APOE4 Copy Number-Dependent Proteomic changes in the Cerebrospinal Fluid

Berger, Miles; Cooter, Mary; Roesler, Alexander S.; Chung, Stacey; Park, John; Modliszeski, Jennifer L.; VanDusen, Keith W.; Thompson, J. Will; Moseley, Arthur; Devinney, Michael J.; Smani, Shayan; Hall, Ashley; Cai, Victor; Browndyke, Jeffrey N.; Lutz, Michael W.; Corcoran, David L.; Initiative, Alzheimer’s Disease Neuroimaging

doi:10.1101/2020.06.30.20143578

Cited by 5 publications

(6 citation statements)

References 82 publications

(74 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Here, MDH1 was observed to increase with amyloid and tau pathology. ALDOA has been previously positively associated with CSF tau levels 79 , as was the case here, and also associated with the APOE ε4 allele 96 . Glucose metabolism, which is the major source of energy for the brain, has long been known to show signs of dysfunction in AD even before the emergence of symptoms [97][98][99][100][101] .…”

Section: Discussionsupporting

confidence: 82%

Large-scale proteome and metabolome analysis of CSF implicates altered glucose metabolism and succinylcarnitine in Alzheimer’s disease

Panyard

McKetney

Deming

et al. 2021

Preprint

View full text Add to dashboard Cite

A major hallmark of Alzheimer's disease (AD) is the aggregation of misfolded proteins (β-amyloid (A) and hyperphosphorylated tau (T)) in the brain. As these proteins can be monitored by cerebrospinal fluid (CSF) measures, the AD proteome in CSF has been of particular interest. Here, we conducted a proteome-wide assessment of the CSF in an AD cohort among participants with and without AD pathology (n = 137 total participants: 56 A-T-, 39 A+T-, and 42 A+T+; 915 proteins analyzed), identifying a diverse set of proteins in the CSF enriched for extracellular and immune system processes. We then interrogated the proteome using the amyloid, tau, and neurodegeneration (ATN) framework of AD and a panel of 9 CSF biomarkers for neurodegeneration and neuroinflammation. After multiple testing correction, we identified a total of 61 proteins significantly associated with AT group (P < 5.46 x 10-5; strongest was SMOC1, P = 1.87 x 10-12) and 636 significant protein-biomarker associations (P < 6.07 x 10-6; strongest was a positive association between neurogranin and EPHA4, P = 2.42 x 10-25) across all measures except for interleukin-6, which had no significantly associated proteins. Community network and pathway enrichment analyses highlighted three biomarker-associated protein networks: one related to amyloid and tau measures, one to CSF neurogranin, and one to the remaining CSF biomarkers. Glucose metabolic pathways were enriched primarily among the amyloid- and tau-associated proteins, including malate dehydrogenase and aldolase A, both of which were replicated as strongly associated with AD (P = 1.07 x 10-19 and P = 7.43 x 10-14, respectively) in an independent CSF proteomics cohort (n = 717 participants). Comparative performance of the CSF proteome in predicting AT categorization was high (mean AUC range 0.891-0.924 with number of protein predictors ranging from 37-97) relative to other omic predictors from the genome, CSF metabolome, and demographics from the same cohort of individuals. Collectively, these results emphasize the importance of the CSF proteome relative to other omics and implicate glucose metabolic dysregulation as amyloid and tau pathology emerges in AD.

show abstract

Section: Discussionsupporting

confidence: 82%

Large-scale proteome and metabolome analysis of CSF implicates altered glucose metabolism and succinylcarnitine in Alzheimer’s disease

Panyard

McKetney

Deming

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…CD33 controls the microglial activation state, turning microglia from housekeepers that clear amyloid into killers that destroy neurons [54][55][56][57]. Its association with AD is supported by some [10,16,[58][59][60][61], but not all [9,28] genetic studies. The CD33 rs3865444(C) risk allele was reported to be associated with greater cell surface expression of CD33 in monocytes, accumulation of amyloid pathology and increased numbers of activated human microglia [62], and increased CD33 expression was also observed in microglial cells in the AD brain [56].…”

Section: Discussionmentioning

confidence: 99%

“…Previously, we observed that elevated blood CRP levels increased the risk of AD for people carrying the APOE ε4 allele [6][7][8]. In addition, low CSF CRP was the biomarker most closely associated with the APOE ε4 copy number, not high CSF CRP levels [9]. We hypothesized that CRP, as a key inflammatory element, could modulate the impact of other genetic variants on AD risk, especially variants in gene loci involved in proinflammation.…”

Section: Introductionmentioning

confidence: 95%

The impact of increasing levels of blood C-reactive protein on the inflammatory loci SPI1 and CD33 in Alzheimer’s disease

et al. 2022

View full text Add to dashboard Cite

Apolipoprotein ε4 (APOE ε4) is the most significant genetic risk factor for late-onset Alzheimer’s disease (AD). Elevated blood C-reactive protein (CRP) further increases the risk of AD for people carrying the APOE ε4 allele. We hypothesized that CRP, as a key inflammatory element, could modulate the impact of other genetic variants on AD risk. We selected ten single nucleotide polymorphisms (SNPs) in reported AD risk loci encoding proteins related to inflammation. We then tested the interaction effects between these SNPs and blood CRP levels on AD incidence using the Cox proportional hazards model in UK Biobank (n = 279,176 white participants with 803 incident AD cases). The five top SNPs were tested for their interaction with different CRP cutoffs for AD incidence in the Framingham Heart Study (FHS) Generation 2 cohort (n = 3009, incident AD = 156). We found that for higher concentrations of serum CRP, the AD risk increased for SNP genotypes in 3 AD-associated genes (SPI1, CD33, and CLU). Using the Cox model in stratified genotype analysis, the hazard ratios (HRs) for the association between a higher CRP level (≥10 vs. <10 mg/L) and the risk of incident AD were 1.94 (95% CI: 1.33–2.84, p < 0.001) for the SPI1 rs1057233-AA genotype, 1.75 (95% CI: 1.20–2.55, p = 0.004) for the CD33 rs3865444-CC genotype, and 1.76 (95% CI: 1.25–2.48, p = 0.001) for the CLU rs9331896-C genotype. In contrast, these associations were not observed in the other genotypes of these genes. Finally, two SNPs were validated in 321 Alzheimer’s Disease Neuroimaging (ADNI) Mild Cognitive Impairment (MCI) patients. We observed that the SPI1 and CD33 genotype effects were enhanced by elevated CRP levels for the risk of MCI to AD conversion. Furthermore, the SPI1 genotype was associated with CSF AD biomarkers, including t-Tau and p-Tau, in the ADNI cohort when the blood CRP level was increased (p < 0.01). Our findings suggest that elevated blood CRP, as a peripheral inflammatory biomarker, is an important moderator of the genetic effects of SPI1 and CD33 in addition to APOE ε4 on AD risk. Monitoring peripheral CRP levels may be helpful for precise intervention and prevention of AD for these genotype carriers.

show abstract

“…Accumulating evidence has demonstrated a significant relationship between APOE and innate immune function in AD (74, 75), but the relationship between APOE4 and adaptive immunity is less understood. Recent work has found that adaptive immunity is dysregulated in APOE4 -carriers, with decreased abundance of C-reactive protein (CRP) relative to APOE3 subjects, as assessed in CSF (76) and following both acute (77) and chronic (78) measurements of CRP in blood serum. Chronically low levels of CRP were also associated with accelerated AD onset (78).…”

Section: Discussionmentioning

confidence: 99%

APOEgenotype or presence of brain amyloid alters the plasma proteome in cognitively normal, elderly subjects

Philippi

Kailash

Raj

et al. 2022

Preprint

View full text Add to dashboard Cite

Background: Processes that drive Alzheimer's disease pathogenesis have long been considered to occur within the central nervous system, yet recent studies have bolstered the possibility that changes in the periphery may be relevant to the disease process. Accumulating evidence has suggested that proteins changing in the blood may be reliable indicators of disease within the brain. Recent advances in geroscience have identified potential mechanisms of blood-brain communication that modulate brain function in ways that could be harnessed for therapy. While blood-borne proteins associated with either youth or old age have been targeted to restore function to the aged brain, it remains unclear whether other dysfunctional systemic states can be exploited for similar benefits. Here we investigate whether APOE allelic variation or presence of brain amyloid are associated with distinct proteomic changes within the systemic environment and what molecular processes are associated with these changes. Methods: Using the SOMAscan assay, we measured 1,305 plasma proteins from 53 homozygous APOE3 and APOE4 subjects (mean age = 68 years; minimum = 54 years) who exhibited no cognitive impairment, some of whom can be categorized as harboring cerebral amyloid based on cerebrospinal fluid Aβ42 measurements. Using the Dream R package for linear mixed effects modeling, we investigated possible contributions of either the APOE-ϵ4 allele or amyloid positivity to changes in the plasma proteome. Ontology-based pathway and module trait correlation analyses were performed to understand disrupted pathways that vary based on APOE genotype or amyloid positivity. Results: We found that expression of the APOE-ϵ4 allele produced distinct changes in the composition of the plasma proteome. Using both pathway enrichment analysis and weighted gene co-expression network analysis, we found that plasma proteins associated with APOE4 expression were linked to pathways related to atherosclerosis, lipid transport, the extracellular matrix, and synaptogenesis signaling. Independent of APOE4, we found that cognitively normal, amyloid-positive subjects exhibit distinct plasma proteome signatures associated with pathways previously linked to AD pathology, relative to amyloid-negative controls. Harboring brain amyloid was associated with plasma proteomic changes linked to dysfunction in blood-brain barrier and other neural cell types. Our results indicate that changes in the plasma proteome are related to possession of AD risk alleles, as well as the presence of amyloid pathology in subjects prior to the onset of symptoms. This work highlights the possibility that pathways in the systemic environment in certain risk contexts may be plausible targets to explore for modulating disease.

show abstract

APOE4 Copy Number-Dependent Proteomic changes in the Cerebrospinal Fluid

Cited by 5 publications

References 82 publications

Large-scale proteome and metabolome analysis of CSF implicates altered glucose metabolism and succinylcarnitine in Alzheimer’s disease

Large-scale proteome and metabolome analysis of CSF implicates altered glucose metabolism and succinylcarnitine in Alzheimer’s disease

The impact of increasing levels of blood C-reactive protein on the inflammatory loci SPI1 and CD33 in Alzheimer’s disease

APOEgenotype or presence of brain amyloid alters the plasma proteome in cognitively normal, elderly subjects

Contact Info

Product

Resources

About