Medial temporal lobe hyperconnectivity is key to Alzheimer’s disease: Insight from physiological aging to dementia

Abstract

AbstractCuring Alzheimer’s disease (AD) remains hampered by an incomplete understanding of its pathophysiology and progression. Dysfunction within medial temporal lobe networks may provide key insights, as AD proteins seem to propagate specifically through the anterior-temporal (AT) and posterior-medial (PM) systems. Using monocentric longitudinal data from 267 participants spanning physiological aging to the full AD continuum, we found that advancing age was associated with decreased PM connectivity and increased AT connectivity over adult life. When specifically assessing AD-relevant connectivity changes, all AD-associated clinicopathological features, including elevated amyloid burden, AD-typical glucose hypometabolism, hippocampal atrophy, greater cognitive impairment and faster progression from MCI to AD-dementia, were consistently linked to AT hyperconnectivity in healthy to AD-demented older adults. Our comprehensive approach allowed us to reveal that excessive connectivity within the AT network is a pivotal mechanism catalysing pathological process and progression of AD. Such findings hold promise for early diagnosis and therapeutic strategies targeting these specific network alterations.