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Pathologic and clinical correlates of region-specific brain GFAP in Alzheimer’s disease

Phillips, Jared M., Winfree, Rebecca L., Seto, Mabel, Schneider, Julie A., Bennett, David A., Dumitrescu, Logan C., Hohman, Timothy J.·2024·Acta Neuropathologica
DOI 10.1007/s00401-024-02828-5PMC PMC11586308
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Abstract

Plasma glial fibrillary acidic protein (GFAP) is an emerging biomarker of Alzheimer’s disease (AD), with higher blood GFAP levels linked to faster cognitive decline, particularly among individuals with high brain amyloid burden. However, few studies have examined brain GFAP expression to clarify if peripheral associations reflect brain changes. This study aimed to correlate region-specific GFAP mRNA expression ( n = 917) and protein abundance (n=386) with diverse neuropathological measures at autopsy in the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP) and to characterize the interaction between brain GFAP and brain amyloid burden on downstream outcomes. We assessed GFAP gene expression in the dorsolateral prefrontal cortex, caudate nucleus, and posterior cingulate cortex with respect to core AD pathology (amyloid-β and tau), cerebrovascular (microinfarcts, macroinfarcts, and cerebral amyloid angiopathy [CAA]), proteinopathic (TDP-43, Lewy bodies), and cognitive outcomes. These associations were further examined at the protein level using tandem-mass tag proteomic measurements from the dorsolateral prefrontal cortex. We also assessed GFAP interactions with AD neuropathology on downstream outcomes. Cortical GFAP gene and protein expression were significantly upregulated in participants with a neuropathologically confirmed AD diagnosis at autopsy (all P FDR < 3.5e−4), but not in individuals positive for tau pathology and negative for amyloid pathology (all P FDR > 0.05). Higher cortical GFAP levels were associated with increased amyloid pathology, CAA pathology, and faster cognitive decline (all P FDR < 3.3e−3). GFAP’s associations with phosphorylated tau burden and cognition were influenced by amyloid burden, being most pronounced among amyloid-positive individuals, confirming previous in vivo biomarker observations. No associations were observed between GFAP gene expression and outcomes in the caudate nucleus. Our results support previous biomarker findings and suggest that higher brain GFAP levels are associated with higher brain amyloid burden and faster cognitive decline among amyloid-positive individuals.

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Fig. 1 GFAP expression across diagnostic status. Cortical GFAP mRNA and protein are higher in those with a clinical or pathologic AD diagnosis than controls, while caudate expression values do not differ across diagnoses. A Final summary clinical diagnosis: normal cognition (NC), mild cognitive impairment (MCI), and Alzheimer’s disease (AD). B Pathologic diagnosis according to neuropathologic staging (CERAD and Braak) NIA-Reagan criteria. Positive: high or intermediate likelihood of AD and negative: low likelihood or no AD. Significance values are derived from pairwise Student t tests and FDR-corrected results. ns: p > 0.05. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001
Fig. 1 GFAP expression across diagnostic status. Cortical GFAP mRNA and protein are higher in those with a clinical or pathologic AD diagnosis than controls, while caudate expression values do not differ across diagnoses. A Final summary clinical diagnosis: normal cognition (NC), mild cognitive impairment (MCI), and Alzheimer’s disease (AD). B Pathologic diagnosis according to neuropathologic staging (CERAD and Braak) NIA-Reagan criteria. Positive: high or intermediate likelihood of AD and negative: low likelihood or no AD. Significance values are derived from pairwise Student t tests and FDR-corrected results. ns: p > 0.05. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001CC BY · PubMed Central
Fig. 2 GFAP associations with brain amyloid. Cortical but not caudate GFAP is positively associated with brain amyloid burden. A–D Regional GFAP protein and mRNA levels by Aβ1-42 burden as measured by immunohistochemistry. E–H Regional GFAP protein and mRNA levels by neuritic plaque burden as measured by silver stain. Unadjusted scatter plots and statistical results from linear regression models adjusting for age at death, sex, and post-mortem interval
Fig. 2 GFAP associations with brain amyloid. Cortical but not caudate GFAP is positively associated with brain amyloid burden. A–D Regional GFAP protein and mRNA levels by Aβ1-42 burden as measured by immunohistochemistry. E–H Regional GFAP protein and mRNA levels by neuritic plaque burden as measured by silver stain. Unadjusted scatter plots and statistical results from linear regression models adjusting for age at death, sex, and post-mortem intervalCC BY · PubMed Central
Fig. 3 GFAP associations with cognitive decline. A–D High cortical but not caudate GFAP is associated with a faster rate of global cognitive decline. Unadjusted scatter plots and statistical results from linear mixed-effects regression models adjusting for age at death, sex, education, time from last study visit to death, and post-mortem interval. Time was represented as years from the final visit, with both time and intercept included as fixed and random effects
Fig. 3 GFAP associations with cognitive decline. A–D High cortical but not caudate GFAP is associated with a faster rate of global cognitive decline. Unadjusted scatter plots and statistical results from linear mixed-effects regression models adjusting for age at death, sex, education, time from last study visit to death, and post-mortem interval. Time was represented as years from the final visit, with both time and intercept included as fixed and random effectsCC BY · PubMed Central
Fig. 4 Significant interactions of GFAP expression and amyloid status. A High GFAP mRNA expression in the dlPFC relates to a high brain phosphorylated tau burden in amyloid-positive individuals. Phosphorylated tau was quantified by immunohistochemistry, and amyloid positivity was defined as CERAD “moderate” or “frequent.” Unadjusted scatter plots and statistical results from linear regression models adjusting for age at death, sex, and post-mortem interval. B High GFAP protein expression in the dlPFC relates to a faster rate of global cognitive decline in amyloid-positive individuals. Amyloid-positivity was defined as CERAD “moderate” or “frequent.” Unadjusted scatter plots and statistical results from linear mixed-effects regression models adjusting for age at death, sex, education, time from last study visit to death, and post-mortem interval. Time was represented as years from the final visit, with both time and intercept included as fixed and random effects
Fig. 4 Significant interactions of GFAP expression and amyloid status. A High GFAP mRNA expression in the dlPFC relates to a high brain phosphorylated tau burden in amyloid-positive individuals. Phosphorylated tau was quantified by immunohistochemistry, and amyloid positivity was defined as CERAD “moderate” or “frequent.” Unadjusted scatter plots and statistical results from linear regression models adjusting for age at death, sex, and post-mortem interval. B High GFAP protein expression in the dlPFC relates to a faster rate of global cognitive decline in amyloid-positive individuals. Amyloid-positivity was defined as CERAD “moderate” or “frequent.” Unadjusted scatter plots and statistical results from linear mixed-effects regression models adjusting for age at death, sex, education, time from last study visit to death, and post-mortem interval. Time was represented as years from the final visit, with both time and intercept included as fixed and random effectsCC BY · PubMed Central

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Cites

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Metadata

Authors
Phillips, J. M., Winfree, R. L., Seto, M., Schneider, J. A., Bennett, D. A., Dumitrescu, L. C., & Hohman, T. J.
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2024-11-24
Volume
148
Issue
1
ISSN
1432-0533
DOI
10.1007/s00401-024-02828-5
PMC
PMC11586308
Cited by
25
References
14
Language
en
Licence
Funders
National Institute on Aging (F31 AG085980, U24 AG074855, R01 AG22018)

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