Association of cerebrospinal fluid Aβ42 with A2M gene in cognitively normal subjects

Millard, Steven P.; Lutz, Franziska; Li, Ge; Galasko, Douglas; Farlow, Martin R.; Quinn, Joseph F.; Kaye, Jeffrey; Leverenz, James B.; Tsuang, Debby W.; Yu, Chang; Peskind, Elaine R.; Bekris, Lynn M.

doi:10.1016/j.neurobiolaging.2013.07.027

Cited by 6 publications

(5 citation statements)

References 64 publications

(82 reference statements)

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“…As expected, the percentage of patients with MCI and AD increased among patients with either 1 or 2 APOE4 alleles. Consistent with prior work [35, 36], increasing APOE4 copy number was associated with lower CSF Aβ levels. Increasing APOE4 copy number was also associated with increases in CSF tau and p-tau levels (Table 1).…”

Section: Resultssupporting

confidence: 90%

APOE4 Copy Number-Dependent Proteomic changes in the Cerebrospinal Fluid

Berger

Cooter

Roesler

et al. 2020

Preprint

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Background: APOE4 has been hypothesized to increase Alzheimer's disease risk by increasing neuroinflammation, though the specific neuroinflammatory pathways involved are unclear. Objectives: To characterize CSF proteomic changes as a function of APOE4 copy number. Methods: We analyzed targeted proteomic data obtained on ADNI CSF samples using a linear regression model adjusting for age, sex, and APOE4 copy number, and a second linear model also adjusting for AD clinical status. False Discovery Rate (FDR) was used to correct for multiple comparisons. Results: In the first model, increasing APOE4 copy number was associated with significant expression decreases in a CRP peptide (q=0.006), and significant expression increases in peptides from ALDOA, CH3L1 (YKL-40), and FABPH (q<0.05 for each). In the second model (controlling for age, sex, and AD clinical status), increasing APOE4 copy number was associated with significant expression decreases in a CRP peptide (q=0.009). In both models, increased APOE4 copy number was associated with trends towards lower expression of all 24 peptides from all 8 different complement proteins measured here, although none of these differences were statistically significant. The odds of this happening by chance for 24 unrelated peptides would be less than 1 in 16 million. Conclusions: Increasing APOE4 copy number was associated with decreased CSF CRP levels and increased CSF ALDOA, CH3L1 and FABH levels; the CRP decrease remained significant after controlling for AD clinical status. Increased APOE4 copy number may also be associated with decreased CSF complement pathway protein levels, a hypothesis for investigation in future studies.

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Section: Resultssupporting

confidence: 90%

APOE4 Copy Number-Dependent Proteomic changes in the Cerebrospinal Fluid

Berger

Cooter

Roesler

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…As expected, the percentage of patients with MCI and AD increased among patients with either 1 or 2 APOE4 alleles. Consistent with prior work [ 35, 36 ], increasing APOE4 copy number was associated with lower CSF Aβ levels. Increasing APOE4 copy number was also associated with increases in CSF tau and p-tau levels ( Table 1 ).…”

Section: Resultssupporting

confidence: 90%

APOE4 Copy Number-Dependent Proteomic Changes in the Cerebrospinal Fluid1

Berger

Cooter

Roesler

et al. 2021

JAD

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Background: APOE4 has been hypothesized to increase Alzheimer’s disease risk by increasing neuroinflammation, though the specific neuroinflammatory pathways involved are unclear. Objective: Characterize cerebrospinal fluid (CSF) proteomic changes related to APOE4 copy number. Methods: We analyzed targeted proteomic data from ADNI CSF samples using a linear regression model adjusting for age, sex, and APOE4 copy number, and additional linear models also adjusting for AD clinical status or for CSF Aβ, tau, or p-tau levels. False discovery rate was used to correct for multiple comparisons correction. Results: Increasing APOE4 copy number was associated with a significant decrease in a CRP peptide level across all five models (q < 0.05 for each), and with significant increases in ALDOA, CH3L1 (YKL-40), and FABPH peptide levels (q < 0.05 for each) except when controlling for AD clinical status or neurodegeneration biomarkers (i.e., CSF tau or p-tau). In all models except the one controlling for CSF Aβ levels, though not statistically significant, there was a consistent inverse direction of association between APOE4 copy number and the levels of all 24 peptides from all 8 different complement proteins measured. The odds of this happening by chance for 24 unrelated peptides would be less than 1 in 16 million. Conclusion: Increasing APOE4 copy number was associated with decreased CSF CRP levels across all models, and increased CSF ALDOA, CH3L1, and FABH levels when controlling for CSF Aβ levels. Increased APOE4 copy number may also be associated with decreased CSF complement pathway protein levels, a hypothesis for investigation in future studies.

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“…The first, one limitation of using a meta-analytic approach for population-based observational studies is that these studies yield only estimates of associations that are influenced by confounding factors such as sex, age or ethnic admixture, either between studies or between cases and controls within each study [7]. For example, five studies [17,24,34,44,69] in current meta-analysis mixed other races in the Caucasian population (Table 1), however, removing these studies in all analyses did not alter the total results. In addition, the clinical characteristics of individual studies may also be a confounding factor.…”

Section: Limitations Of This Meta-analysismentioning

confidence: 99%

Alpha 2-Macroglobulin Polymorphisms and Susceptibility to Alzheimer’s Disease: A Comprehensive Meta-Analysis Based on 62 Studies

Zhang,

Liu,

Duan

et al. 2023

ADR

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Background: The relationship between alpha 2-macroglobulin (A2M) gene and Alzheimer’s disease (AD) has been widely studied across populations; however, the results are inconsistent. Objective: This study aimed to evaluate the association of A2M gene with AD by the application of meta-analysis. Methods: Relevant studies were identified by comprehensive searches. The quality of each study was assessed using the Newcastle-Ottawa Scale. Allele and genotype frequencies were extracted from each of the included studies. Odds ratio (OR) with corresponding 95% confidence intervals (CI) was calculated using a random-effects or fixed-effects model. The Cochran Q statistic and I2 metric was used to evaluate heterogeneity, and Egger’s test and Funnel plot were used to assess publication bias. Results: A total of 62 studies were identified and included in the current meta-analysis. The G allele of rs226380 reduced AD risk (OR: 0.64, 95% CI: 0.47–0.87, pFDR = 0.012), but carrier with the TT genotype was more likely to develop AD in Asian populations (OR: 1.56, 95% CI: 1.12–2.19, pFDR = 0.0135). The V allele of the A2M-I/V (rs669) increased susceptibility to AD in female population (OR, 95% CI: 2.15, 1.38–3.35, pFDR = 0.0024); however, the II genotype could be a protective factor in these populations (OR, 95% CI: 0.43, 0.26–0.73, pFDR = 0.003). Sensitivity analyses confirmed the reliability of the original results. Conclusions: Existing evidence indicate that A2M single nucleotide polymorphisms (SNPs) may be associated with AD risk in sub-populations. Future studies with larger sample sizes will be necessary to confirm the results.

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Association of cerebrospinal fluid Aβ42 with A2M gene in cognitively normal subjects

Cited by 6 publications

References 64 publications

APOE4 Copy Number-Dependent Proteomic changes in the Cerebrospinal Fluid

APOE4 Copy Number-Dependent Proteomic changes in the Cerebrospinal Fluid

APOE4 Copy Number-Dependent Proteomic Changes in the Cerebrospinal Fluid1

Alpha 2-Macroglobulin Polymorphisms and Susceptibility to Alzheimer’s Disease: A Comprehensive Meta-Analysis Based on 62 Studies

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