Molecular signatures across Alzheimer’s disease and Andean populations

The rapid advancement of omics technologies and ultrasensitive biomarkers-detection platforms has profoundly reshaped research in both medical and evolutionary biology, supporting the concept of molecular signatures as a new strategy for characterizing pathological processes and adaptive traits. This thesis explores different molecular signatures in two separated contexts: the pathophysiology of Alzheimer's disease (AD) and the high-altitude adaptation of Andean populations. Accordingly, the discussion is structured in two main sections. The first one examines the AD clinical continuum across multiple molecular levels. It begins with a locus-specific methylation analysis of two regions within the APOE 5’UTR, performed on both peripheral blood mononuclear cells (PBMCs) and hippocampal (HIC) samples to identify differentially methylated CpG sites and assess their association with clinical parameters. The following two chapters focus on transcriptomic signatures. The first explores AD-related changes in both mRNA and lncRNA through a whole-transcriptome analysis carried out using a newly developed Compi pipeline. The second examines the small extracellular vesicles (SEVs)-derived miRNome from patients with AD and frontotemporal dementia (FTD). This section ends with a study measuring established AD-related fluid biomarkers in plasma and cerebrospinal fluid (CSF) across the AD continuum, aimed at evaluating their relationships with clinical parameters, disease phenotypes and patients’ profiles. Conversely, the second section addresses the identification of epigenetic and molecular signatures underlying high-altitude adaptation in two Andean groups. Specifically, it presents a comparative analysis of the whole methylome of the Kichwa, who inhabit high-altitude regions of the Ecuadorian Andes, and the Ashaninka, residing at low-altitude areas of the Peruvian Amazon. The aim is to provide insights into altitude-related adaptations and achieve an unprecedented resolution of epigenetic variation within these populations. Taken together, these studies highlight the importance of molecular signatures to unravel both disease mechanisms and adaptive processes, bridging clinical and evolutionary perspectives.