Amyloid-β and tau pathologies relate to distinctive brain dysconnectomics in preclinical autosomal-dominant Alzheimer’s disease

• Published in: Proceedings of the National Academy of Sciences - PNAS 2022-04, Vol.119 (15), p.1-8
• Main Authors: Guzmán-Vélez, Edmarie, Diez, Ibai, Schoemaker, Dorothee, Pardilla-Delgado, Enmanuelle, Vila-Castelar, Clara, Fox-Fuller, Joshua T., Baena, Ana, Sperling, Reisa A., Johnson, Keith A., Lopera, Francisco, Sepulcre, Jorge, Quiroz, Yakeel T.
• Format: Article
• Language: English
• Subjects: Age; Alzheimer Disease - diagnostic imaging; Alzheimer Disease - genetics; Alzheimer Disease - physiopathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Biological Sciences; Brain; Brain - diagnostic imaging; Brain architecture; Cognitive ability; Cognitive Dysfunction - diagnostic imaging; Connectome; Cortex (cingulate); Cortex (parietal); Cortex (temporal); Dementia; Dementia disorders; Heterozygote; Humans; In vivo methods and tests; Integration; Magnetic Resonance Imaging - methods; Memory Disorders - diagnostic imaging; Memory Disorders - genetics; Memory, Episodic; Mutation; Neostriatum; Neural networks; Neurodegenerative diseases; Pathology; Positron-Emission Tomography - methods; Prefrontal cortex; Presenilin 1; Presenilin-1 - genetics; Salience; Tau protein; tau Proteins - metabolism; Thalamus; Topology; β-Amyloid
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2113641119

The human brain is composed of functional networks that have a modular topology, where brain regions are organized into communities that form internally dense (segregated) and externally sparse (integrated) subnetworks that underlie higher-order cognitive functioning. It is hypothesized that amyloid-β and tau pathology in preclinical Alzheimer’s disease (AD) spread through functional networks, disrupting neural communication that results in cognitive dysfunction. We used high-resolution (voxel-level) graph-based network analyses to test whether in vivo amyloid-β and tau burden was associated with the segregation and integration of brain functional connections, and episodic memory, in cognitively unimpaired Presenilin-1 E280A carriers who are expected to develop early-onset AD dementia in ∼13 y on average. Compared to noncarriers, mutation carriers exhibited less functional segregation and integration in posterior default-mode network (DMN) regions, particularly the precuneus, and in the retrospenial cortex, which has been shown to link medial temporal regions and cortical regions of the DMN. Mutation carriers also showed greater functional segregation and integration in regions connected to the salience network, including the striatum and thalamus. Greater tau burden was associated with lower segregated and integrated functional connectivity of DMN regions, particularly the precuneus and medial prefrontal cortex. In turn, greater tau pathology was related to higher segregated and integrated functional connectivity in the retrospenial cortex and the anterior cingulate cortex, a hub of the salience network. These findings enlighten our understanding of how AD-related pathology distinctly alters the brain’s functional architecture in the preclinical stage, possibly contributing to pathology propagation and ultimately resulting in dementia.