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Cereb Cortex. 2019 Dec 4. pii: bhz224. doi: 10.1093/cercor/bhz224. [Epub ahead of print]

Atrophy of Basal Forebrain Initiates with Tau Pathology in Individuals at Risk for Alzheimer's Disease.

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Laboratory of Functional Neuroscience, Pablo de Olavide University, 41013 Seville, Spain.
CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, 28031 Madrid, Spain.
Service of Neurology, IDIVAL, University Hospital Marques de Valdecilla, University of Cantabria, 39008 Santander, Spain.
Center for Molecular and Behavioral Neuroscience, Rutgers, The State University of New Jersey, Newark, 07102 NJ, USA.
Department of Neurology, Institut d'Investigacions Biomediques Sant Pau-Hospital Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, 08025 Barcelona, Spain.


Evidence suggests that the basal forebrain (BF) cholinergic system degenerates early in the course of Alzheimer's disease (AD), likely due to the vulnerability of BF cholinergic neurons to tau pathology. However, it remains unclear whether the presence of tauopathy is the only requirement for initiating the BF degeneration in asymptomatic subjects at risk for AD (AR-AD), and how BF structural deficits evolve from normal aging to preclinical and prodromal AD. Here, we provide human in vivo magnetic resonance imaging evidence supporting that abnormal cerebrospinal fluid levels of phosphorylated tau (T+) are selectively associated with bilateral volume loss of the nucleus basalis of Meynert (nbM, Ch4) in AR-AD individuals. Spreading of atrophy to medial septum and vertical limb of diagonal band Broca (Ch1-Ch2) occurred in both preclinical and prodromal AD. With the exception of A+, all groups revealed significant correlations between volume reduction of BF cholinergic compartments and atrophy of their innervated regions. Overall, these results support the central role played by tauopathy in instigating the nbM degeneration in AR-AD individuals and the necessary coexistence of both AD proteinopathies for spreading damage to larger BF territories, thus affecting the core of the BF cholinergic projection system.


basal forebrain; biomarkers, cholinergic system; magnetic resonance imaging; nucleus basalis Meynert; preclinical Alzheimer’s disease


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