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. 2025 Apr 26;17(1):93.
doi: 10.1186/s13195-025-01727-5.

Clinical phenotypes of Alzheimer's disease: investigating atrophy patterns and their pathological correlates

Niels Reijner  1   2   3 , I Frigerio  4   5   6 , M M A Bouwman  4   5   6 , B D C Boon  7 , N Guizard  8 , T Jubault  8 , J J M Hoozemans  5   9 , A J M Rozemuller  5   9 , F H Bouwman  10 , F Barkhof  10   11   12 , E Gordon  8 , W D J van de Berg  4   5 , L E Jonkman  4   5   6
Affiliations

Clinical phenotypes of Alzheimer's disease: investigating atrophy patterns and their pathological correlates

Niels Reijner et al. Alzheimers Res Ther. .

Abstract

Background: In Alzheimer's disease (AD), MRI atrophy patterns can distinguish between amnestic (typical) and non-amnestic (atypical) clinical phenotypes and are increasingly used for diagnosis and outcome measures in clinical trials. However, understanding how protein accumulation and other key features of neurodegeneration influence these imaging measurements, are lacking. The current study aimed to assess regional MRI patterns of cortical atrophy across clinical AD phenotypes, and their association with amyloid-beta (Aβ), phosphorylated tau (pTau), neuro-axonal degeneration and microvascular deterioration.

Methods: Post-mortem in-situ 3DT1 3 T-MRI data was obtained from 33 AD (17 typical, 16 atypical) and 16 control brain donors. Additionally, ante-mortem 3DT1 3 T-MRI scans of brain donors were collected if available. Regional volumes were obtained from MRI scans using an atlas based parcellation software. Eight cortical brain regions were selected from formalin-fixed right hemispheres of brain donors and then immunostained for Aβ, pTau, neurofilament light, and collagen IV. Group comparisons and volume-pathology associations were analyzed using linear mixed models corrected for age, sex, post-mortem delay, and intracranial volume.

Results: Compared to controls, both typical and atypical AD showed volume loss in the temporo-occipital cortex, while typical AD showed additional volume loss in the parietal cortex. Posterior cingulate volume was lower in typical AD compared to atypical AD (- 6.9%, p = 0.043). In AD, a global positive association between MRI cortical volume and Aβ load (βs = 0.21, p = 0.010), and a global negative association with NfL load (βs = - 0.18, p = 0.018) were observed. Regionally, higher superior parietal gyrus volume was associated with higher Aβ load in typical AD (βs = 0.47, p = 0.004), lower middle frontal gyrus volume associated with higher NfL load in atypical AD (βs = - 0.50, p < 0.001), and lower hippocampal volume associated with higher COLIV load in typical AD (βs = - 1.69, p < 0.001). Comparing post-mortem with ante-mortem scans showed minimal volume differences at scan-intervals within 2 years, highlighting the translational aspect of this study.

Conclusion: For both clinical phenotypes, cortical volume is affected by Aβ and neuro-axonal damage, but in opposing directions. Differences in volume-pathology relationships between clinical phenotypes are region-specific. The findings of this study could improve the interpretation of MRI datasets in heterogenous AD cohorts, both in research and clinical settings.

Keywords: Alzheimer’s disease; Clinical phenotypes; Cortical volume; Pathological features; Post-mortem.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: All donors had signed an informed consent for brain donation and the use of materials and clinical information for research purposes. The procedures for brain tissue collection of NBB and NABCA have been approved by the Medical Ethical Committee of Amsterdam UMC, Vrije Universiteit Amsterdam. Consent for publication: Not applicable. Competing interests: Laura E. Jonkman reports financial support was provided by Topsector Life Sciences & Health - Topconsortium Kennis en Innovatie (LSH-TKI). Wilma D.J. van de Berg reports financial support was provided by Health Holland, Horizon Europe, Hoffman-La Roche and Genentech. reports relationships with Roche Tissue Diagnositcs, Discoveric Bio and AC Immune that includes: contract research. Reports relationships with Hoffmann-La Roche and Prothena that includes: non-financial support in the form of research consumables. Frederik Barkhof reports relationships with Biogen, Merck, Eisai, and Prothena that include: steering committee or Data Safety Monitoring Board membership. Relationships with Combinostics, Scottish Brain Sciences, and Alzheimer Europe that include: advisory board membership. Relationships with Roche, Celltrion, Rewind Therapeutics, Merck, and Bracco that include: consulting. Relationships with ADDI, Merck, Biogen, GE Healthcare, and Roche that include: research agreements. reports a relationship with NIHR University College London Hospitals Biomedical Research Centre that includes: employment. Relationships with Queen Square Analytics LTD that include: Co-founder and shareholder. Femke H. Bouwman reports relationship with Optina Dx and Optos that include: contract research. Reports relationships with biogen that include: paid expert testimony. Reports relationships with Roche that include: speaking and lecturing fees. Elizabeth Gordon, Nicolas Guizard and Thomas Jubault are employees at Qynapse, which holds the IP and rights to the algorithms employed by QyScore in the image analysis used for the manuscript. Jeroen J.M. Hoozemans is employed by F. Hoffmann-La Roche. Baayla D.C. Boon functions as the Programs Chair of the Atypical Alzheimer’s Disease Professional Interest Area, organized by Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART). Authors not mentioned here declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Quantification of pathological markers. A Examples of imaged pathology and matching quantification results for Amyloid-β, pTau, NfL and COLIV. Positive signal % over a given area is quantified as area %. B Examples of best rectangle fit and vessel wall thickness measurements in COLIV positive vessels
Fig. 2
Fig. 2
Group Comparisons of regional volume between controls and clinical AD phenotype groups. AAL3 atlas regions are grouped by lobes and brain structures and sorted in alphabetical order. Comparisons in order from outer ring to inner ring: control vs typical AD, control vs atypical AD, typical AD vs atypical AD. Volume differences are displayed as Cohen's D effect sizes, with negative effect size (blue) denoting a lower volume in the second group of each paired comparison. Significant group differences are annotated with * = p ≤ 0.05, corrected for multiple comparisons. Highlighted in red boxes are regions selected for association with pathological quantification
Fig. 3
Fig. 3
Global and regional cortical MRI volume of selected regions. Global data indicates all eight selected regions combined. A boxplots of cortical MRI volume as % of control mean, which was set at 100% for each region. B Radar plot of clinical phenotypes visualizing control, typical and atypical AD. C Radar plot visualizing atypical subtypes, namely dysexecutive, behavioral, logopenic and visuospatial groups. Radar plots denote the mean volume for each region per group. * = p ≤ 0.05, ** = p ≤ 0.01, *** = p ≤ 0.001. Hip = hippocampus, ParaHip = parahippocampal gyrus, GFM = middle frontal gyrus, GTM = middle temporal gyrus, GPS = superior parietal gyrus, Precun = precuneus, PCC = posterior cingulate cortex, OC = occipital cortex
Fig. 4
Fig. 4
Pathological load of cortical Aβ, pTau, axonal damage and microvascular deterioration in AD phenotypes and controls. Boxplots of immunoreactivity of histological markers Amyloid beta (A) pTau (D) NfL (G) and COLIV (J) as area% load in selected brain regions in control and AD phenotype groups (behavioral, dysexecutive, logopenic and visuospatial). Radar plots showing the distribution of pathology load among control, typical AD, atypical AD (B, E, H, K), and distinct subtype groups (C, F, I, L). * = p ≤ 0.05, ** = p ≤ 0.01, *** = p ≤ 0.001. Hip = hippocampus, ParaHip = parahippocampal gyrus, GFM = middle frontal gyrus, GTM = middle temporal gyrus, GPS = superior parietal gyrus, Precun = precuneus, PCC = posterior cingulate cortex, OC = occipital cortex
Fig. 5
Fig. 5
Global volume-pathology associations for AD clinical phenotypes. A Results of multilevel model for control and AD phenotype groups for each immunohistological marker. Data are presented as β (± SE) for volume change rates or as βs (± SE) for standardized volume change rates. Significant results are displayed in bold. B Scatter plots and regression slopes of each immunohistological marker for controls and AD phenotype groups
Fig. 6
Fig. 6
Regional Volume-Pathology associations for AD clinical phenotypes. Standardized betas of volume-pathology associations are presented in a heatmap to provide a better overview of all regional associations. For each significant association, scatterplots with regression lines are plotted. By definition, control cases have little-to-no pTau load in the selected regions therefore control volume-pathology associations for pTau are not included and are designated by the – sign. Hip = hippocampus, ParaHip = parahippocampal gyrus, GFM = middle frontal gyrus, GTM = middle temporal gyrus, GPS = superior parietal gyrus, Precun = precuneus, PCC = posterior cingulate cortex, OC = occipital cortex
Fig. 7
Fig. 7
Scatter plot ante-mortem to post-mortem scan interval and volume difference. Each data point represents a comparison between the ante- and post-mortem scan of a given case. Vertical lines are drawn at 0% (green) − 10% and 10% (black) and at − 20% and 20% (red) volume difference to indicate no, small, and large volume differences, respectively. Time difference between ante and post-mortem interval is presented as ante- to post-mortem interval. Volume difference was calculated as the percentage difference between ante-mortem to post-mortem scan volume. Hip = hippocampus, ParaHip = parahippocampal gyrus, GFM = middle frontal gyrus, GTM = middle temporal gyrus, GPS = superior parietal gyrus, Precun = precuneus, PCC = posterior cingulate cortex, OC = occipital cortex
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