👤 Eike J Spruth

Early and accurate detection of Alzheimer's disease (AD) is essential for timely intervention and development of disease-modifying treatments. The DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) provides a deeply phenotyped cohort covering preclinical and early clinical stages, including subjective cognitive decline (SCD) and mild cognitive impairment (MCI). Astrocyte reactivity and its biomarkers, particularly glial fibrillary acidic protein (GFAP), have gained increasing attention in AD research; however, the relationship between GFAP and amyloid in early disease, as well as its potential prognostic value beyond its association with amyloid status, remains insufficiently understood. To evaluate the performance of CSF and plasma GFAP across early disease stages, compare these measures according to amyloid status, and assess the prognostic value of GFAP for clinical progression across diagnostic stages during longitudinal follow-up. This study used data from the multicenter DELCODE cohort in Germany, including participants with available plasma and/or CSF samples and standardized clinical, cognitive, imaging, and biomarker assessments. GFAP concentrations in plasma and CSF were quantified using validated immunoassay platforms. Standard CSF AD biomarkers and ApoE genotype were measured using established assays. Amyloid status was defined by the CSF Aβ42/40 ratio. Longitudinal follow-up occurred annually for up to ∼10 years, with clinical conversion determined according to NIA-AA criteria. Plasma and CSF GFAP increased across the AD continuum, with higher levels in MCI and AD (p < 0.001). Plasma GFAP showed a stronger association with amyloid status than CSF GFAP across all groups. In MCI, plasma GFAP combined with age and ApoE4 yielded an AUC of 0.87. Elevated plasma GFAP predicted increased risk of conversion to MCI (HR = 2.19, p < 0.001; adjusted HR = 1.70, p = 0.0056) and AD dementia (HR = 3.5; adjusted HR = 2.49 both p < 0.001). Plasma GFAP is a sensitive, minimally invasive biomarker with diagnostic relevance for amyloid detection and prognostic relevance for clinical progression in early AD. Show less

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. Show less

CSF biomarkers have immense diagnostic and prognostic potential for Alzheimer disease (AD). However, AD is still diagnosed relatively late in the disease process, sometimes even years after the initial manifestation of cognitive symptoms. Thus, further identification of biomarkers is required to detect related pathology in the preclinical stage and predict cognitive decline. Our study aimed to assess the association of neurogranin and β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) with cognitive decline in individuals with subjective cognitive decline (SCD). We enrolled participants with available neurogranin and BACE1 measurements in CSF from the DELCODE (DZNE-Longitudinal Cognitive Impairment and Dementia, Germany) cohort. The longitudinal change of Preclinical Alzheimer's Cognitive Composite score was assessed as the primary outcome in participants with SCD and controls. The secondary outcome was defined as conversion of SCD to mild cognitive impairment (MCI) during follow-up. Levels of neurogranin, BACE1, and neurogranin/BACE1 ratio across groups were compared by analysis of covariance after adjustment for demographics. The linear mixed-effects model and Cox regression analysis were applied to evaluate their association with cognitive decline and progression of SCD to MCI, respectively. A total of 530 participants (mean age: 70.76 ± 6.01 years, 48.7% female) were analyzed in the study. The rate of cognitive decline was faster in individuals with SCD with higher neurogranin and neurogranin/BACE1 ratio (β = -0.138, SE = 0.065, Our findings suggest that CSF neurogranin and BACE1 begin to change in the preclinical stage of AD and they are associated with clinical progression in individuals with SCD. Show less