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Mol Psychiatry. 2017 Feb;22(2):306-311. doi: 10.1038/mp.2016.37. Epub 2016 Mar 29.

Amyloid-β and hyperphosphorylated tau synergy drives metabolic decline in preclinical Alzheimer's disease.

Author information

1
Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Douglas Hospital, McGill University, Montreal, QC, Canada.
2
CAPES Foundation, Ministry of Education of Brazil, Brasília, Brazil.
3
Montreal Neurological Institute, Montreal, QC, Canada.
4
Douglas Hospital Research Centre, McGill University, Montreal, QC, Canada.
5
Department of Epidemiology, Biostatistics & Occupational Health, McGill University, Montreal, QC, Canada.
6
Department of Psychiatry, McGill University Faculty of Medicine, Montreal, QC, Canada.
7
Alzheimer's Disease Research Unit, The McGill University Research Centre for Studies in Aging, Montreal, McGill University, Montreal, QC, Canada.
8
Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.

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-β1-42 and 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.

PMID:
27021814
PMCID:
PMC5262471
DOI:
10.1038/mp.2016.37
[Indexed for MEDLINE]
Free PMC Article

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