Anterior-temporal network hyperconnectivity is key to Alzheimer’s disease: from ageing to dementia

Abstract Curing Alzheimer's disease remains hampered by an incomplete understanding of its pathophysiology and progression. Exploring dysfunction in medial temporal lobe networks, particularly the anterior-temporal (AT) and posterior-medial (PM) systems, might provide key insights, because these networks exhibit alterations in functional connectivity along the entire Alzheimer's continuum, potentially influencing disease propagation. However, the specific changes in each network and their clinical relevance across stages are not yet fully understood. This requires consideration of commonly used biomarkers, clinical progression, individual variability and age confounds. Here, we leveraged monocentric longitudinal data from 261 participants spanning the adult lifespan and the Alzheimer's continuum. The sample included cognitively unimpaired adults aged 19–85 years (n = 209; 8 of 64 older adults >60 years of age were amyloid-β-positive) and amyloid-β-positive patients fulfilling diagnostic criteria for mild cognitive impairment (MCI, n = 26; 18 progressed to Alzheimer-dementia within 7 years) or Alzheimer's-type dementia (n = 26). Participants underwent structural and resting-state functional MRI, florbetapir and 18F-fluorodeoxyglucose-PET and global cognitive assessments, with up to three visits over a maximum period of 47 months. Network connectivity was assessed using seed-based analyses with the perirhinal and parahippocampal cortices as seeds, within data-driven masks reflecting the AT and PM networks. Generalized additive and linear mixed models were run to assess age-specific effects and Alzheimer's-related alterations. In this context, we explored various markers of pathological and clinical severity, including cerebral amyloid uptake, glucose metabolism, hippocampal volume, global cognition, diagnostic staging and time to dementia onset. Our findings revealed distinct patterns of connectivity linked to normal ageing or Alzheimer's disease. Advancing age throughout adulthood was associated with lower PM connectivity and more subtle changes in AT connectivity, and Alzheimer's disease was characterized by AT hyperconnectivity without global changes in PM connectivity. Specifically, AT connectivity was higher in MCI and Alzheimer-dementia patients compared with older controls and was positively associated with amyloid burden, glucose hypometabolism, hippocampal atrophy and global cognitive deficits in older adults, ranging from unimpaired to demented. Additionally, higher AT connectivity was correlated with faster progression to Alzheimer-dementia in MCI patients. This comprehensive approach allowed us to reveal that excessive connectivity within the AT network is linked intrinsically to the pathological and clinical progression of Alzheimer's disease. These insights might guide future research to a better understanding of cascading events leading to the disease and hold promise for developing prognostic tools and therapeutic interventions targeting these specific network alterations.