Abstract
Background Down syndrome (DS) is the most common genetic cause of Alzheimer’s Disease (AD), but diagnosis of AD in DS is challenging due to the intellectual disability which accompanies DS. When disease-modifying agents for AD are approved, reliable biomarkers will be required to identify when and how long people with DS should undergo treatment. Three cardinal neuropathological features characterize AD, and AD in DS – Aβ amyloid plaques, tau neurofibrillary tangles, and neuronal loss. Here, we quantified plasma biomarkers of all 3 neuropathological features in a large cohort of people with DS aged from 3 months to 68 years. Methods Using ultra-sensitive single molecule array (Simoa) assays, we measured 3 analytes (Aβ42, NfL, and tau) in plasmas of 100 individuals with DS and 100 age- and sex-matched controls. Tau was measured using an assay (NT1) which detects forms of tau containing at least residues 6-198, and the stability of the 3 analytes was established using plasma from ten healthy volunteers collected at 6 intervals over a five day period. Results High Aβ42 and NT1 tau, and low NfL, were observed in infants. Across all ages, Aβ42 levels were higher in DS than controls. Levels of Aβ42 decreased with age in both DS and controls, but this decrease was greater in DS than controls and became prominent in the third decade of life. NT1 tau fell in adolescents and young adults, but increased in older individuals with DS. NfL levels were low in infants, children, adolescents and young adults, but thereafter increased in DS compared to controls. Conclusions High levels of Aβ42 and tau in both young controls and DS suggest these proteins are produced by normal physiological processes, whereas, the changes seen in later life are consistent with emergence of pathological alterations. Our plasma biomarker results are in good agreement with prior neuropathology studies and indicate that the third and fourth decades (i.e. 20 to 40 years of age) of life are pivotal periods during which AD processes manifest in DS. Application of the assays used here to longitudinal studies of individuals with DS aged 20 to 50 years of age, should further validate the use of these biomarkers, and in time may allow identification and monitoring of people with DS best suited for treatment with emerging AD therapies.
Feasibility of Assessing Diet with a Mobile Food Record for Adolescents and Young Adults with Down Syndrome
