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Selective vulnerability of human basal forebrain subsystems in ageing and neuropsychiatric disorders
Eisenstein T, Hu MT, Klein JC.. medRxiv, 2026-10-15
Topic: Brain imaging, connectivity and assessment
INTRODUCTION The 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. METHODS Here, 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. RESULTS The 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 Parkinson’s disease, whereas Ch1–3 carried no independent prospective structural vulnerability. DISCUSSION These 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.
Key findings
- RESULTS The two compartments followed distinguishable age-related profiles across mid-to-late adulthood, which persisted when examined using longitudinal data.
- DISCUSSION These 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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Study details
- Study designcross-sectional
- Evidence strengthModerate
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 31 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 19 of the 62 points we could judge it on, which is 31 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (medRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 4 / 12 | A snapshot of people at one point in time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 19 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 19 of the 62 points we could judge it on is 31 out of 100. |
| Total | 31 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Eisenstein, T., Hu, M. T., & Klein, J. C. (2026). Selective vulnerability of human basal forebrain subsystems in ageing and neuropsychiatric disorders. medRxiv. https://doi.org/10.64898/2026.10.13.26365385
Vancouver
Eisenstein T, Hu MT, Klein JC. Selective vulnerability of human basal forebrain subsystems in ageing and neuropsychiatric disorders. medRxiv. 2026. doi:10.64898/2026.10.13.26365385.
BibTeX
@article{eisenstein2026-bec5f4b9,
author = {Eisenstein, T. and Hu, M. T. and Klein, J. C.},
title = {{Selective vulnerability of human basal forebrain subsystems in ageing and neuropsychiatric disorders}},
journal = {medRxiv},
year = {2026},
doi = {10.64898/2026.10.13.26365385},
url = {https://doi.org/10.64898/2026.10.13.26365385}
}
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