Resting-State Functional Connectivity Disruption as a Pathological Biomarker in Autosomal Dominant Alzheimer Disease

Abstract

AIM\nIdentify a global resting state functional connectivity (gFC) signature in mutation carriers (MC) from the Dominantly Inherited Alzheimer Network (DIAN). Assess the gFC with regards to amyloid (A), tau (T), and neurodegeneration (N) biomarkers and estimated years to symptom onset (EYO).\n\n\nINTRODUCTION\nCross-sectional measures were assessed in MC (n=171) and mutation non-carriers (NC) (n=70) participants. A FC matrix that encompassed multiple resting state networks (RSNs) was computed for each participant.\n\n\nMETHODS\nA gFC was compiled as a single index indicating functional connectivity strength. Global FC signature was modeled as a non-linear function of EYO. gFC was linearly associated with other biomarkers used for assessing the AT(N) framework including: cerebrospinal fluid (CSF), positron emission tomography (PET) molecular biomarkers, and structural magnetic resonance imaging.\n\n\nRESULTS\nThe gFC was reduced in MC compared to NC participants. When MC participants were differentiated by clinical dementia rating (CDR), the gFC was significantly decreased in MC CDR > 0 (demented) compared to either MC CDR 0 (cognitively normal) or NC participants. The gFC varied non-linearly with EYO and initially decreased at EYO = -24 years, followed by a stable period followed by a further decline near EYO =0 years. Irrespective of EYO, a lower gFC associated with values of amyloid PET, CSF Aβ1-42, CSF p-tau, CSF t-tau, FDG and hippocampal volume.\n\n\nCONCLUSIONS\nThe gFC correlated with biomarkers used for defining the AT(N) framework. A biphasic change in the gFC suggested early changes associated with CSF amyloid and later changes associated with hippocampal volume.