Early β-amyloid accumulation and hypoconnectivity in the default mode network are related to its disengagement from global brain activity

Importance The 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. Objective To determine if resting-state global brain activity is linked to early Aβ deposition in the DMN. Design This is a retrospect analysis of multi-modal and longitudinal data from the Alzheimer’s disease Neuroimaging Initiative (ADNI) cohort. Setting The ADNI was a multicenter project involving 63 research centers. Participants The 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+). Exposure Resting-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 Measures Cortical Aβ accumulation measured by [18][1]F-AV45 amyloid-positron emission tomography (PET), CSF Aβ42, and total and phosphorylated tau protein levels in all participants. Results Glymphatic 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 Relevance Resting-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. Question Why does the β-amyloid (Aβ) plaque deposit preferentially in the default mode network (DMN) regions at early preclinical stages of Alzheimer’s disease? Findings In 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. Meaning Resting-state global brain activity plays a role in the early Aβ accumulation in the DMN, presumably due to its involvement in glymphatic clearance. ### Competing Interest Statement Richard B. Mailman: 1. Unrelated research funding: National Institutes of Health (R01 NS105471). 2. Unrelated: Holds patents related to D1 dopamine agonists as therapeutic agents (not being prosecuted). Past D1-related grant, consulting, and travel from Pfizer Central Research (none since 2017). Received travel expenses from Cerevel Therapeutics in 2019 and 2022. Consultant to Cerevel Therapeutics (2022-present). Past expert witness or consultant to several law firms and US Department of Justice. Past consultant to Jazz Pharma (publishing costs only). The Penn State College of Medicine actively manages Dr. Mailman's disclosed potential conflicts of interest. Xuemei Huang: 1. Unrelated research: Michael J. Fox Foundation for Parkinson's Research; Bristol Myers Squibb/Biogen; Pfizer. 2. Unrelated: Has interest in patents related to D1 technology that are not being actively prosecuted; this conflict of interest has been disclosed to, and managed by, the Penn State University. * Aβ : β-amyloid AD : Alzheimer’s disease ADNI : Alzheimer’s Disease Neuroimaging Initiative APOE : apolipoprotein E AQP4 : astroglial aquaporin-4 BOLD : blood-oxygen-level-dependent CSF : cerebrospinal fluid DMN : default mode network EPI : echo-planar image FC : functional connectivity FPN : frontoparietal network FWHM : full width at half maximum gBOLD : global BOLD IIH : Idiopathic intracranial hypertension MCI : mild cognitive impairment MNI-152 : 152-brain Montreal Neurological Institute MRI : Magnetic resonance imaging PD : Parkinson’s disease PET : positron emission tomography PG : principal gradient P-tau : phosphorylated tau rBOLD : regional BOLD rsfMRI : resting-state fMRI SM : somatosensory SMC : significant memory concern SUVR : Standardized uptake value ratio T-tau : total tau TE : echo time TR : repetition time [1]: #ref-18