title: Amyloid-β and hyperphosphorylated tau synergy drives metabolic decline in preclinical Alzheimer's disease.
abstract: This study was designed to test the interaction between amyloid-β and tau proteins as a determinant of metabolic decline in preclinical Alzheimer's disease (AD). We assessed 120 cognitively normal individuals with [18F]florbetapir positron emission tomography (PET) and cerebrospinal fluid (CSF) measurements at baseline, as well as [18F]fluorodeoxyglucose ([18F]FDG) PET at baseline and at 24 months. A voxel-based interaction model was built to test the associations between continuous measurements of CSF biomarkers, [18F]florbetapir and [18F]FDG standardized uptake value ratios (SUVR). We found that the synergistic interaction between [18F]florbetapir SUVR and CSF phosphorylated tau (p-tau) measurements, rather than the sum of their independent effects, was associated with a 24-month metabolic decline in basal and mesial temporal, orbitofrontal, and anterior and posterior cingulate cortices (P<0.001). In contrast, interactions using CSF amyloid-β1-42and total tau biomarkers did not associate with metabolic decline over a time frame of 24 months. The interaction found in this study further support the framework that amyloid-β and hyperphosphorylated tau aggregates synergistically interact to cause downstream AD neurodegeneration. In fact, the regions displaying the metabolic decline reported here were confined to brain networks affected early by amyloid-β plaques and neurofibrillary tangles. Preventive clinical trials may benefit from using a combination of amyloid-β PET and p-tau biomarkers to enrich study populations of cognitively normal subjects with a high probability of disease progression in studies, using [18F]FDG as a biomarker of efficacy.
authors.affiliation: Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Douglas Hospital, McGill University, Montreal, QC, Canada.
authors.forename: T A
authors.initials: TA
authors.lastname: Pascoal
authors.affiliation: Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Douglas Hospital, McGill University, Montreal, QC, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Mathotaarachchi
authors.affiliation: Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Douglas Hospital, McGill University, Montreal, QC, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Mohades
authors.affiliation: Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Douglas Hospital, McGill University, Montreal, QC, Canada.|CAPES Foundation, Ministry of Education of Brazil, Brasília, Brazil.
authors.forename: A L
authors.initials: AL
authors.lastname: Benedet
authors.affiliation: Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Douglas Hospital, McGill University, Montreal, QC, Canada.
authors.forename: C-O
authors.initials: CO
authors.lastname: Chung
authors.affiliation: Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Douglas Hospital, McGill University, Montreal, QC, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Shin
authors.affiliation: Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Douglas Hospital, McGill University, Montreal, QC, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.affiliation: Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Douglas Hospital, McGill University, Montreal, QC, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Beaudry
authors.affiliation: Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Douglas Hospital, McGill University, Montreal, QC, Canada.
authors.forename: M S
authors.initials: MS
authors.lastname: Kang
authors.affiliation: Montreal Neurological Institute, Montreal, QC, Canada.
authors.forename: J-P
authors.initials: JP
authors.lastname: Soucy
authors.affiliation: Douglas Hospital Research Centre, McGill University, Montreal, QC, Canada.|Department of Epidemiology, Biostatistics & Occupational Health, McGill University, Montreal, QC, Canada.|Department of Psychiatry, McGill University Faculty of Medicine, Montreal, QC, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Labbe
authors.affiliation: Alzheimer's Disease Research Unit, The McGill University Research Centre for Studies in Aging, Montreal, McGill University, Montreal, QC, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Gauthier
authors.affiliation: Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Douglas Hospital, McGill University, Montreal, QC, Canada.|Montreal Neurological Institute, Montreal, QC, Canada.|Alzheimer's Disease Research Unit, The McGill University Research Centre for Studies in Aging, Montreal, McGill University, Montreal, QC, Canada.|Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
authors.forename: P
authors.identifier: 0000-0001-9116-1376
authors.initials: P
authors.lastname: Rosa-Neto
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D003071:Cognition / Q000502:physiology; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods; D016875:tau Proteins / Q000134:cerebrospinal fluid / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D016875:tau Proteins; D019788:Fluorodeoxyglucose F18