Choroidal-ventricular system abnormalities are linked to amyloid-β aggregation in Alzheimer's disease

Seyyed Ali Hosseini^{1

2

3}, Etienne Aumont^{1

2

3}, Nesrine Rahmouni^{1

2

3}, Marcel S Woo^{1

4

5}, Arthur C Macedo^{1

2

3}, Brandon Hall^{1

2

3}, Tevy Chan^{1

2

3}, Joseph Therriault^{1

2

3}, Lydia Trudel^{1

2

3}, Yansheng Zheng^{1

2

3}, Gleb Bezgin^{1

2

3}, Aurélie Lebrun^{1

2

3}, Jaime Fernandez Arias^{1

2

3}, Kely Quispialaya Socualaya^{1

2

3}, Cécile Tissot⁶, Stijn Servaes^{1

2

3}, Yi-Ting Wang^{1

2

3}, Delphine Oliva-Lopez^{1

2

3}, Stuart Mitchell^{1

2

3}, Robert Hopewell^{1

3}, Chris Hung-Hsin Hsiao², Catherine Saleh², Jenna Stevenson³, Firoza Lussier⁷, Liyong Wu¹, Min Chu¹, Sanjeev Chawla⁸, Vladimir Fonov², Gassan Massarweh², Yasser Iturria Medina², Jean-Paul Soucy², Karine Provost², David A Rudko^{2

9}, Thomas Karikari^{7

10

11}, Andréa Lessa Benedet¹⁰, Nicholas J Ashton^{10

12

13

14}, Henrik Zetterberg^{10

15

16

17

18

19

20}, Maxime Montembeault³, Paolo Vitali², Kaj Blennow^{10

15

21

22}, Serge Gauthier^{2

3}, D Louis Collins², Jesse Klostranec²³, Tharick A Pascoal⁷, Pedro Rosa-Neto^{1

2

3

24}

Affiliations

¹ Translational Neuroimaging Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
² Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
³ The McGill University Research Center for Studies in Aging, Douglas Mental Health Institute, Montreal, Quebec, Canada.
⁴ Translational Neurodegeneration Laboratory, Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁵ Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg- Eppendorf, Hamburg, Germany.
⁶ Lawrence Berkeley National Laboratory, Berkeley, California, USA.
⁷ Department Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁸ Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁹ Department of Biomedical Engineering, McGill University, Montreal, Quebec, Canada.
¹⁰ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.
¹¹ Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
¹² Wallenberg Centre for Molecular Medicine, University of Gothenburg, Gothenburg, Sweden.
¹³ King's College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Institute Clinical Neuroscience Institute, London, UK.
¹⁴ NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK.
¹⁵ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
¹⁶ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
¹⁷ UK Dementia Research Institute at UCL, London, UK.
¹⁸ Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China.
¹⁹ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
²⁰ Centre for Brain Research, Indian Institute of Science, Bangalore, India.
²¹ Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.
²² Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, P.R. China.
²³ Department of Diagnostic and Interventional Neuroradiology, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
²⁴ Departments of Neurology and Radiology, The Peter O'Donnell Jr. Brain Institute (OBI), University of Texas Southwestern Medical Centre (UTSW), Dallas, Texas, USA.

PMID: 41738400
PMCID: PMC12933412
DOI: 10.1002/alz.71205

Choroidal-ventricular system abnormalities are linked to amyloid-β aggregation in Alzheimer's disease

Seyyed Ali Hosseini et al. Alzheimers Dement. 2026 Feb.

. 2026 Feb;22(2):e71205.

doi: 10.1002/alz.71205.

Authors

Affiliations

¹ Translational Neuroimaging Laboratory, McConnell Brain Imaging Centre, Montreal Neurological Institute Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
² Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
³ The McGill University Research Center for Studies in Aging, Douglas Mental Health Institute, Montreal, Quebec, Canada.
⁴ Translational Neurodegeneration Laboratory, Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁵ Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg- Eppendorf, Hamburg, Germany.
⁶ Lawrence Berkeley National Laboratory, Berkeley, California, USA.
⁷ Department Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁸ Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁹ Department of Biomedical Engineering, McGill University, Montreal, Quebec, Canada.
¹⁰ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.
¹¹ Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
¹² Wallenberg Centre for Molecular Medicine, University of Gothenburg, Gothenburg, Sweden.
¹³ King's College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Institute Clinical Neuroscience Institute, London, UK.
¹⁴ NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation, London, UK.
¹⁵ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
¹⁶ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
¹⁷ UK Dementia Research Institute at UCL, London, UK.
¹⁸ Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China.
¹⁹ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
²⁰ Centre for Brain Research, Indian Institute of Science, Bangalore, India.
²¹ Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.
²² Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, P.R. China.
²³ Department of Diagnostic and Interventional Neuroradiology, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
²⁴ Departments of Neurology and Radiology, The Peter O'Donnell Jr. Brain Institute (OBI), University of Texas Southwestern Medical Centre (UTSW), Dallas, Texas, USA.

PMID: 41738400
PMCID: PMC12933412
DOI: 10.1002/alz.71205

Abstract

Introduction: Enlargement of the choroidal-ventricular system occurs in aging and Alzheimer's disease (AD), but emerging evidence links these abnormalities to amyloid beta (Aβ) aggregation. We tested this hypothesis by assessing associations between AD pathophysiology and choroidal-ventricular system measures across the AD continuum.

Methods: Ventricular volume, choroid-plexus volume, and ventricular radioactivity after positron emission tomography (PET) tracer injections were analyzed in 385 Translational Biomarkers in Aging and Dementia (TRIAD) and 282 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants using linear models and partial correlations. A composite score combining these measures was also tested against established AD biomarkers.

Results: With advancing AD stages, ventricular and choroid-plexus volumes increased while ventricular radioactivity declined. These measures were interrelated, and abnormalities appeared even in amyloid-negative elderly. Across cohorts, they correlated with amyloid- and tau-PET, cerebrospinal fluid (CSF) and plasma p-tau isoforms, glial fibrillary acidic protein (GFAP), and cognition. Voxel-wise analyses showed strong associations with cortical Aβ, mediating downstream tau effects.

Discussion: Changes in the choroidal-ventricular system are mutually correlated and carry an additive-effect on cortical Aβ load.

Keywords: Alzheimer disease; amyloid‐beta; biomarkers; brain ventricles; cerebrospinal fluid; choroid plexus; cognition disorders; glial fibrillary acidic protein; neurodegenerative diseases; positron‐emission tomography; tau proteins.

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Conflict of interest statement

Henrik Zetterberg has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Enigma, LabCorp, Merck Sharp & Dohme, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, ScandiBio Therapeutics AB, Siemens Healthineers, Triplet Therapeutics, and Wave. He has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, LabCorp, Lilly, Novo Nordisk, Oy Medix Biochemica AB, Roche, and WebMD. He is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is part of the GU Ventures Incubator Program, and a shareholder of CERimmune Therapeutics (all outside the submitted work). Marcel S. Woo receives honoraria from Lilly and Eisai outside the scope of this manuscript. Karine Provost serves as consultant for Eli Lilly, Biospective, and Optina Diagnostics. All other authors declare no competing interests.

Figures

**FIGURE 1**
The overall trend of cerebrospinal fluid (CSF) clearance system parameter abnormality across A/T stages. CSF clearance system parameters including choroid plexus volume (CPV_corrected) and ventricular volume (VV_corrected), both corrected for intracranial volume (ICV), and ventricular radioactivity (VR) standardized uptake value ratio (SUVR) were Z scored and normalized based on the mean and standard deviation (SD) of Young Translational Biomarkers in Aging and Dementia (TRIAD) or cognitively unimpaired (CU) A−T− Alzheimer's Disease Neuroimaging Initiative (ADNI). CPV_corrected and VV_corrected enlargement and VR SUVR decline started due to aging and further abnormality observed due to Alzheimer's disease (AD) in the presence of amyloid‐beta (Aβ) and tau, in both cohorts.

**FIGURE 2**
The choroidal–ventricular parameters exhibited strong inter‐correlations with one another. Choroid plexus volume (CPV_corrected), ventricular volume (VV_corrected), and ventricular radioactivity (VR) standardized uptake value ratio (SUVR) were highly correlated with each other. Additionally, they showed strong inter‐correlations, with an overall correlation of β = 0.58 (p < 0.001) in Translational Biomarkers in Aging and Dementia (TRIAD) and β = 0.36 (p < 0.001) in Alzheimer's Disease Neuroimaging Initiative (ADNI). In this figure, due to the overall decline in VR, we reversed it for better visualization.

**FIGURE 3**
The choroidal–ventricular parameter composite score is strongly related to Alzheimer's disease (AD) pathophysiology. The choroidal–ventricular parameter composite score showed abnormality with aging and further alterations in AD across both cohorts with one‐way analysis of variance (ANOVA). "*", "**", and "***" represent Tukey post‐hoc tests following ANOVA for pairwise comparisons p‐values in the following ranges: 0.05 to 0.01, 0.01 to 0.001, and less than 0.001, respectively (A&D). Additionally, scatter plots show the relationship between the composite score and neocortical amyloid‐beta (Aβ) standardized uptake value ratio (SUVR) in the Translational Biomarkers in Aging and Dementia (TRIAD) cohort (B) and Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (E), stratified by biomarker‐defined groups: CU(Y) = cognitively normal young controls (green), A−T− (brown), A+T− (blue), and A+T+ (pink). Regression lines and Spearman correlation coefficients (r) with corresponding p‐values are displayed for each group. Spearman correlation p‐values were adjusted for multiple comparisons using the Benjamini–Hochberg false discovery rate (FDR) method, with q < 0.05 considered statistically significant. Point color intensity represents temporal tau SUVR, indicating higher tau burden in individuals with elevated choroidal–ventricular parameter composite scores and Aβ load. The composite score demonstrated strong positive associations with neocortical Aβ in preclinical and symptomatic A−T− groups, while no significant association was observed in CU(Y) individuals. Distinct patterns of association between the composite score and hippocampal volume (intracracial volume [ICV] ‐corrected) were observed across A/T stages (C&F), with no correlation in the A–T− group in TRIAD and no correlations across A/T stages in ADNI.

**FIGURE 4**
The choroidal–ventricular alterations evolve dynamically along the Alzheimer's disease (AD) continuum. The annualized change in the choroidal‐ventricular composite score (ΔComposite/year) across A/T stages in the combined Translational Biomarkers in Aging and Dementia plus Alzheimer's Disease Neuroimaging Initiative (TRIAD + ADNI) dataset increased stepwise from A−T− to A+T– and from A+T− to A+T+, indicating progressive choroidal‐ventricular remodeling along the AD continuum. "*", "**", and "***" represent Tukey post‐hoc tests following analysis of variance (ANOVA) for pairwise comparisons p‐values in the following ranges: 0.05 to 0.01, 0.01 to 0.001, and less than 0.001, respectively.

**FIGURE 5**
The choroidal–ventricular parameter composite score is an early change contributing to protein aggregation. In this conceptual framework, the x‐axis represents Braak stage rather than time. Unlike other Alzheimer's disease (AD) biomarker models, it does not depict a linear temporal progression of the disease. Instead, it illustrates various pathophysiological changes in relation to the spatial distribution of tau pathology as measured by tau‐positron emission tomography (PET). The y‐axis represents biomarker values standardized (z‐scored) across all participants to enable comparison between biomarkers. Inflection points were identified within the same locally estimated scatterplot smoothing (LOESS) fit and confirmed by local extrema of the first derivative. It is evident from this figure that the choroidal‐ventricular parameter composite score abnormality preceded cerebrospinal fluid (CSF) amyloid‐beta (Aβ) 42 decline as a marker of protein aggregation, and they are followed by Aβ‐PET standardized uptake value ratio (SUVR) abnormality.

**FIGURE 6**
The choroidal–ventricular parameter composite score is associated with protein aggregation; however, amyloid‐beta (Aβ) carries the effect of it on tau. Voxel‐wise linear analysis for the older adult groups (65 years old and over, N = 265 in Translational Biomarkers in Aging and Dementia (TRIAD) and N = 244), false discovery rate (FDR)‐corrected for multiple comparisons at P < 0.001, visualized as T‐statistical parametric maps, and overlaid on a structural template indicated significant association of the composite score and Aβ‐positron emission tomography (PET) over the cortex. Additionally, its association with tau‐PET was significantly mediated by Aβ over the cortex. * Covariates: age, sex, apolipoprotein E4 (APOE4), gray matter volume.

**FIGURE 7**
Almost all cerebrospinal fluid (CSF) and plasma biomarkers in Alzheimer's disease (AD) are correlated with the choroidal‐ventricular parameter score and showed the same trends (Translational Biomarkers in Aging and Dementia [TRIAD]). Scatterplots show correlations between the choroidal–ventricular composite score and:(A) CSF amyloid‐beta (Aβ) 40, (B) CSF Aβ42, (C) CSF Aβ42/40 ratio, (D) CSF total tau, (E) CSF p‐tau181, (F) plasma p‐tau181, (G) CSF p‐tau217, (H) plasma p‐tau217, (I) CSF p‐tau231, (J) plasma p‐tau231, (K) CSF glial fibrillary acidic protein (GFAP), and (L) plasma GFAP. Point colour indicates neocortical Aβ standardized uptake value ratio (SUVR; blue = lower, red = higher). Shaded areas represent 95% confidence intervals. CSF and plasma p‐taus (181, 217, 231) as sensitive and early marker of protein aggregation, GFAP as marker of astrocyte activation, and Aβ42 as marker of Aβ aggregation were all significantly correlated with the choroidal–ventricular parameter composite score.

**FIGURE 8**
Almost all memory and cognitive scores are correlated with the choroidal‐ventricular parameter composite score and showed the same trends (Alzheimer's Disease Neuroimaging Initiative [ADNI]). Associations between the choroidal–ventricular parameter composite score and (A) cerebrospinal fluid (CSF) amyloid‐beta (Aβ) 40, (B) CSF Aβ42, (C) Clinical Dementia Rating–Sum of Boxes (CDR‐SOB), (D) Mini‐Mental State Examination (MMSE), (E) Montreal Cognitive Assessment (MoCA), (F) Rey Auditory Verbal Learning Test (RAVLT) immediate recall, (G) RAVLT learning, and (H) Everyday Cognition–Study Partner (Ecog‐SP) total score, with point colour indicating neocortical Aβ standardized uptake value ratio (SUVR; blue = lower, red = higher). Different memory and cognitive scores, including MMSE that assesses global cognitive function, MoCA as an early cognitive impairment marker, and CDR‐SOB which measures dementia severity by evaluating functional and cognitive decline across multiple domains, were significantly correlated with the composite score.

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Choroidal-ventricular system abnormalities are linked to amyloid-β aggregation in Alzheimer's disease

Affiliations

Choroidal-ventricular system abnormalities are linked to amyloid-β aggregation in Alzheimer's disease

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Substances

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