Specific Susceptibility to COVID-19 in Adults with Down Syndrome.

The current SARS-CoV-2 outbreak, which causes COVID-19, is particularly devastating for individuals with chronic medical conditions, in particular those with Down Syndrome (DS) who often exhibit a higher prevalence of respiratory tract infections, immune dysregulation and potential complications. The incidence of Alzheimer's disease (AD) is much higher in DS than in the general population, possibly increasing further the risk of COVID-19 infection and its complications. Here we provide a biological overview with regard to specific susceptibility of individuals with DS to SARS-CoV-2 infection as well as data from a recent survey on the prevalence of COVID-19 among them. We see an urgent need to protect people with DS, especially those with AD, from COVID-19 and future pandemics and focus on developing protective measures, which also include interventions by health systems worldwide for reducing the negative social effects of long-term isolation and increased periods of hospitalization.

Immune Dysregulation and the Increased Risk of Complications and Mortality Following Respiratory Tract Infections in Adults With Down Syndrome.

The risk of severe outcomes following respiratory tract infections is significantly increased in individuals over 60 years, especially in those with chronic medical conditions, i.e., hypertension, diabetes, cardiovascular disease, dementia, chronic respiratory disease, and cancer. Down Syndrome (DS), the most prevalent intellectual disability, is caused by trisomy-21 in ~1:750 live births worldwide. Over the past few decades, a substantial body of evidence has accumulated, pointing at the occurrence of alterations, impairments, and subsequently dysfunction of the various components of the immune system in individuals with DS. This associates with increased vulnerability to respiratory tract infections in this population, such as the influenza virus, respiratory syncytial virus, SARS-CoV-2 (COVID-19), and bacterial pneumonias. To emphasize this link, here we comprehensively review the immunobiology of DS and its contribution to higher susceptibility to severe illness and mortality from respiratory tract infections.

Mechanistic Analysis of Age-Related Clinical Manifestations in Down Syndrome.

Down syndrome (DS) is the most common genetic cause of Alzheimer's disease (AD) due to trisomy for all or part of human chromosome 21 (Hsa21). It is also associated with other phenotypes including distinctive facial features, cardiac defects, growth delay, intellectual disability, immune system abnormalities, and hearing loss. All adults with DS demonstrate AD-like brain pathology, including amyloid plaques and neurofibrillary tangles, by age 40 and dementia typically by age 60. There is compelling evidence that increased APP gene dose is necessary for AD in DS, and the mechanism for this effect has begun to emerge, implicating the C-terminal APP fragment of 99 amino acid (ß-CTF). The products of other triplicated genes on Hsa21 might act to modify the impact of APP triplication by altering the overall rate of biological aging. Another important age-related DS phenotype is hearing loss, and while its mechanism is unknown, we describe its characteristics here. Moreover, immune system abnormalities in DS, involving interferon pathway genes and aging, predispose to diverse infections and might modify the severity of COVID-19. All these considerations suggest human trisomy 21 impacts several diseases in an age-dependent manner. Thus, understanding the possible aging-related mechanisms associated with these clinical manifestations of DS will facilitate therapeutic interventions in mid-to-late adulthood, while at the same time shedding light on basic mechanisms of aging.

Cross-Sectional Exploration of Plasma Biomarkers of Alzheimer's Disease in Down Syndrome: Early Data from the Longitudinal Investigation for Enhancing Down Syndrome Research (LIFE-DSR) Study.

With improved healthcare, the Down syndrome (DS) population is both growing and aging rapidly. However, with longevity comes a very high risk of Alzheimer's disease (AD). The LIFE-DSR study (NCT04149197) is a longitudinal natural history study recruiting 270 adults with DS over the age of 25. The study is designed to characterize trajectories of change in DS-associated AD (DS-AD). The current study reports its cross-sectional analysis of the first 90 subjects enrolled. Plasma biomarkers phosphorylated tau protein (p-tau), neurofilament light chain (NfL), amyloid ß peptides (Aß1-40, Aß1-42), and glial fibrillary acidic protein (GFAP) were undertaken with previously published methods. The clinical data from the baseline visit include demographics as well as the cognitive measures under the Severe Impairment Battery (SIB) and Down Syndrome Mental Status Examination (DS-MSE). Biomarker distributions are described with strong statistical associations observed with participant age. The biomarker data contributes to understanding DS-AD across the spectrum of disease. Collectively, the biomarker data show evidence of DS-AD progression beginning at approximately 40 years of age. Exploring these data across the full LIFE-DSR longitudinal study population will be an important resource in understanding the onset, progression, and clinical profiles of DS-AD pathophysiology.