Probing the proteome to explore potential correlates of increased Alzheimer's‐related cerebrovascular disease in adults with Down syndrome

Moni, Fahmida; Petersen, Melissa; Zhang, Fan; Lao, Patrick J.; Zimmerman, Molly E.; Gu, Yian; Gutierrez, José; Rizvi, Batool; Laing, Krystal K; Igwe, Kay C.; Sathishkumar, Mithra; Keator, David; Andrews, Howard; Krinsky‐McHale, Sharon J.; Head, Elizabeth; Lee, Joseph H.; Lai, Florence; Yassa, Michael A.; Rosas, H. Diana; Silverman, Wayne; Lott, Ira T.; Schupf, Nicole; O’Bryant, Sid; Brickman, Adam M.

doi:10.1002/alz.12627

Cited by 4 publications

(2 citation statements)

References 45 publications

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“…Our findings are consistent with our previous study, which showed more consistent associations between peripheral proteomic markers of inflammation and MRI markers of cerebrovascular disease in presymptomatic phases of AD among adults with DS. 32 Further, postmortem data revealed a unique inflammatory profile in adults with DS and inflammatory proteins related to astrocytosis were elevated in the early stages of AD. 58 Adults with DS also show evidence of blood-brain barrier (BBB) disruption at autopsy.…”

Section: Discussionmentioning

confidence: 97%

“…31 In adults with DS, MRI markers of CVD are associated with proteomic patterns reflective of inflammation earlier in the disease and with patterns reflective of neurodegeneration later in the disease. 32 Glial fibrillary acidic protein (GFAP) is a cytoskeletal protein found in astrocytes, released during astrogliosis, and can be measured reliably in cerebrospinal and blood compartments. 33 GFAP concentration is elevated in people with and at-risk for AD [34][35][36] and appears to mediate the relationship between Aβ and tau pathology.…”

Section: Introductionmentioning

confidence: 99%

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Cerebrovascular disease drives Alzheimer plasma biomarker concentrations in adults with Down syndrome

Edwards,

Lao,

Alshikho

et al. 2023

Preprint

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ImportanceBy age 40 years over 90% of adults with Down syndrome (DS) have Alzheimer’s disease (AD) pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with DS have elevated cerebrovascular disease (CVD) markers that track with the clinical progression of AD, suggesting a role for CVD that is hypothesized to be mediated by inflammatory factors.ObjectiveTo examine the pathways through which small vessel CVD contributes to AD-related pathophysiology and neurodegeneration in adults with DS.DesignCross sectional analysis of neuroimaging, plasma, and clinical data.SettingParticipants were enrolled in Alzheimer’s Biomarker Consortium – Down Syndrome (ABC-DS), a multisite study of AD in adults with DS.ParticipantsOne hundred eighty-five participants (mean [SD] age=45.2 [9.3] years) with available MRI and plasma biomarker data were included. White matter hyperintensity (WMH) volumes were derived from T2-weighted FLAIR MRI scans and plasma biomarker concentrations of amyloid beta (Aβ42/Aβ40), phosphorylated tau (p-tau217), astrocytosis (glial fibrillary acidic protein, GFAP), and neurodegeneration (neurofilament light chain, NfL) were measured with ultrasensitive immunoassays.Main Outcomes and MeasuresWe examined the bivariate relationships of WMH, Aβ42/Aβ40, p-tau217, and GFAP with age-residualized NfL across AD diagnostic groups. A series of mediation and path analyses examined causal pathways linking WMH and AD pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis.ResultsThere was a direct and indirect bidirectional effect through GFAP of WMH on p-tau217 concentration, which was associated with NfL concentration in the entire sample. Among cognitively stable participants, WMH was directly and indirectly, through GFAP, associated with p-tau217 concentration, and in those with MCI, there was a direct effect of WMH on p-tau217 and NfL concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia.Conclusions and RelevanceThe findings suggest that among individuals with DS, CVD promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of AD. This work joins an emerging literature that implicates CVD and its interface with neuroinflammation as a core pathological feature of AD in adults with DS.Key PointsQuestionDo white matter hyperintensities, a magnetic resonance imaging marker of small vessel cerebrovascular disease, predict plasma Alzheimer’s biomarker concentrations of amyloid, tau, and neuroinflammatory pathophysiology and downstream neurodegeneration in adults with Down syndrome?FindingsIncreases in white matter hyperintensity volume precede and promote inflammation- and tau-related pathophysiology, directly and indirectly, leading to downstream neurodegeneration.MeaningSmall vessel cerebrovascular disease may contribute to the pathophysiological progression of Alzheimer’s disease in adults with Down syndrome. These findings support the hypothesis that cerebrovascular disease is a core feature of Alzheimer’s disease in adults with Down syndrome.

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Section: Discussionmentioning

confidence: 97%