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Observational Study
. 2025 Jul 25;17(1):172.
doi: 10.1186/s13195-025-01796-6.

Hypometabolic subtypes of AD are linked to comorbid hippocampal sclerosis and Lewy body pathology

Fedor Levin  1 , Martin Dyrba  2 , Stefan J Teipel  2   3 , Michel J Grothe  4
Affiliations
Observational Study

Hypometabolic subtypes of AD are linked to comorbid hippocampal sclerosis and Lewy body pathology

Fedor Levin et al. Alzheimers Res Ther. .

Abstract

Background: Neuroimaging studies have identified distinct 'typical/neocortical' and 'limbic-predominant' hypometabolic subtypes of AD with different clinical and biomarker characteristics. We investigated associations of these subtypes with postmortem neuropathological measures in an observational study.

Methods: Antemortem FDG-PET scans of 74 participants from the ADNI autopsy cohort were classified into previously described typical/neocortical and limbic-predominant subtype patterns. We used Bayesian regression and ANCOVA to test associations between the subtypes and neuropathological features.

Results: Results were inconclusive for Thal phases, Braak stages, CERAD neuritic plaque scores, hippocampal tangle density, and TDP-43 pathology (BF10 between 0.447 and 1.146). However, the limbic-predominant subtype was associated with hippocampal sclerosis (BF10 = 3.842, moderate level of evidence), whereas the typical/neocortical subtype was associated with Lewy body pathology (BF10 = 10.093, strong level of evidence).

Conclusions: These findings highlight the influence of AD and non-AD-specific pathologies on neurodegeneration patterns and may provide directions for research into hypometabolic pattern analysis as an indirect marker of comorbid pathology.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: Data collection and sharing in ADNI was approved by the Institutional Review Board of each participating institution and all procedures involving human participants were in accordance with the ethical standards of the 1964 Helsinki declaration and its later amendments. Written informed consent was obtained from all ADNI participants and/or authorized representatives before any protocol-specific procedures were carried out. Consent for publication: Not applicable. Competing interests: SJT served as member of advisory boards of Lilly, Eisai, and Biogen, and is member of the independent data safety and monitoring board of the study ENVISION (Biogen). FL, MD, MJG have no disclosures to report.

Figures

Fig. 1
Fig. 1
TDP-43 pathology severity and similarity to the limbic-predominant hypometabolic subtype. TDP-43 pathology severity is represented by the number of brain areas with TDP-43 immunoreactive inclusions, as assessed in amygdala, hippocampus, entorhinal/inferior temporal cortex and neocortex. Similarity to the limbic-predominant subtype is represented by the ratio of Euclidean distance to the average typical/neocortical subtype profile and Euclidean distance to the average limbic-predominant subtype profile
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