Reductions in brainstem volume as a key macrostructural indicator in at-risk populations for Alzheimer’s disease

Tom Lancaster; Kevin Murphy; Hannah L. Chandler

doi:10.1186/s13195-025-01829-0

Reductions in brainstem volume as a key macrostructural indicator in at-risk populations for Alzheimer’s disease

Tom Lancaster
, Kevin Murphy
, Hannah L. Chandler

Department of Psychology

Cardiff University

Research output: Contribution to journal › Article › peer-review

Abstract

Background
Alterations to brain macrostructure, assessed via T1-weighted magnetic resonance imaging are observed in preclinical models of Alzheimer’s disease (AD), reflecting susceptibility, prodromal stages of AD or correlates of early AD pathophysiology. While changes in cingulate and medial temporal lobe structures may be functionally implicated in cognitive decline, little is known about the viability of brain-based biomarkers that support autonomic functions implicated in preclinical AD risk such as the brainstem.

Methods
In a series of multiple linear regressions, we assess the volume of the brainstem in two asymptomatic at-AD-risk samples, assessed via the presence of either mild cognitive impairment (MCI, N = 148), or extremely high polygenic risk (N = 13) with matched demographics (mean age = 67 [range 58–76], in both cases). We further determine the strength of the association, compared to 150 other structural MRI features.

Results
We observed brainstem volume reductions (MCI: b = -0.29, P = 0.018; Genetic risk: b = -1.29, P = 0.002) in both samples. The magnitude of each preclinical AD marker (MCI / AD-polygenic risk)– brainstem association was empirically larger (Z > 2.3, P < 0.05, in both cases) than 150 frequently segmented MRI features. We further replicate the negative AD-polygenic risk score– brainstem association in UK Biobank (N = 31968; b = -0.002, P = 0.03), with weaker evidence that the association was larger than all other MRI features (Z = 1.622; P = 0.052).

Conclusions
These observations suggest that AD risk, assessed via the presence of MCI or extremely high AD-polygenic risk score is linked to reduced brainstem volume before most typically observed morphological brain alterations. This conforms with evidence implicating the brainstem as one of the earliest sites of morphological neurodegeneration and provides a plausible biological mechanism linking prodromal autonomic symptoms to AD risk in later life. These observations warrant future investigation into the molecular correlates of AD-linked brainstem dysfunction, assessment as a candidate biomarker, and the exploration of brainstem mediated treatment strategies in AD prevention.

Original language	English
Article number	177
Journal	Alzheimer's Research and Therapy
Volume	17
Early online date	26 Jul 2025
DOIs	https://doi.org/10.1186/s13195-025-01829-0
Publication status	Published - 26 Jul 2025

Data Availability Statement

Research reported in this publication was supported by the National Institute On Aging of the National Institutes of Health under Award Number U01AG052564 and by funds provided by the McDonnell Center for Systems Neuroscience at Washington University in St. Louis. The HCP-Aging 2.0 Release data used in this report came from DOI: 10.15154/1520707.

Acknowledgements

This study was supported by the National Institute for Health and Care Research (NIHR) Exeter Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Genotyping was performed at deCODE Genetics. This paper represents independent research part funded by the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London.

Funding

European Regional Development Fund - PNU-80762-CU-14; Wellcome Trust - 104943/Z/14/Z, 104943/Z/14/Z; Wellcome - WT224267, WT224267 TL acknowledges funding via Ser Cymru II fellowship [PNU-80762-CU-14]. HC funded by Wellcome Strategic Award [104943/Z/14/Z]. HC, KM are funded by a Wellcome Senior Fellowship [WT200804 and WT224267]. This work is supported by the UK Dementia Research Institute which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council (UKDRI-3003), Alzheimer’s Society and Alzheimer’s Research UK.

Keywords

Alzheimer’s disease
Mild cognitive impairment
Polygenic risk score
Brainstem
Preclinical
MRI

Access to Document

10.1186/s13195-025-01829-0Licence: CC BY

Cite this

@article{7ae955d651e1448aac07fd2282934aed,

title = "Reductions in brainstem volume as a key macrostructural indicator in at-risk populations for Alzheimer{\textquoteright}s disease",

abstract = "Background Alterations to brain macrostructure, assessed via T1-weighted magnetic resonance imaging are observed in preclinical models of Alzheimer{\textquoteright}s disease (AD), reflecting susceptibility, prodromal stages of AD or correlates of early AD pathophysiology. While changes in cingulate and medial temporal lobe structures may be functionally implicated in cognitive decline, little is known about the viability of brain-based biomarkers that support autonomic functions implicated in preclinical AD risk such as the brainstem. Methods In a series of multiple linear regressions, we assess the volume of the brainstem in two asymptomatic at-AD-risk samples, assessed via the presence of either mild cognitive impairment (MCI, N = 148), or extremely high polygenic risk (N = 13) with matched demographics (mean age = 67 [range 58–76], in both cases). We further determine the strength of the association, compared to 150 other structural MRI features. Results We observed brainstem volume reductions (MCI: b = -0.29, P = 0.018; Genetic risk: b = -1.29, P = 0.002) in both samples. The magnitude of each preclinical AD marker (MCI / AD-polygenic risk)– brainstem association was empirically larger (Z > 2.3, P < 0.05, in both cases) than 150 frequently segmented MRI features. We further replicate the negative AD-polygenic risk score– brainstem association in UK Biobank (N = 31968; b = -0.002, P = 0.03), with weaker evidence that the association was larger than all other MRI features (Z = 1.622; P = 0.052). Conclusions These observations suggest that AD risk, assessed via the presence of MCI or extremely high AD-polygenic risk score is linked to reduced brainstem volume before most typically observed morphological brain alterations. This conforms with evidence implicating the brainstem as one of the earliest sites of morphological neurodegeneration and provides a plausible biological mechanism linking prodromal autonomic symptoms to AD risk in later life. These observations warrant future investigation into the molecular correlates of AD-linked brainstem dysfunction, assessment as a candidate biomarker, and the exploration of brainstem mediated treatment strategies in AD prevention.",

keywords = "Alzheimer{\textquoteright}s disease, Mild cognitive impairment, Polygenic risk score, Brainstem, Preclinical, MRI",

author = "Tom Lancaster and Kevin Murphy and Chandler, \{Hannah L.\}",

year = "2025",

month = jul,

day = "26",

doi = "10.1186/s13195-025-01829-0",

language = "English",

volume = "17",

journal = "Alzheimer's Research and Therapy",

issn = "1758-9193",

publisher = "BioMed Central",

}

TY - JOUR

T1 - Reductions in brainstem volume as a key macrostructural indicator in at-risk populations for Alzheimer’s disease

AU - Lancaster, Tom

AU - Murphy, Kevin

AU - Chandler, Hannah L.

PY - 2025/7/26

Y1 - 2025/7/26

N2 - Background Alterations to brain macrostructure, assessed via T1-weighted magnetic resonance imaging are observed in preclinical models of Alzheimer’s disease (AD), reflecting susceptibility, prodromal stages of AD or correlates of early AD pathophysiology. While changes in cingulate and medial temporal lobe structures may be functionally implicated in cognitive decline, little is known about the viability of brain-based biomarkers that support autonomic functions implicated in preclinical AD risk such as the brainstem. Methods In a series of multiple linear regressions, we assess the volume of the brainstem in two asymptomatic at-AD-risk samples, assessed via the presence of either mild cognitive impairment (MCI, N = 148), or extremely high polygenic risk (N = 13) with matched demographics (mean age = 67 [range 58–76], in both cases). We further determine the strength of the association, compared to 150 other structural MRI features. Results We observed brainstem volume reductions (MCI: b = -0.29, P = 0.018; Genetic risk: b = -1.29, P = 0.002) in both samples. The magnitude of each preclinical AD marker (MCI / AD-polygenic risk)– brainstem association was empirically larger (Z > 2.3, P < 0.05, in both cases) than 150 frequently segmented MRI features. We further replicate the negative AD-polygenic risk score– brainstem association in UK Biobank (N = 31968; b = -0.002, P = 0.03), with weaker evidence that the association was larger than all other MRI features (Z = 1.622; P = 0.052). Conclusions These observations suggest that AD risk, assessed via the presence of MCI or extremely high AD-polygenic risk score is linked to reduced brainstem volume before most typically observed morphological brain alterations. This conforms with evidence implicating the brainstem as one of the earliest sites of morphological neurodegeneration and provides a plausible biological mechanism linking prodromal autonomic symptoms to AD risk in later life. These observations warrant future investigation into the molecular correlates of AD-linked brainstem dysfunction, assessment as a candidate biomarker, and the exploration of brainstem mediated treatment strategies in AD prevention.

AB - Background Alterations to brain macrostructure, assessed via T1-weighted magnetic resonance imaging are observed in preclinical models of Alzheimer’s disease (AD), reflecting susceptibility, prodromal stages of AD or correlates of early AD pathophysiology. While changes in cingulate and medial temporal lobe structures may be functionally implicated in cognitive decline, little is known about the viability of brain-based biomarkers that support autonomic functions implicated in preclinical AD risk such as the brainstem. Methods In a series of multiple linear regressions, we assess the volume of the brainstem in two asymptomatic at-AD-risk samples, assessed via the presence of either mild cognitive impairment (MCI, N = 148), or extremely high polygenic risk (N = 13) with matched demographics (mean age = 67 [range 58–76], in both cases). We further determine the strength of the association, compared to 150 other structural MRI features. Results We observed brainstem volume reductions (MCI: b = -0.29, P = 0.018; Genetic risk: b = -1.29, P = 0.002) in both samples. The magnitude of each preclinical AD marker (MCI / AD-polygenic risk)– brainstem association was empirically larger (Z > 2.3, P < 0.05, in both cases) than 150 frequently segmented MRI features. We further replicate the negative AD-polygenic risk score– brainstem association in UK Biobank (N = 31968; b = -0.002, P = 0.03), with weaker evidence that the association was larger than all other MRI features (Z = 1.622; P = 0.052). Conclusions These observations suggest that AD risk, assessed via the presence of MCI or extremely high AD-polygenic risk score is linked to reduced brainstem volume before most typically observed morphological brain alterations. This conforms with evidence implicating the brainstem as one of the earliest sites of morphological neurodegeneration and provides a plausible biological mechanism linking prodromal autonomic symptoms to AD risk in later life. These observations warrant future investigation into the molecular correlates of AD-linked brainstem dysfunction, assessment as a candidate biomarker, and the exploration of brainstem mediated treatment strategies in AD prevention.

KW - Alzheimer’s disease

KW - Mild cognitive impairment

KW - Polygenic risk score

KW - Brainstem

KW - Preclinical

KW - MRI

U2 - 10.1186/s13195-025-01829-0

DO - 10.1186/s13195-025-01829-0

M3 - Article

SN - 1758-9193

VL - 17

JO - Alzheimer's Research and Therapy

JF - Alzheimer's Research and Therapy

M1 - 177

ER -

Reductions in brainstem volume as a key macrostructural indicator in at-risk populations for Alzheimer’s disease

Abstract

Data Availability Statement

Acknowledgements

Funding

Keywords

Access to Document

Fingerprint

Cite this