👤 Katja Mengel

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

Based on a dataset comprising coding DNA sequences of 23 anthropoid primates, we herein investigate if rates of sequence evolution of SPerm Adhesion Molecule1 (SPAM1, also PH-20), which participates in sperm-egg interaction, is lower in more sexually dimorphic species. For comparison, we analyze sequence evolution of apolipoproteinA-IV (APOA4) and apolipoprotein A-V (APOA5), which should evolve under less or even no sexual selection given their expression in blood, digestive tract, liver, and lungs. Regression analyses provides significant support for a negative dependence of SPAM1 derived branch-specific ratios of non-synonymous to synonymous substitution rates (dN/dS) on sexual size dimorphism (SSD) in a subsample comprising New World and Old World monkeys. We moreover observed a tendency for a positive correlation of substitution rates of SPAM1 with relative testes weight (RTW) and significantly lowered dN/dS estimates in uni-male and uni-male/multi-male breeding monkeys. Importantly, the pattern was not reproduced when analyzing partial APOA4 and APOA5 sequences. These findings illustrate that different levels of sperm competition, probably fueled by female cryptic choice, account for species-specific sequence evolution of SPAM1 in monkeys. Remarkably, present data do not support a correlation of species-specific sequence evolution of SPAM1 with sexual selection levels in hominoids (apes including humans). This can partly be ascribed to a relaxation of functional constraint of SPAM1 in some hominoid species. Additional factors confounding regression analyses specifically in hominoids might be higher levels of sperm competition than reflected by SSD and RTW in some species, a rather strong effect of female mate choice on paternity rates in others, and - in particular in humans - socio-cultural factors not measurable by SSD and RTW. Show less