TY - JOUR
T1 - Associations of circulating C-reactive proteins, APOE ε4, and brain markers for Alzheimer's disease in healthy samples across the lifespan
AU - Wang, Yunpeng
AU - Grydeland, Håkon
AU - Roe, James M.
AU - Pan, Mengyu
AU - Magnussen, Fredrik
AU - Amlien, Inge K.
AU - Watne, Leiv Otto
AU - Idland, Ane Victoria
AU - Bertram, Lars
AU - Gundersen, Thomas E.
AU - Pascual-Leone, Alvaro
AU - Cabello-Toscano, Maria
AU - Tormos, Jose M.
AU - Bartres-Faz, David
AU - Drevon, Christian A.
AU - Fjell, Anders M.
AU - Walhovd, Kristine W.
N1 - Funding Information:
This study is supported by the European Research Council under grant agreements 283634, 725025 (to AMF) and 313440 (to KBW); the Norwegian Research Council to YW (No.302854); the National Association for Public Health's dementia research program, Norway (to AMF), and the e Medical Student Research Program at the University of Oslo, Norway, funded the first years of the COGNORM study. Part of the research was conducted using the UK Biobank resource under application number 32048. We are grateful to all participants for their time and commitment. The funding sources had no role in the study design. The ABCD data were obtained from the Adolescent Brain Cognitive Development (ABCD) Study (https://abcdstudy.org), held in the NIMH Data Archive (NDA). ABCD is a multisite, longitudinal study designed to recruit more than 10,000 children aged 9-10 years into early adulthood. The ABCD Study is supported by the National Institutes of Health and additional federal partners under award numbers U01DA041022, U01DA041028, U01DA041048, U01DA041089, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U24DA041123, U24DA041147, U01DA041093, and U01DA041025. A full list of supporters is available at https://abcdstudy.org/federal-partners.html. A listing of participating sites and a complete listing of the study investigators can be found at https://abcdstudy.org/scientists/workgroups/. ABCD consortium investigators designed and implemented the study and/or provided data but did not necessarily participate in analysis or writing of this report. This manuscript reflects the views of the authors and may not reflect the opinions or views of the NIH or ABCD consortium investigators. Part of the computations in this work were performed on resources provided by UNINETT Sigma2-the National Infrastructure for High Performance Computing and Data Storage in Norway – with project no. (nn9769k/ns9769k).
Funding Information:
This study is supported by the European Research Council under grant agreements 283634, 725025 (to AMF) and 313440 (to KBW); the Norwegian Research Council to YW (No.302854); the National Association for Public Health's dementia research program, Norway (to AMF), and the e Medical Student Research Program at the University of Oslo, Norway, funded the first years of the COGNORM study. Part of the research was conducted using the UK Biobank resource under application number 32048. We are grateful to all participants for their time and commitment. The funding sources had no role in the study design. The ABCD data were obtained from the Adolescent Brain Cognitive Development (ABCD) Study (https://abcdstudy.org), held in the NIMH Data Archive (NDA). ABCD is a multisite, longitudinal study designed to recruit more than 10,000 children aged 9-10 years into early adulthood. The ABCD Study is supported by the National Institutes of Health and additional federal partners under award numbers U01DA041022, U01DA041028, U01DA041048, U01DA041089, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U24DA041123, U24DA041147, U01DA041093, and U01DA041025. A full list of supporters is available at https://abcdstudy.org/federal-partners.html. A listing of participating sites and a complete listing of the study investigators can be found at https://abcdstudy.org/scientists/workgroups/. ABCD consortium investigators designed and implemented the study and/or provided data but did not necessarily participate in analysis or writing of this report. This manuscript reflects the views of the authors and may not reflect the opinions or views of the NIH or ABCD consortium investigators. Part of the computations in this work were performed on resources provided by UNINETT Sigma2-the National Infrastructure for High Performance Computing and Data Storage in Norway – with project no. (nn9769k/ns9769k).
Publisher Copyright:
© 2021 The Authors
PY - 2022/2
Y1 - 2022/2
N2 - The apolipoprotein E gene ε4 allele (APOE ε4) and higher circulating level of C-reactive protein (CRP) have been extensively investigated as risk factors for Alzheimer's disease (AD). Paradoxically, APOE ε4 has been associated with lower levels of blood CRP in middle-aged and older populations. However, few studies have investigated this intriguing relation and its impact on neurological markers for AD in younger ages, nor across the whole lifespan. Here, we examine associations of blood CRP levels, APOE ε4, and biomarkers for AD in a cognitively healthy lifespan cohort (N up to 749; 20–81 years of age) and replicate the findings in UK Biobank (N = 304 322; 37–72 years of age), the developmental ABCD study (N = 10 283; 9–11 years of age), and a middle-aged sample (N = 339; 40–65 years of age). Hippocampal volume, brain amyloid-β (Aβ) plaque levels, cerebrospinal fluid (CSF) levels of Aβ and tau species, and neurofilament protein light protein (NFL) were used as AD biomarkers in subsamples. In addition, we examined the genetic contribution to the variation of CRP levels over different CRP ranges using polygenic scores for CRP (PGS-CRP). Our results show APOE ε4 consistently associates with low blood CRP levels across all age groups (p < 0.05). Strikingly, both ε4 and PGS-CRP associated mainly with blood CRP levels within the low range (<5mg/L). We then show both APOE ε4 and high CRP levels associate with smaller hippocampus volumes across the lifespan (p < 0.025). APOE ε4 was associated with high Aβ plaque levels in the brain (FDR-corrected p = 8.69x10-4), low levels of CSF Aβ42 (FDR-corrected p = 6.9x10-2), and lower ratios of Aβ42 to Aβ40 (FDR-corrected p = 5.08x10-5). Blood CRP levels were weakly correlated with higher ratio of CSF Aβ42 to Aβ40 (p = 0.03, FDR-corrected p = 0.4). APOE ε4 did not correlate with blood concentrations of another 9 inflammatory cytokines, and none of these cytokines correlated with AD biomarkers. Conclusion: The inverse correlation between APOE ε 4 and blood CRP levels existed before any pathological AD biomarker was observed, and only in the low CRP level range. Thus, we suggest to investigate whether APOE ε 4 can confer risk by being associated with a lower inflammatory response to daily exposures, possibly leading to greater accumulation of low-grade inflammatory stress throughout life. A lifespan perspective is needed to understand this relationship concerning risk of developing AD.
AB - The apolipoprotein E gene ε4 allele (APOE ε4) and higher circulating level of C-reactive protein (CRP) have been extensively investigated as risk factors for Alzheimer's disease (AD). Paradoxically, APOE ε4 has been associated with lower levels of blood CRP in middle-aged and older populations. However, few studies have investigated this intriguing relation and its impact on neurological markers for AD in younger ages, nor across the whole lifespan. Here, we examine associations of blood CRP levels, APOE ε4, and biomarkers for AD in a cognitively healthy lifespan cohort (N up to 749; 20–81 years of age) and replicate the findings in UK Biobank (N = 304 322; 37–72 years of age), the developmental ABCD study (N = 10 283; 9–11 years of age), and a middle-aged sample (N = 339; 40–65 years of age). Hippocampal volume, brain amyloid-β (Aβ) plaque levels, cerebrospinal fluid (CSF) levels of Aβ and tau species, and neurofilament protein light protein (NFL) were used as AD biomarkers in subsamples. In addition, we examined the genetic contribution to the variation of CRP levels over different CRP ranges using polygenic scores for CRP (PGS-CRP). Our results show APOE ε4 consistently associates with low blood CRP levels across all age groups (p < 0.05). Strikingly, both ε4 and PGS-CRP associated mainly with blood CRP levels within the low range (<5mg/L). We then show both APOE ε4 and high CRP levels associate with smaller hippocampus volumes across the lifespan (p < 0.025). APOE ε4 was associated with high Aβ plaque levels in the brain (FDR-corrected p = 8.69x10-4), low levels of CSF Aβ42 (FDR-corrected p = 6.9x10-2), and lower ratios of Aβ42 to Aβ40 (FDR-corrected p = 5.08x10-5). Blood CRP levels were weakly correlated with higher ratio of CSF Aβ42 to Aβ40 (p = 0.03, FDR-corrected p = 0.4). APOE ε4 did not correlate with blood concentrations of another 9 inflammatory cytokines, and none of these cytokines correlated with AD biomarkers. Conclusion: The inverse correlation between APOE ε 4 and blood CRP levels existed before any pathological AD biomarker was observed, and only in the low CRP level range. Thus, we suggest to investigate whether APOE ε 4 can confer risk by being associated with a lower inflammatory response to daily exposures, possibly leading to greater accumulation of low-grade inflammatory stress throughout life. A lifespan perspective is needed to understand this relationship concerning risk of developing AD.
UR - http://www.scopus.com/inward/record.url?scp=85121252923&partnerID=8YFLogxK
U2 - 10.1016/j.bbi.2021.12.008
DO - 10.1016/j.bbi.2021.12.008
M3 - Journal articles
C2 - 34920091
AN - SCOPUS:85121252923
SN - 0889-1591
VL - 100
SP - 243
EP - 253
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
ER -