, H.; Ferretti, M. T.; Fiandaca, M.; Frank, R. A.; Garaci, F.; Genthon, R.; George, N.; Giorgi, F. S.; Graziani, M.; Haberkamp, M.; Habert, M. O.; Hampel, H.; Herholz, K.; Karran, E.; Kim, S. H.; Koronyo, Y.; Koronyo-Hamaoui, M.; Lamari, F.; Langevin, T.; Lehericy, S.; Lista, S.; Lorenceau, J.; Mapstone, M.; Neri, C.; Nistico, R.; Nyasse-Messene, F.; O'Bryant, S. E.; Perry, G.; Ritchie, C.; Rojkova, K.; Rossi, S.; Santarnecchi, E.; Schneider, L. S.; Sporns, O.; Toschi, N.; Verdooner, S. R.; Vergallo, A.; Villain, N.; Welikovitch, L.; Woodcock, J.; Younesi, E

Sex differences in functional and molecular neuroimaging biomarkers of Alzheimer's disease in cognitively normal older adults with subjective memory complaints

Introduction: Observational multimodal neuroimaging studies indicate sex differences in Alzheimer's disease pathophysiological markers. Methods: Positron emission tomography brain amyloid load, neurodegeneration (hippocampus and basal forebrain volumes adjusted to total intracranial volume, cortical thickness, and 2-deoxy-2-[fluorine-18]fluoro-D-glucose–positron emission tomography metabolism), and brain resting-state functional connectivity were analyzed in 318 cognitively intact older adults from the INSIGHT-preAD cohort (female n = 201, male n = 117). A linear mixed-effects model was performed to investigate sex effects and sex∗apolipoprotein E genotype interaction on each marker as well as sex∗amyloid group interaction for non-amyloid markers. Results: Men compared with women showed higher anterior cingulate cortex amyloid load (P =.009), glucose hypometabolism in the precuneus (P =.027), posterior cingulate (P <.001) and inferior parietal (P =.043) cortices, and lower resting-state functional connectivity in the default mode network (P =.024). No brain volumetric markers showed differences between men and women. Sex∗apolipoprotein E genotype and sex∗amyloid status interactions were not significant. Discussion: Our findings suggest that cognitively intact older men compared with women have higher resilience to pathophysiological processes of Alzheimer's disease