Recent studies suggested that regulatory Tregs (CD4+CD25+ Foxp3+ T-cells) may play a key role in the pathophysiology of various neurodegenerative disorders, including Alzheimer ́s disease (AD). However, the impact of Tregs modulation of immune responses during disease progression is poorly understood and still controversial. It has been suggested that onset of clinical symptoms in AD may correlate with a systemic immune suppression, impairing the ability to mount a proper immune response needed to mitigate neuroinflammation and the progressive amyloid beta (Aβ) deposition. We hypothesize that systemic immune alterations (particularly in Tregs levels and activity) at different stages of the AD pathology may interfere with the ability to fight against AD. In a 2021 study, Jiping Fu et al., reported that Mild Cognitive Impairment (MCI) patients have higher Tregs proportions compared with AD-related dementia patients. Thus, the main objective of this proposal is to depict a high-resolution transcriptomic landscape of blood immune cells during spontaneous disease progression (Control vs. MCI vs. AD patients), which will facilitate a better understanding of the protective and/or pathogenic immune responses at different stages of the disease. We are proposing to expand our RedLat genomic assessment of whole-genome sequencing (WGS) to transcriptomic (immune single-cell RNAseq).