Early β-amyloid accumulation and hypoconnectivity in the default mode network are related to its disengagement from global brain activity
Authors: Han Feng , Liu Xufu , Mailman Richard B. , Huang Xuemei , Liu Xiao ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: July 2022

AbstractImportanceThe specific pattern/trajectory of β-amyloid (Aβ) pathology spreading in Alzheimer’s disease (AD), from default mode network (DMN) regions to sensory-motor areas, is well known, but poorly understood.ObjectiveTo determine if resting-state global brain activity is linked to early Aβ deposition in the DMN.DesignThis is a retrospect analysis of multi-modal and longitudinal data from the Alzheimer’s disease Neuroimaging Initiative (ADNI) cohort.SettingThe ADNI was a multicenter project involving 63 research centers.ParticipantsThe study included 144 participants (72.6 ± 7.5 years; 73 females) of whom 28 were controls, 21 had significant memory concerns, 72 had cognitive impairment (N=72), and 23 had AD. There were both baseline and 2-year follow-up data for Aβ-PET for 112 of the subjects. They were classified into following stages based on the CSF Aβ42 (CSF+: <192 ng/L) and cortical Aβ (PET+: >0.872 SUVR) levels: non-Aβ-accumulators (CSF-/PET-); early-Aβ-accumulators (CSF+/PET-); and late-Aβ-accumulators (CSF+/PET+).ExposureResting-state brain activity was assessed by functional magnetic resonance imaging (rsfMRI), whereas glymphatic function was estimated by the coupling between fMRI blood-oxygen-level-dependent (BOLD) signals and CSF movements.Main Outcomes and MeasuresCortical Aβ accumulation measured by18F-AV45 amyloid-positron emission tomography (PET), CSF Aβ42, and total and phosphorylated tau protein levels in all participants.ResultsGlymphatic function assessed by fMRI was strongly (ρ > 0.43,P< 0.042) associated with various markers of protein aggregation in early Aβ accumulators in whom Aβ just begins to accumulate cortically in the DMN. Among these early accumulators, the preferential Aβ accumulation in the DMN regions in the subsequent two years was correlated with lower gBOLD signal (ρ = 0.51,P= 0.027) and lower local glymphatic function (ρ = 0.48,P= 0.041) in the same regions at baseline.Conclusions and RelevanceResting-state global brain activity and related glymphatic function are linked to Aβ pathology, particularly its preferential deposition in the DMN at the earliest AD stages. This suggests potential novel early therapeutic directions that might provide disease modification.KeyPointsQuestionWhy does the β-amyloid (Aβ) plaque deposit preferentially in the default mode network (DMN) regions at early preclinical stages of Alzheimer’s disease?FindingsIn this analytic observational cohort study with 144 subjects, we found that the preferential reduction of global resting-state brain activity in the DMN, as well as its coupling with cerebrospinal fluid movement, was significantly correlated with the preferential Aβ accumulation in these DMN regions among 19 subjects with early Aβ accumulation.MeaningResting-state global brain activity plays a role in the early Aβ accumulation in the DMN, presumably due to its involvement in glymphatic clearance.