Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity

TLDR

The precise brain region where amyloid‑β fibrils first accumulate in Alzheimer's disease remains unknown. The study seeks to identify the earliest preclinical Alzheimer's disease stage in participants from the ADNI and BioFINDER cohorts. Researchers employed CSF Aβ42 measurements and amyloid PET imaging from these cohorts to detect early amyloid deposition. Aβ accumulation initiates earliest in core default‑mode network regions—precuneus, medial orbitofrontal, and posterior cingulate—before CSF or PET abnormalities, and is associated with reduced connectivity within the DMN and between the DMN and frontoparietal network, without concurrent atrophy or hypometabolism.

Abstract

It is not known exactly where amyloid-β (Aβ) fibrils begin to accumulate in individuals with Alzheimer's disease (AD). Recently, we showed that abnormal levels of Aβ42 in cerebrospinal fluid (CSF) can be detected before abnormal amyloid can be detected using PET in individuals with preclinical AD. Using these approaches, here we identify the earliest preclinical AD stage in subjects from the ADNI and BioFINDER cohorts. We show that Aβ accumulation preferentially starts in the precuneus, medial orbitofrontal, and posterior cingulate cortices, i.e., several of the core regions of the default mode network (DMN). This early pattern of Aβ accumulation is already evident in individuals with normal Aβ42 in the CSF and normal amyloid PET who subsequently convert to having abnormal CSF Aβ42. The earliest Aβ accumulation is further associated with hypoconnectivity within the DMN and between the DMN and the frontoparietal network, but not with brain atrophy or glucose hypometabolism. Our results suggest that Aβ fibrils start to accumulate predominantly within certain parts of the DMN in preclinical AD and already then affect brain connectivity.