Cerebrospinal fluid neuroinflammatory biomarkers along the Alzheimer disease continuum in Down syndrome

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is the main medical problem and cause of death for adults with Down syndrome (DS). Glial activation is an early phenomenon central to AD pathophysiology; however, whether glial biomarker profiles in DS differ from sporadic AD remains unanswered. We compared cerebrospinal fluid (CSF) glial biomarkers along the AD continuum between DS individuals and sporadic AD cases and its relationship with CSF neurodegeneration biomarkers.MethodSingle‐center cross‐sectional study. We classified individuals with DS into three clinical subgroups: without cognitive impairment (aDS), prodromal AD (pDS) or with AD dementia (dDS). We determined CSF‐YKL40 and progranulin protein (PGRN) levels by ELISA (Quidel and Adipogen, respectively) and we compare them along the AD continuum in DS. For comparisons, we included subjects with sporadic prodromal AD (pAD) and AD dementia (ADd) and healthy controls. We studied correlations of YKL40 and PGRN with CSF‐total‐tau (Fujirebio‐Europe), phospho‐tau (Fujirebio‐Europe) and NfL (UmanDiagnostics) within participants with DS. We used Mann‐Whitney tests corrected for multiple comparisons and Spearman coefficients for correlations.ResultParticipants included were 56 aDS, 17 pDS, 27 dDS, 28 pAD, 55 ADd and 147 controls. YKL40 levels were lower in aDS compared to controls (p<0.0001) and along the AD continuum in DS compared to sporadic cases (pDS vs pAD, p= 0.0004 and dDS vs ADd, p=0.0002) (Figure 1a). Symptomatic AD was associated with an 88.8% increase in YKL40 levels in DS and with a 69.9% increase in sporadic AD. There were no differences in PGRN levels along the AD continuum in DS or between DS and sporadic AD; however, PGRN levels were lower in aDS than in HC (Figure 1b). Both YKL40 and PGRN levels positively correlated with total‐tau (r=0.3, p<0.001; r=0.4, p<0.001), phospho‐tau (r=0.87, p<0.001; r=0.41, p<0.001) and NfL, (r=0.82, p<0.001; r=0.43 p<0.001) levels in the group with DS.ConclusionCSF glial biomarkers in subjects with DS differ from that in healthy controls and sporadic AD. However, symptomatic AD is characterized by similar changes in astrocyte and microglial activation markers such as YKL‐40 and PGRN. Differences in the immune system and response to AD might have important therapeutic implications and deserve further research.