TY  - JOUR
AU  - Özlü, Serap
AU  - Dyrba, Martin
AU  - Grazia, Alice
AU  - Brosseron, Frederic
AU  - Buerger, Katharina
AU  - Dechent, Peter
AU  - Düzel, Emrah
AU  - Ewers, Michael
AU  - Fliessbach, Klaus
AU  - Glanz, Wenzel
AU  - Hansen, Niels
AU  - Hellmann-Regen, Julian
AU  - Hetzer, Stefan
AU  - Janowitz, Daniel
AU  - Kilimann, Ingo
AU  - Kronmüller, Marie
AU  - Laske, Christoph
AU  - Lüsebrink, Falk
AU  - Mengel, David
AU  - Perneczky, Robert
AU  - Peters, Oliver
AU  - Priller, Josef
AU  - Ramirez, Alfredo
AU  - Rauchmann, Boris Stephan
AU  - Rostamzadeh, Ayda
AU  - Schneider, Anja
AU  - Sodenkamp, Sebastian
AU  - Spottke, Annika
AU  - Spruth, Eike Jakob
AU  - Synofzik, Matthis
AU  - Wiltfang, Jens
AU  - Heneka, Michael T
AU  - Jessen, Frank
AU  - Teipel, Stefan
TI  - CSF biomarkers of neuroinflammation are associated with regional atrophy.
JO  - Journal of neurology
VL  - 273
IS  - 1
SN  - 0367-004X
CY  - [Darmstadt]
PB  - Steinkopff
M1  - DZNE-2025-01498
SP  - 46
PY  - 2025
AB  - Neuroinflammation is central to Alzheimer's disease (AD) pathogenesis, yet its contribution to region-specific brain atrophy remains unclear. We examined whether cerebrospinal fluid (CSF) biomarkers predict longitudinal atrophy in the hippocampus and basal forebrain and mediate the impact of AD pathology.Data from 227 DELCODE participants with baseline CSF measures and longitudinal structural MRI were analyzed. Four latent factors (synaptic, microglia, chemokine/cytokine, complement) were derived to capture shared variance across biomarkers. Latent factors represent unobserved biological domains inferred from related CSF markers. In addition, four single biomarkers (neurogranin, sTREM2, YKL-40, ferritin) were tested separately. Regional atrophy rates were estimated using linear mixed-effects models including biomarker × time, A/T classification, diagnosis, and covariates (age, sex, education, ApoE-ε4). Individual slopes were then entered into mediation models.Higher synaptic latent factor (β = - 0.019, pFDR = 0.021) and YKL-40 (β = - 0.020, pFDR = 0.025) significantly predicted hippocampal atrophy. Only these two markers remained significant after correction for multiple comparisons. Mediation analyses revealed significant indirect effects of the synaptic latent factor and YKL-40 on hippocampal atrophy across all A/T groups. No biomarker was associated with basal forebrain atrophy (pFDR > 0.05).Latent factors captured shared biological variance across related biomarkers and provided a more robust representation of underlying biological domains than single biomarkers. This approach identified synaptic dysfunction and astroglial activation as key links between AD pathology and hippocampal neurodegeneration. These findings highlight synaptic and glial pathways as promising targets for disease-modifying interventions.
KW  - Humans
KW  - Male
KW  - Atrophy: pathology
KW  - Atrophy: cerebrospinal fluid
KW  - Female
KW  - Biomarkers: cerebrospinal fluid
KW  - Aged
KW  - Magnetic Resonance Imaging
KW  - Hippocampus: pathology
KW  - Hippocampus: diagnostic imaging
KW  - Alzheimer Disease: cerebrospinal fluid
KW  - Alzheimer Disease: pathology
KW  - Chitinase-3-Like Protein 1: cerebrospinal fluid
KW  - Neuroinflammatory Diseases: cerebrospinal fluid
KW  - Neuroinflammatory Diseases: pathology
KW  - Longitudinal Studies
KW  - Middle Aged
KW  - Aged, 80 and over
KW  - Alzheimer’s disease (Other)
KW  - Basal forebrain (Other)
KW  - Biomarker (Other)
KW  - Hippocampus (Other)
KW  - Neuroinflammation (Other)
KW  - Biomarkers (NLM Chemicals)
KW  - Chitinase-3-Like Protein 1 (NLM Chemicals)
KW  - CHI3L1 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41442069
C2  - pmc:PMC12738631
DO  - DOI:10.1007/s00415-025-13564-5
UR  - https://pub.dzne.de/record/283091
ER  -