Plasma amyloid and tau as dementia biomarkers in Down syndrome: Systematic review and meta‐analyses

Abstract

Individuals with Down syndrome (DS) are at high risk of developing Alzheimer's disease (AD). Discovering reliable biomarkers which could facilitate early AD diagnosis and be used to predict/monitor disease course would be extremely valuable. To examine if analytes in blood related to amyloid plaques may constitute such biomarkers, we conducted meta‐analyses of studies comparing plasma amyloid beta (Aβ) levels between DS individuals and controls, and between DS individuals with and without dementia. PubMed, Embase, and Google Scholar were searched for studies investigating the relationship between Aβ plasma concentrations and dementia in DS and 10 studies collectively comprising >1,600 adults, including >1,400 individuals with DS, were included. RevMan 5.3 was used to perform meta‐analyses. Meta‐analyses showed higher plasma Aβ40 (SMD = 1.79, 95% CI [1.14, 2.44], Z = 5.40, p < .00001) and plasma Aβ42 levels (SMD = 1.41, 95% CI [1.15, 1.68], Z = 10.46, p < .00001) in DS individuals than controls, and revealed that DS individuals with dementia had higher plasma Aβ40 levels (SMD = 0.23, 95% CI [0.05, 0.41], Z = 2.54, p = .01) and lower Aβ42/Aβ40 ratios (SMD = −0.33, 95% CI [−0.63, −0.03], Z = 2.15, p = .03) than DS individuals without dementia. Our results indicate that plasma Aβ40 levels may constitute a promising biomarker for predicting dementia status in individuals with DS. Further investigations using new ultra‐sensitive assays are required to obtain more reliable results and to investigate to what extent these results may be generalizable beyond the DS population.

Dynamics of plasma biomarkers in Down syndrome: the relative levels of Aβ42 decrease with age, whereas NT1 tau and NfL increase

“…In the absence of large longitudinal cohorts, we gathered specimens from 100 DS individuals aged from 3 months to 68 years and compared their values with those of age-and sex-matched controls. As expected for individuals with 3 copies of the APP gene (and consistent with prior studies [15,[31][32][33]) we observed higher plasma Aβ42 levels in individuals with DS compared to controls. In the first decade of life, a time when there is little amyloid deposition [34,35], plasma Aβ42 levels were on average a little higher (~1.6 fold) in DS than the expected 1.5-fold elevation due to gene dosage.…”

“…Whether blood-based biomarkers of AD evolve in a similar temporal pattern is not yet clear. Prior studies of putative AD biomarkers examined restricted age groups [12][13][14], and earlier studies employed sub-optimal assays [15]. Most previous investigations on AD biomarkers in DS were limited to analysis of plasma Aβ.…”

The AT(N) framework for Alzheimer's disease in adults with Down syndrome

“…A positive correlation of tau and a negative correlation of CSF Aβ1‐42 have been reported with age 71 and several studies have documented correlations of the changes in amyloid in DS with AD 72‐75 . Higher levels of Aβ42 or the Aβ42/Aβ40 ratio appear to be associated with the onset of AD in DS, 76,77 although this is not entirely consistent in the literature 78 . CSF Aβ42 levels are first increased in early life and then become lower with age, representing deposition of Aβ into plaques 64,79,80 .…”

Maternal antibodies facilitate Amyloid-β clearance by activating Fc-receptor-Syk-mediated phagocytosis

“…DS shares common pathological symptoms with Alzheimer’s disease (AD) (Choong, Tosh, Pulford, & Fisher, 2015), as individuals with DS experience AD-related cognitive decline in their 4 th and 5 th decades of their lives (Choong et al, 2015; Wiseman et al, 2015). This is preceded by a significant and widespread AD-related pathology, detected as early as at the age of 12 years (Burger & Vogel, 1973), which includes intraneural neurofibrillary tangles, amyloid-β (Aβ) angiopathy, extracellular Aβ neuritic plaques (Alhajraf, Ness, Hye, & Strydom, 2019), and microgliosis (Heneka, 2019; Raha-Chowdhury et al, 2018; Tejera & Heneka, 2019). This is in part due to over-expression of the APP and DYRK1A genes, located on the triplicated chromosome 21 (Korbel et al, 2009), although Aβ deposition is also promoted by non- APP mediated mechanisms in this pathology (Wiseman et al, 2015; Wiseman et al, 2018).…”