RESUMEN
Multiple cognitive domains, including learning, memory, and psychomotor speed, show significant reductions with age. Likewise, several cerebrospinal fluid (CSF) neurodegenerative biomarkers, including total tau (t-tau, a marker of neuronal body injury) and neurofilament light chain (NfL, a marker of axonal injury) show age-related increases in normal aging. In the current study, we aimed to investigate whether the age-effect within different cognitive domains was mediated by age-associated CSF markers for neurodegenerative changes. We fitted 10 mediation models using structural equation modeling to investigate this in a cohort of 137 healthy adults, aged 40-80 years, from the Norwegian Dementia Disease Initiation (DDI) study. Here, t-tau and NfL were defined as mediators between age and different cognitive tests. The models showed that NfL mediated the age-effect for CERAD learning and memory recall (learning: ß = -0.395, p < 0.05; recall: ß = -0.261, p < 0.01). No such effect was found in the other models. Our findings suggest that the age-related lower performance in verbal learning and memory may be linked to NfL-associated neurodegenerative changes in cognitively healthy adults.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Filamentos Intermedios , Péptidos beta-Amiloides/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Disfunción Cognitiva/psicología , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Envejecimiento/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Enfermedad de Alzheimer/psicologíaRESUMEN
BACKGROUND: The soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) is considered a biomarker of microglia activity. The objective of this study was to investigate the trajectory of CSF sTREM2 levels over time and examine its association with sex. METHODS: A total of 1,017 participants from the Alzheimer's Disease Neuroimaging Initiative Study (ADNI) with at least one CSF sTREM2 record were included. The trajectory of CSF sTREM2 was analyzed using a growth curve model. The association between CSF sTREM2 levels and sex was assessed using linear mixed-effect models. RESULTS: CSF sTREM2 levels were increased with age over time (P < 0.0001). No significant sex difference was observed in sTREM2 levels across the entire sample; however, among the APOE ε4 allele carriers, women exhibited significantly higher sTREM2 levels than men (ß = 0.146, P = 0.002). CONCLUSION: Our findings highlight the association between CSF sTREM2 levels and age-related increments, underscoring the potential influence of aging on sTREM2 dynamics. Furthermore, our observations indicate a noteworthy association between sex and CSF sTREM2 levels, particularly in individuals carrying the APOE ε4 allele.
Asunto(s)
Enfermedad de Alzheimer , Biomarcadores , Glicoproteínas de Membrana , Neuroimagen , Receptores Inmunológicos , Humanos , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico por imagen , Femenino , Masculino , Glicoproteínas de Membrana/líquido cefalorraquídeo , Glicoproteínas de Membrana/genética , Receptores Inmunológicos/genética , Anciano , Estudios Longitudinales , Neuroimagen/métodos , Biomarcadores/líquido cefalorraquídeo , Anciano de 80 o más Años , Apolipoproteína E4/genética , Envejecimiento/líquido cefalorraquídeo , Caracteres Sexuales , Persona de Mediana EdadRESUMEN
Cerebrospinal fluid total-tau (t-tau) and neurofilament light chain (NfL) are biomarkers of neurodegeneration and are increased in Alzheimer's disease (AD). In order to adjust for age-related increases in t-tau and NfL, cross-sectional age-adjusted norms were developed based on amyloid negative cognitively normal (CN) adults aged 41-78 years (CN, n = 137). The age-adjusted norms for t-tau and NfL did not improve receiver operating curve based diagnostic accuracies in individuals with mild cognitive impairment (MCI) due to AD (AD-MCI, n = 144). Furthermore, while NfL was correlated with higher age in AD-MCI, no significant correlation was found for t-tau. The cox proportional hazard models, applied in 429 participants with baseline t-tau and NfL, showed higher hazard ratio of progression to MCI or dementia without age-adjustments (HR = 3.39 for t-tau and HR = 3.17 for NfL), as compared to using our norms (HR = 2.29 for t-tau and HR = 1.89 for NfL). Our results indicate that utilizing normative reference data could obscure significant age-related increases in these markers associated with neurodegeneration and AD leading to a potential loss of overall diagnostic accuracy.