Associations of circulating C-reactive proteins, APOE ε4, and brain markers for Alzheimer’s disease in healthy samples across the lifespan
•The APOE ε4 allele and high circulating levels of C-reactive protein (CRP) are associated with the risk of Alzheimer’s disease.•Whereas APOE ε4 carriers show lower CRP levels than non-carriers in clinical samples of middle- and older- age, here we show that this APOE ε4-CRP relation also exists amo...
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| creator | Wang, Yunpeng Grydeland, Håkon Roe, James M. Pan, Mengyu Magnussen, Fredrik Amlien, Inge K. Watne, Leiv Otto Idland, Ane-Victoria Bertram, Lars Gundersen, Thomas E. Pascual-Leone, Alvaro Cabello-Toscano, Maria Tormos, Jose M. Bartres-Faz, David Drevon, Christian A. Fjell, Anders M. Walhovd, Kristine W. |
| description | •The APOE ε4 allele and high circulating levels of C-reactive protein (CRP) are associated with the risk of Alzheimer’s disease.•Whereas APOE ε4 carriers show lower CRP levels than non-carriers in clinical samples of middle- and older- age, here we show that this APOE ε4-CRP relation also exists among subjects as young as 20 years old.•APOE ε4 and PGS for CRP only associate with low CRP ranges, and the higher the CRP levels, the less their variations were attributable to genetic variation.•Both APOE ε4 and high CRP levels are associated with small hippocampal volume, but only APOE ε4 shows association with other biomarkers for AD, and CRP levels do not.
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 |
| doi_str_mv | 10.1016/j.bbi.2021.12.008 |
| format | Article |
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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.
The inverse correlation between APOEε 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 APOEε 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.</description><identifier>ISSN: 0889-1591</identifier><identifier>EISSN: 1090-2139</identifier><identifier>DOI: 10.1016/j.bbi.2021.12.008</identifier><identifier>PMID: 34920091</identifier><language>eng</language><publisher>Netherlands: Elsevier Inc</publisher><subject>Aged ; Alzheimer Disease - metabolism ; Alzheimer’s disease ; Amyloid beta-Peptides - metabolism ; APOE ; Apolipoprotein E4 - genetics ; Apolipoprotein E4 - metabolism ; Biomarkers - metabolism ; Brain - metabolism ; C-Reactive Protein - metabolism ; CRP ; Hippocampal volume ; Humans ; Inflammation ; Longevity - genetics ; Middle Aged ; Peptide Fragments - metabolism ; tau Proteins - metabolism</subject><ispartof>Brain, behavior, and immunity, 2022-02, Vol.100, p.243-253</ispartof><rights>2021 The Authors</rights><rights>Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3118-121c92f4e96abf95f1cdb2763983f0d9461a24b76132592ef2b47ff0e20469e63</citedby><cites>FETCH-LOGICAL-c3118-121c92f4e96abf95f1cdb2763983f0d9461a24b76132592ef2b47ff0e20469e63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0889159121006395$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34920091$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Yunpeng</creatorcontrib><creatorcontrib>Grydeland, Håkon</creatorcontrib><creatorcontrib>Roe, James M.</creatorcontrib><creatorcontrib>Pan, Mengyu</creatorcontrib><creatorcontrib>Magnussen, Fredrik</creatorcontrib><creatorcontrib>Amlien, Inge K.</creatorcontrib><creatorcontrib>Watne, Leiv Otto</creatorcontrib><creatorcontrib>Idland, Ane-Victoria</creatorcontrib><creatorcontrib>Bertram, Lars</creatorcontrib><creatorcontrib>Gundersen, Thomas E.</creatorcontrib><creatorcontrib>Pascual-Leone, Alvaro</creatorcontrib><creatorcontrib>Cabello-Toscano, Maria</creatorcontrib><creatorcontrib>Tormos, Jose M.</creatorcontrib><creatorcontrib>Bartres-Faz, David</creatorcontrib><creatorcontrib>Drevon, Christian A.</creatorcontrib><creatorcontrib>Fjell, Anders M.</creatorcontrib><creatorcontrib>Walhovd, Kristine W.</creatorcontrib><title>Associations of circulating C-reactive proteins, APOE ε4, and brain markers for Alzheimer’s disease in healthy samples across the lifespan</title><title>Brain, behavior, and immunity</title><addtitle>Brain Behav Immun</addtitle><description>•The APOE ε4 allele and high circulating levels of C-reactive protein (CRP) are associated with the risk of Alzheimer’s disease.•Whereas APOE ε4 carriers show lower CRP levels than non-carriers in clinical samples of middle- and older- age, here we show that this APOE ε4-CRP relation also exists among subjects as young as 20 years old.•APOE ε4 and PGS for CRP only associate with low CRP ranges, and the higher the CRP levels, the less their variations were attributable to genetic variation.•Both APOE ε4 and high CRP levels are associated with small hippocampal volume, but only APOE ε4 shows association with other biomarkers for AD, and CRP levels do not.
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.
The inverse correlation between APOEε 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 APOEε 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.</description><subject>Aged</subject><subject>Alzheimer Disease - metabolism</subject><subject>Alzheimer’s disease</subject><subject>Amyloid beta-Peptides - metabolism</subject><subject>APOE</subject><subject>Apolipoprotein E4 - genetics</subject><subject>Apolipoprotein E4 - metabolism</subject><subject>Biomarkers - metabolism</subject><subject>Brain - metabolism</subject><subject>C-Reactive Protein - metabolism</subject><subject>CRP</subject><subject>Hippocampal volume</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Longevity - genetics</subject><subject>Middle Aged</subject><subject>Peptide Fragments - metabolism</subject><subject>tau Proteins - metabolism</subject><issn>0889-1591</issn><issn>1090-2139</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU1uFDEQhS0EIkPgAGyQlyzSHZfd7WmL1WgUfqRIyQLWlttdZjz0z-DqiRRWXIADcBCuwSE4CZ5MYJlVqaTvPdWrx9hLECUI0Ofbsm1jKYWEEmQpRPOILUAYUUhQ5jFbiKYxBdQGTtgzoq0QolbQPGUnqjJSCAML9mNFNPno5jiNxKfAfUx-3-d9_MzXRULn53iDfJemGeNIZ3x1fXXBf_-qzrgbO94mF0c-uPQFE_EwJb7qv20wDpj-fP9JvIuEjpBnaIOunze3nNyw65G482ki4vMGeR8D0s6Nz9mT4HrCF_fzlH16e_Fx_b64vHr3Yb26LLwCaAqQ4I0MFRrt2mDqAL5r5VIr06ggOlNpcLJqlxqUrI3EINtqGYJAKSptUKtT9vrom2N93SPNdojkse_diNOerNQAutZSHVA4onfXJgx2l2LOe2tB2EMLdmtzC_bQggVpcwtZ8-reft8O2P1X_Ht7Bt4cAcwhbyImSz7i6LGLCf1suyk-YP8XQH6Z3Q</recordid><startdate>202202</startdate><enddate>202202</enddate><creator>Wang, Yunpeng</creator><creator>Grydeland, Håkon</creator><creator>Roe, James M.</creator><creator>Pan, Mengyu</creator><creator>Magnussen, Fredrik</creator><creator>Amlien, Inge K.</creator><creator>Watne, Leiv Otto</creator><creator>Idland, Ane-Victoria</creator><creator>Bertram, Lars</creator><creator>Gundersen, Thomas E.</creator><creator>Pascual-Leone, Alvaro</creator><creator>Cabello-Toscano, Maria</creator><creator>Tormos, Jose M.</creator><creator>Bartres-Faz, David</creator><creator>Drevon, Christian A.</creator><creator>Fjell, Anders M.</creator><creator>Walhovd, Kristine W.</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>202202</creationdate><title>Associations of circulating C-reactive proteins, APOE ε4, and brain markers for Alzheimer’s disease in healthy samples across the lifespan</title><author>Wang, Yunpeng ; Grydeland, Håkon ; Roe, James M. ; Pan, Mengyu ; Magnussen, Fredrik ; Amlien, Inge K. ; Watne, Leiv Otto ; Idland, Ane-Victoria ; Bertram, Lars ; Gundersen, Thomas E. ; Pascual-Leone, Alvaro ; Cabello-Toscano, Maria ; Tormos, Jose M. ; Bartres-Faz, David ; Drevon, Christian A. ; Fjell, Anders M. ; Walhovd, Kristine W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3118-121c92f4e96abf95f1cdb2763983f0d9461a24b76132592ef2b47ff0e20469e63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Aged</topic><topic>Alzheimer Disease - metabolism</topic><topic>Alzheimer’s disease</topic><topic>Amyloid beta-Peptides - metabolism</topic><topic>APOE</topic><topic>Apolipoprotein E4 - genetics</topic><topic>Apolipoprotein E4 - metabolism</topic><topic>Biomarkers - metabolism</topic><topic>Brain - metabolism</topic><topic>C-Reactive Protein - metabolism</topic><topic>CRP</topic><topic>Hippocampal volume</topic><topic>Humans</topic><topic>Inflammation</topic><topic>Longevity - genetics</topic><topic>Middle Aged</topic><topic>Peptide Fragments - metabolism</topic><topic>tau Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Yunpeng</creatorcontrib><creatorcontrib>Grydeland, Håkon</creatorcontrib><creatorcontrib>Roe, James M.</creatorcontrib><creatorcontrib>Pan, Mengyu</creatorcontrib><creatorcontrib>Magnussen, Fredrik</creatorcontrib><creatorcontrib>Amlien, Inge K.</creatorcontrib><creatorcontrib>Watne, Leiv Otto</creatorcontrib><creatorcontrib>Idland, Ane-Victoria</creatorcontrib><creatorcontrib>Bertram, Lars</creatorcontrib><creatorcontrib>Gundersen, Thomas E.</creatorcontrib><creatorcontrib>Pascual-Leone, Alvaro</creatorcontrib><creatorcontrib>Cabello-Toscano, Maria</creatorcontrib><creatorcontrib>Tormos, Jose M.</creatorcontrib><creatorcontrib>Bartres-Faz, David</creatorcontrib><creatorcontrib>Drevon, Christian A.</creatorcontrib><creatorcontrib>Fjell, Anders M.</creatorcontrib><creatorcontrib>Walhovd, Kristine W.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Brain, behavior, and immunity</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Yunpeng</au><au>Grydeland, Håkon</au><au>Roe, James M.</au><au>Pan, Mengyu</au><au>Magnussen, Fredrik</au><au>Amlien, Inge K.</au><au>Watne, Leiv Otto</au><au>Idland, Ane-Victoria</au><au>Bertram, Lars</au><au>Gundersen, Thomas E.</au><au>Pascual-Leone, Alvaro</au><au>Cabello-Toscano, Maria</au><au>Tormos, Jose M.</au><au>Bartres-Faz, David</au><au>Drevon, Christian A.</au><au>Fjell, Anders M.</au><au>Walhovd, Kristine W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Associations of circulating C-reactive proteins, APOE ε4, and brain markers for Alzheimer’s disease in healthy samples across the lifespan</atitle><jtitle>Brain, behavior, and immunity</jtitle><addtitle>Brain Behav Immun</addtitle><date>2022-02</date><risdate>2022</risdate><volume>100</volume><spage>243</spage><epage>253</epage><pages>243-253</pages><issn>0889-1591</issn><eissn>1090-2139</eissn><abstract>•The APOE ε4 allele and high circulating levels of C-reactive protein (CRP) are associated with the risk of Alzheimer’s disease.•Whereas APOE ε4 carriers show lower CRP levels than non-carriers in clinical samples of middle- and older- age, here we show that this APOE ε4-CRP relation also exists among subjects as young as 20 years old.•APOE ε4 and PGS for CRP only associate with low CRP ranges, and the higher the CRP levels, the less their variations were attributable to genetic variation.•Both APOE ε4 and high CRP levels are associated with small hippocampal volume, but only APOE ε4 shows association with other biomarkers for AD, and CRP levels do not.
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.
The inverse correlation between APOEε 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 APOEε 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.</abstract><cop>Netherlands</cop><pub>Elsevier Inc</pub><pmid>34920091</pmid><doi>10.1016/j.bbi.2021.12.008</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Brain, behavior, and immunity, 2022-02, Vol.100, p.243-253 |
| issn | 0889-1591 1090-2139 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | Aged Alzheimer Disease - metabolism Alzheimer’s disease Amyloid beta-Peptides - metabolism APOE Apolipoprotein E4 - genetics Apolipoprotein E4 - metabolism Biomarkers - metabolism Brain - metabolism C-Reactive Protein - metabolism CRP Hippocampal volume Humans Inflammation Longevity - genetics Middle Aged Peptide Fragments - metabolism tau Proteins - metabolism |
| title | Associations of circulating C-reactive proteins, APOE ε4, and brain markers for Alzheimer’s disease in healthy samples across the lifespan |
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