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. 2020 Apr;16(4):681-695.
doi: 10.1016/j.jalz.2019.09.004. Epub 2020 Jan 16.

Plasma biomarkers of astrocytic and neuronal dysfunction in early- and late-onset Alzheimer's disease

Fanny M Elahi  1 , Kaitlin B Casaletto  1 , Renaud La Joie  1 , Samantha M Walters  1 , Danielle Harvey  2 , Amy Wolf  1 , Lauren Edwards  1 , Wilfredo Rivera-Contreras  1 , Anna Karydas  1 , Yann Cobigo  1 , Howard J Rosen  1 , Charles DeCarli  3 , Bruce L Miller  1 , Gil D Rabinovici  1   4 , Joel H Kramer  1
Affiliations

Plasma biomarkers of astrocytic and neuronal dysfunction in early- and late-onset Alzheimer's disease

Fanny M Elahi et al. Alzheimers Dement. 2020 Apr.

Abstract

Introduction: We investigated plasma proteomic markers of astrocytopathy, brain degeneration, plasticity, and inflammation in sporadic early-onset versus late-onset Alzheimer's disease (EOAD and LOAD).

Methods: Plasma was analyzed using ultra-sensitive immuno-based assays from 33 EOAD, 30 LOAD, and 36 functionally normal older adults.

Results: Principle component analyses identified 3 factors: trophic (BDNF, VEGF, TGFβ), degenerative (GFAP, NfL), and inflammatory (TNFα, IL-6, IP-10, IL-10). Trophic factor was elevated in both AD groups and associated with cognition and gray matter volumes. Degenerative factor was elevated in EOAD, with higher levels associated with worse functioning in this group. Biomarkers of inflammation were not significantly different between groups and were only associated with age.

Disucssion: Plasma proteomic biomarkers provide novel means of investigating molecular processes in vivo and their contributions to clinical outcomes. We present initial investigations of several of these fluid biomarkers, capturing aspects of astrocytopathy, neuronal injury, cellular plasticity, and inflammation in EOAD versus LOAD.

Keywords: Astrocytopathy; Brain homeostasis; Cerebral small vessel disease; Early-onset Alzheimer's disease; Exosomes; Growth hormones; Immune activation; Inflammation; Late-onset Alzheimer's disease; Neurodegeneration; White matter disease.

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Conflict of interest statement

CONFLICT OF INTERESTS

The authors have declared that no conflict of interest exists.

Figures

FIGURE 1
FIGURE 1
Experimental design.
FIGURE 2
FIGURE 2
Factor loadings by plasma biomarker for three main principle components.
FIGURE 3
FIGURE 3
Comparison of plasma biomarkers across control, EOAD, and LOAD groups. Comparison of plasma biomarkers across groups (controls, EOAD, LOAD). The values depicted were log-transformed to normalize distributions. Stars depict significance levels from age-adjusted ANCOVA models with post hoc Tukey HSD test: **≤.01; *≤.05. Abbreviations: EOAD, early-onset Alzheimer’s disease; LOAD, late-onset Alzheimer’s disease; HSD, honestly significant difference.
FIGURE 4
FIGURE 4
Principle components compared across control, EOAD and LOAD groups. Comparison of principle components (degenerative, trophic, and inflammatory factors) across groups. Stars depict significance levels from age-adjusted ANCOVA models with post hoc Tukey HSD test: **≤.01; *≤.05. Abbreviations: EOAD, early-onset Alzheimer’s disease; LOAD, late-onset Alzheimer’s disease; HSD, honestly significant difference.
FIGURE 5
FIGURE 5
Principle components compared across groups based on extent of WMH. Comparison of principle components (degenerative, trophic, and inflammatory factors) across groups divided based on extent of white matter injury. Stars depict significance levels from age-adjusted ANCOVA models with post-hoc Tukey HSD test: **≤.01; *≤.05. Abbreviations: AD−WMH, Alzheimer’s disease without white matter hyperintensity (Fazekas score 0–1); AD+WMH, Alzheimer’s disease with white matter hyperintensity (Fazekas score 2–3); HSD, honestly significant difference.
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