The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau-associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD-associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here,

Este trabajo fue realizado en el marco del proyecto UBACyT 2016 N° 20020150200041BA, otorgado al primer autor del trabajo. En honor a la Dra. Irene Injoque-Ricle, gran compañera de trabajo y amiga.

Background: Factors associated with early life educational performance can be related to neurodevelopment, cognitive functioning and, consequently, the risk for dementia, but have received less attention than adult biomarkers. Method:A systematic review of the evidence available up to October 2020 in PubMed and Scopus was carried out. Original articles addressing both developmental learning disorders (LD) and late-onset neurodegenerative diseases (NDD) were included.Result: A significant prevalence of LD was found in patients with atypical variants of Alzheimer's disease (AD). Furthermore, an association was found between primary progressive aphasia -logopenic variant and language-related LD, and also between posterior cortical atrophy and non-language-related LD. These results could be explained by the selective vulnerability hypothesis, which states that the vulnerability of a particular brain network or area could predispose both to developmental LD and late-onset NDD. Conclusion:Developmental LDs can be considered as risk factors for late-onset NDD, especially for atypical AD variants. Given the scarcity of results and the limitations reported, a greater number of studies are required, with larger samples and, preferably, of longitudinal design in order to address this issue.