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Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Here we examined whether longitudinal decreases in basal forebrain and entorhinal cortex grey matter volume were interdependent and sequential. In a large cohort of age-matched older adults ranging from cognitively normal to AD, we demonstrate that basal forebrain volume predicts longitudinal entorhinal degeneration.
Models of parallel degeneration or entorhinal origin received negligible support. We then integrated volumetric measures with an amyloid biomarker sensitive to pre-symptomatic AD pathology. Comparison between cognitively matched normal adult subgroups, delineated according to the amyloid biomarker, revealed abnormal degeneration in basal forebrain, but not entorhinal cortex.
Abnormal degeneration in both basal forebrain and entorhinal cortex was only observed among prodromal mildly amnestic individuals. We provide evidence that basal forebrain pathology precedes and predicts both entorhinal pathology and memory impairment, challenging the widely held belief that AD has a cortical origin.
Recent breakthroughs in molecular genetics have identified a trans -synaptic mechanism by which these pathologies spread across anatomically and functionally linked cortical regions 1 , 2 , 3 , 4 within a large-scale brain network 5 , 6 , 7. These findings have potential for novel biomarkers and therapeutic strategies aimed at identifying the earliest signs of pathology and preventing its spread, before the onset of clinical AD.