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

Abstract

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 β peptides (Aβ1-40, Aβ1-42), 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.

Innate Immune System Activation and Neuroinflammation in Down Syndrome and Neurodegeneration: Therapeutic Targets or Partners?

“…Activation of astrocytes and microglia, the secretion of inflammatory cytokines (e.g., IL-1, IL-6, and TNFα), and acute phase proteins are observed in both the brains and blood of people with DS, indicating an “inflammatory endophenotype” (Petersen and O’Bryant, 2019 ). In a cross-sectional analysis of people with DS, plasma glial fibrillary acidic protein (GFAP), a marker of astrogliosis, was found to increase starting in their mid-40s (Hendrix et al, 2021 ).…”

“…Higher plasma levels of GFAP are correlated with lower measures of episodic memory and microstructural integrity in AD, MCI, and also in healthy aged donors (Bettcher et al, 2021 ). As discussed, people with DS also have increasing levels of plasma GFAP starting in their mid-40s (Hendrix et al, 2021 ). Thus, although initially thought to be a secondary effect of aberrant protein accumulation, changes in the innate immune system and neuroinflammation are now thought to be a core, early feature of both DS and AD that interface with, and may contribute to, clinical manifestations of cognitive disorders and decline (Lucin and Wyss-Coray, 2009 ; Heneka et al, 2015 ).…”

“…Biomarkers of neuroinflammation, amyloid and tau pathology, and neurodegeneration increase over the lifetimes of the vast majority of individuals with DS. Neuroinflammatory biomarkers such as GFAP may begin increasing as early as the late teenage years and progressively increase throughout life (Hendrix et al, 2021 ). Changes in amyloid biomarkers are detectable after 20 years of age, with APOE genotype significantly contributing to risk (Rubinsztein et al, 1999 ; Deb et al, 2000 ), likely due to apoE-catalyzed amyloid-β (Aβ) polymerization during the early seeding stages of amyloid formation (Potter and Wisniewski, 2012 ).…”

Postmortem Neocortical 3H-PiB Binding and Levels of Unmodified and Pyroglutamate Aβ in Down Syndrome and Sporadic Alzheimer’s Disease

“…Recent improvements in medical care have contributed to the increased longevity of individuals with DS, and advancements in diagnostic biomarkers have facilitated studies of key questions regarding the interconnected clinical and neuropathological features that develop with age in DS (Neale et al, 2018 ; Handen et al, 2020 ; Head and Ances, 2020 ; Petersen et al, 2020 , 2021 ; Rafii et al, 2020 ; Hendrix et al, 2021 ). Positron emission tomography (PET) studies using Pittsburgh Compound-B ( 11 C-PiB) and related amyloid-binding radiopharmaceuticals provide insight into regional distributions and temporal changes in Aβ pathology in living people with AD (Klunk et al, 2004 ; Rowe et al, 2007 ; Cohen et al, 2012 ; Mathis et al, 2017 ; Villemagne et al, 2021 ) and this technology is being applied increasingly to studies of individuals with DS (Landt et al, 2011 ; Handen et al, 2012 ; Hartley et al, 2014 , 2017 , 2020 ; Annus et al, 2016 , 2017 ; Lao et al, 2016 , 2017 , 2018 ; Cole et al, 2017 ; Cohen et al, 2018 ; Neale et al, 2018 ; Mak et al, 2019a , b ; Mihaila et al, 2019 ; Tudorascu et al, 2019 , 2020 ; Wilson et al, 2019 ; Cody et al, 2020 ; Zammit et al, 2020 , 2021 ).…”

Aging in Down Syndrome: Latest Clinical Advances and Prospects

“…Several clinical cohorts in the US and Europe are working together to determine the best panels of blood biomarkers for adults with DS related to dementia. In Hendrix et al’s (2021) [ 4 ] paper, the Longitudinal Investigation for Enhancing Down Syndrome Research (LIFE-DSR) Study reported early findings from a natural history study of adults with DS in the USA. The LIFE-DSR study consists of 11 sites, who are collectively recruiting 270 individuals with DS over the age of 25.…”