RESUMEN
INTRODUCTION: The molecular basis of cognitive resilience (CR) among pathologically confirmed Alzheimer's disease (AD) cases is not well understood. METHODS: Abundance of 13 cell types and neuronal subtypes in brain bulk RNA-seq data from the anterior caudate, dorsolateral prefrontal cortex (DLPFC), and posterior cingulate cortex (PCC) obtained from 434 AD cases, 318 cognitively resilient AD cases, and 188 controls in the Religious Orders Study and Rush Memory and Aging Project was estimated by deconvolution. RESULTS: PVALB+ neuron abundance was negatively associated with cognitive status and tau pathology in the DLPFC and PCC (Padj < 0.001) and the most reduced neuronal subtype in AD cases compared to controls in DLPFC (Padj = 8.4 × 10-7) and PCC (Padj = 0.0015). We identified genome-wide significant association of neuron abundance with TMEM106B single nucleotide polymorphism rs13237518 in PCC (p = 6.08 × 10-12). rs13237518 was also associated with amyloid beta (p = 0.0085) and tangles (p = 0.0073). DISCUSSION: High abundance of PVALB+ neurons may be a marker of CR. TMEM106B variants may influence CR independent of AD pathology. HIGHLIGHTS: Neuron retention and a lack of astrocytosis are highly predictive of Alzheimer's disease (AD) resilience. PVALB+ GABAergic and RORB+ glutamatergic neurons are associated with cognitive status. A TMEM106B single nucleotide polymorphism is related to lower AD risk, higher neuron count, and increased AD pathology.
Asunto(s)
Enfermedad de Alzheimer , Polimorfismo de Nucleótido Simple , Humanos , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Masculino , Femenino , Anciano de 80 o más Años , Anciano , Neuronas/patología , Neuronas/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Estudio de Asociación del Genoma Completo , Giro del Cíngulo/patología , Reserva Cognitiva/fisiología , Encéfalo/patología , Péptidos beta-Amiloides/metabolismo , Proteínas tau/metabolismoRESUMEN
Mapping quantitative trait loci (QTLs) for molecular traits from chromatin to metabolites (i.e., xQTLs) provides insight into the locations and effect modes of genetic variants that influence these molecular phenotypes and the propagation of functional consequences of each variant. xQTL studies indirectly interrogate the functional landscape of the molecular basis of complex diseases, including the impact of non-coding regulatory variants, the tissue specificity of regulatory elements, and their contribution to disease by integrating with genome-wide association studies (GWAS). We summarize a variety of molecular xQTL studies in human tissues and cells. In addition, using the Alzheimer's Disease Sequencing Project (ADSP) as an example, we describe the ADSP xQTL project, a collaborative effort across the ADSP Functional Genomics Consortium (ADSP-FGC). The project's ultimate goal is a reference map of Alzheimer's-related QTLs using existing datasets from multiple omics layers to help us study the consequences of genetic variants identified in the ADSP. xQTL studies enable the identification of the causal genes and pathways in GWAS loci, which will likely aid in the discovery of novel biomarkers and therapeutic targets for complex diseases. © 2022 Wiley Periodicals LLC.