Selective vulnerability of human basal forebrain subsystems in ageing and neuropsychiatric disorders
- 1University of Oxford
Abstract
INTRODUCTIONThe basal forebrain (BF) provides the principal cholinergic innervation to the cortex and the hippocampus and is among the earliest regions affected by neurodegenerative processes. Yet, whether its subnuclei differ in how their structural integrity changes with age and in their vulnerability to neurological and psychiatric disorders is unresolved.
METHODSHere, in 81,870 UK Biobank participants aged 45-87 years, we built age- and sex-specific normative models of grey-matter volume in the nucleus basalis of Meynert (Ch4) and the septal/diagonal-band (Ch1-3) compartments of the BF and derived individual deviation from these norms. We then tested the selectivity of their normative deviation profile across cross-sectional and longitudinal ageing, manifest neurological and psychiatric disorders, pre-diagnostic neurodegeneration, prospective disease incidence, and neuropsychiatric polygenic liability.
RESULTSThe two compartments followed distinguishable age-related profiles across mid-to-late adulthood, which persisted when examined using longitudinal data. Deviation from norms was generally concentrated in Ch4 across neurological diseases and, in almost no condition, greater in the Ch1-3. The Ch4 deficit was further detectable years before diagnosis, was not substantially explained by common inherited genetic risk, and was linked with incident dementia and Parkinsons disease, whereas Ch1-3 carried no independent prospective structural vulnerability.
DISCUSSIONThese findings identify an anatomically specific age-related profile of the human BF, with structural vulnerability manifest and pre-diagnostic neurological disorders, which is not substantially explained by common inherited risk.
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BibTeX
@misc{eisenstein2026selective,
title = {{Selective vulnerability of human basal forebrain subsystems in ageing and neuropsychiatric disorders}},
author = {T. Eisenstein and M. T. Hu and J. C. Klein},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.13.26365385},
url = {https://www.medrxiv.org/content/10.64898/2026.10.13.26365385v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Selective vulnerability of human basal forebrain subsystems in ageing and neuropsychiatric disorders
AU - T. Eisenstein
AU - M. T. Hu
AU - J. C. Klein
PY - 2026
DA - 2026/10/13
PB - medRxiv
DO - 10.64898/2026.10.13.26365385
UR - https://www.medrxiv.org/content/10.64898/2026.10.13.26365385v1
AB - INTRODUCTIONThe basal forebrain (BF) provides the principal cholinergic innervation to the cortex and the hippocampus and is among the earliest regions affected by neurodegenerative processes. Yet, whether its subnuclei differ in how their structural integrity changes with age and in their vulnerability to neurological and psychiatric disorders is unresolved. METHODSHere, in 81,870 UK Biobank participants aged 45-87 years, we built age- and sex-specific normative models of grey-matter volume in the nucleus basalis of Meynert (Ch4) and the septal/diagonal-band (Ch1-3) compartments of the BF and derived individual deviation from these norms. We then tested the selectivity of their normative deviation profile across cross-sectional and longitudinal ageing, manifest neurological and psychiatric disorders, pre-diagnostic neurodegeneration, prospective disease incidence, and neuropsychiatric polygenic liability. RESULTSThe two compartments followed distinguishable age-related profiles across mid-to-late adulthood, which persisted when examined using longitudinal data. Deviation from norms was generally concentrated in Ch4 across neurological diseases and, in almost no condition, greater in the Ch1-3. The Ch4 deficit was further detectable years before diagnosis, was not substantially explained by common inherited genetic risk, and was linked with incident dementia and Parkinsons disease, whereas Ch1-3 carried no independent prospective structural vulnerability. DISCUSSIONThese findings identify an anatomically specific age-related profile of the human BF, with structural vulnerability manifest and pre-diagnostic neurological disorders, which is not substantially explained by common inherited risk.
ER -