Alpha‐Synuclein Pathology in Down Syndrome‐Associated Alzheimer's Disease: Insights from Seed Amplification Assay and Neuropathology

TL;DR

People with Down syndrome often develop Alzheimer's and Lewy body pathology, and this study finds that misfolded alpha-synuclein can be detected in cerebrospinal fluid from an early age.

Contribution

First study to explore alpha-synuclein pathology in Down syndrome-associated Alzheimer's using seed amplification assays and link it to brain pathology.

Findings

Alpha-synuclein positivity was found in 9.2% of Down syndrome individuals, similar to autosomal dominant Alzheimer's.

Lewy body pathology was present in 47% of brain cases, with amygdala and olfactory bulb most affected.

Plasma neurofilament light chain levels were higher in alpha-synuclein positive individuals.

Abstract

Down syndrome (DS) is a genetic cause of Alzheimer's disease (AD), with virtually all individuals developing AD pathology by their fourth decade due to Amyloid Precursor Protein (APP) gene overexpression. In addition to amyloid beta (Aβ) plaques and hyperphosphorylated tau (p‐Tau) aggregates, DS‐associated AD (DSAD) often includes α‐synuclein (αSyn) aggregates, contributing to Lewy body pathology (LBP). The αSyn Seed Amplification Assay (SAA) in cerebrospinal fluid (CSF) enables the in vivo detection of misfolded αSyn. While αSyn‐SAA has revealed αSyn pathology in autosomal dominant (6%–11%) and sporadic (21%–45%) AD, its role in DSAD remains unexplored. This study investigates αSyn‐SAA positivity in DSAD, linking in vivo findings to fluid biomarkers and neuropathology.

We analyzed CSF of 270 adults with DS from the DABNI and AD21 cohorts by αSyn‐SAA, encompassing asymptomatic and symptomatic AD stages (prodromal/dementia). Additional biomarkers included CSF Aβ1‐42/1‐40, CSF and plasma p‐Tau181 and neurofilament light chain (NfL) levels. Neuropathological evaluations in 19 brain donors, including 5 with antemortem CSF, assessed AD neuropathology and LBP.

As shown in Table 1, αSyn‐SAA positivity was observed in 9.2% of participants, consistent across age groups (Figure 1) and cognitive stages. Symptomatic αSyn‐SAA‐positive individuals exhibited significantly higher plasma NfL levels compared to αSyn‐SAA‐negative individuals (31.0 vs. 21.1 pg/mL, p =  0.027). Neuropathological analysis revealed LBP in 47% of cases, with the amygdala and olfactory bulb being the most frequently affected regions (Table 2). Among the five donors with antemortem CSF, the only αSyn‐SAA‐positive case corresponded to an individual with severe neocortical LBP.

This study examines the relationship between LBP and DSAD, identifying a prevalence of αSyn‐SAA positivity comparable to autosomal dominant AD but lower than sporadic AD. A potential association was noted between severe neocortical LBP and αSyn seeding activity, while age and cognitive status did not significantly influence positivity rates. Misfolded αSyn was detectable from early ages in individuals with DS. Further research is required to elucidate the mechanisms underlying LBP in DSAD, assess its clinical impact on cognitive and motor symptoms, and explore relationships with other biomarkers.

Figures