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

This study was designed to test the interaction between amyloid-beta and tau proteins as a determinant of metabolic decline in preclinical Alzheimer's disease (AD). We assessed 120 cognitively normal individuals with [F-18] florbetapir positron emission tomography (PET) and cerebrospinal fluid (CSF) measurements at baseline, as well as [F-18] fluorodeoxyglucose ([F-18]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, [F-18] florbetapir and [F-18] FDG standardized uptake value ratios (SUVR). We found that the synergistic interaction between [F-18] 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-beta(1-42) 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-beta 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-beta plaques and neurofibrillary tangles. Preventive clinical trials may benefit from using a combination of amyloid-beta PET and p-tau biomarkers to enrich study populations of cognitively normal subjects with a high probability of disease progression in studies, using [F-18] FDG as a biomarker of efficacy.