Multivariate analysis of blood and brain transcriptome in Alzheimer’s reveals unique APOE ε4‐related immune pathways
Background While Alzheimer’s disease (AD) is generally considered a brain disease, plasma levels of AD‐related proteins including amyloid‐β, phosphorylated tau, and neurofilament light chain are associated with neurodegeneration and neuroinflammation. The APOE ε4 allele has shown cerebrovascular eff...
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| Veröffentlicht in: | Alzheimer's & dementia 2021-12, Vol.17, p.e054237-n/a |
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| container_title | Alzheimer's & dementia |
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| creator | Panitch, Rebecca Hu, Junming Farrer, Lindsay A. Jun, Gyungah R |
| description | Background
While Alzheimer’s disease (AD) is generally considered a brain disease, plasma levels of AD‐related proteins including amyloid‐β, phosphorylated tau, and neurofilament light chain are associated with neurodegeneration and neuroinflammation. The APOE ε4 allele has shown cerebrovascular effects including acceleration of blood brain barrier (BBB) breakdown.
Method
We evaluated differential expression (DE) of previously established AD genes in brains obtained from 344 pathologically confirmed AD cases and 232 controls and in blood obtained from 112 clinically diagnosed AD cases and 67 controls from the Religious Orders Study and Memory and Aging Project. We analyzed DE between AD and controls in the blood and brain jointly using O’Brien’s multivariate approach in the total sample and APOE genotype groups (ε2/ε3, ε3/ε3, ε3/ε4). To identify biologically important pathways, gene set enrichment analysis was performed within APOE genotype groups using DE results for all genes ranked by Z‐score from the combined blood and brain analyses. Pathway results were corrected by the false‐discovery rate (FDR).
Result
Nominally significant (P |
| doi_str_mv | 10.1002/alz.054237 |
| format | Article |
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While Alzheimer’s disease (AD) is generally considered a brain disease, plasma levels of AD‐related proteins including amyloid‐β, phosphorylated tau, and neurofilament light chain are associated with neurodegeneration and neuroinflammation. The APOE ε4 allele has shown cerebrovascular effects including acceleration of blood brain barrier (BBB) breakdown.
Method
We evaluated differential expression (DE) of previously established AD genes in brains obtained from 344 pathologically confirmed AD cases and 232 controls and in blood obtained from 112 clinically diagnosed AD cases and 67 controls from the Religious Orders Study and Memory and Aging Project. We analyzed DE between AD and controls in the blood and brain jointly using O’Brien’s multivariate approach in the total sample and APOE genotype groups (ε2/ε3, ε3/ε3, ε3/ε4). To identify biologically important pathways, gene set enrichment analysis was performed within APOE genotype groups using DE results for all genes ranked by Z‐score from the combined blood and brain analyses. Pathway results were corrected by the false‐discovery rate (FDR).
Result
Nominally significant (P<0.05) DE was observed in both brain and blood for INDPP5D (upregulated) and HLA‐DQA1 (downregulated). Gene‐set enrichment analysis revealed 21 significant pathways (FDR‐adjusted P<0.05) in at least one APOE genotype subgroup. Ten pathways were significantly enriched in the ε3/ε4 group and six of these were unique to these subjects (apoptosis, estrogen response late, hypoxia, il6/jak/stat3 signaling, inflammatory response, and p53 pathway). The other four pathways (allograft rejection, interferon gamma response, peroxisome, and TNFA signaling via NFKB) were enriched for AD upregulated genes from the ε3/ε4 group and different from AD downregulated genes identified in APOE ε4‐ subjects.
Conclusion
Expression profiles from two AD genes involved in immune function, INPP5D and HLA‐DQA1, were consistent in both blood and brain. The same immune related pathways are enriched in AD upregulated genes in APOE ε4+ subjects and in AD downregulated genes in ε4‐ subjects. These results suggest that the ε4 allele contributes to a unique expression profile in both blood and brain, potentially related to ε4’s effect on the cerebrovasculature.</description><identifier>ISSN: 1552-5260</identifier><identifier>EISSN: 1552-5279</identifier><identifier>DOI: 10.1002/alz.054237</identifier><identifier>PMID: 35109177</identifier><language>eng</language><publisher>United States</publisher><ispartof>Alzheimer's & dementia, 2021-12, Vol.17, p.e054237-n/a</ispartof><rights>2021 the Alzheimer's Association</rights><rights>2021 the Alzheimer's Association.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Falz.054237$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Falz.054237$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35109177$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Panitch, Rebecca</creatorcontrib><creatorcontrib>Hu, Junming</creatorcontrib><creatorcontrib>Farrer, Lindsay A.</creatorcontrib><creatorcontrib>Jun, Gyungah R</creatorcontrib><title>Multivariate analysis of blood and brain transcriptome in Alzheimer’s reveals unique APOE ε4‐related immune pathways</title><title>Alzheimer's & dementia</title><addtitle>Alzheimers Dement</addtitle><description>Background
While Alzheimer’s disease (AD) is generally considered a brain disease, plasma levels of AD‐related proteins including amyloid‐β, phosphorylated tau, and neurofilament light chain are associated with neurodegeneration and neuroinflammation. The APOE ε4 allele has shown cerebrovascular effects including acceleration of blood brain barrier (BBB) breakdown.
Method
We evaluated differential expression (DE) of previously established AD genes in brains obtained from 344 pathologically confirmed AD cases and 232 controls and in blood obtained from 112 clinically diagnosed AD cases and 67 controls from the Religious Orders Study and Memory and Aging Project. We analyzed DE between AD and controls in the blood and brain jointly using O’Brien’s multivariate approach in the total sample and APOE genotype groups (ε2/ε3, ε3/ε3, ε3/ε4). To identify biologically important pathways, gene set enrichment analysis was performed within APOE genotype groups using DE results for all genes ranked by Z‐score from the combined blood and brain analyses. Pathway results were corrected by the false‐discovery rate (FDR).
Result
Nominally significant (P<0.05) DE was observed in both brain and blood for INDPP5D (upregulated) and HLA‐DQA1 (downregulated). Gene‐set enrichment analysis revealed 21 significant pathways (FDR‐adjusted P<0.05) in at least one APOE genotype subgroup. Ten pathways were significantly enriched in the ε3/ε4 group and six of these were unique to these subjects (apoptosis, estrogen response late, hypoxia, il6/jak/stat3 signaling, inflammatory response, and p53 pathway). The other four pathways (allograft rejection, interferon gamma response, peroxisome, and TNFA signaling via NFKB) were enriched for AD upregulated genes from the ε3/ε4 group and different from AD downregulated genes identified in APOE ε4‐ subjects.
Conclusion
Expression profiles from two AD genes involved in immune function, INPP5D and HLA‐DQA1, were consistent in both blood and brain. The same immune related pathways are enriched in AD upregulated genes in APOE ε4+ subjects and in AD downregulated genes in ε4‐ subjects. These results suggest that the ε4 allele contributes to a unique expression profile in both blood and brain, potentially related to ε4’s effect on the cerebrovasculature.</description><issn>1552-5260</issn><issn>1552-5279</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNo9kEtOwzAYhC0EoqWw4QDIF2jxs0mWUVUeUlFZdMUm-lM7qpHzwE5ahVWPwJaDcA0O0ZMQFOjqH83MP4sPoWtKJpQQdgv2fUKkYDw4QUMqJRtLFkSnRz0lA3Th_SshgoRUnqMBl5RENAiGqH1qbG224AzUGkMBtvXG4zLDqS1L1TkKpw5MgWsHhV87U9VlrnFnxPZ9o02u3WH_6bHTWw3W46Ywb43G8fNyjr-_xGH_4bTtthU2ed4UGldQb3bQ-kt0lnUP-urvjtDqbr6aPYwXy_vHWbwYV5TLYBwytVY0goASSlXIhJgqoVMhgAvOpZxGPKJrYJKHAEwpknEtSKYCpiKiJR-hm362atJcq6RyJgfXJv8IugLtCztjdXvMKUl-4SYd3KSHm8SLl17xHzfncGs</recordid><startdate>202112</startdate><enddate>202112</enddate><creator>Panitch, Rebecca</creator><creator>Hu, Junming</creator><creator>Farrer, Lindsay A.</creator><creator>Jun, Gyungah R</creator><scope>NPM</scope></search><sort><creationdate>202112</creationdate><title>Multivariate analysis of blood and brain transcriptome in Alzheimer’s reveals unique APOE ε4‐related immune pathways</title><author>Panitch, Rebecca ; Hu, Junming ; Farrer, Lindsay A. ; Jun, Gyungah R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p1357-82dcd19a71011d82446d4eb44a34335569391ca2538aa2dd0f3e40fd72d90e53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Panitch, Rebecca</creatorcontrib><creatorcontrib>Hu, Junming</creatorcontrib><creatorcontrib>Farrer, Lindsay A.</creatorcontrib><creatorcontrib>Jun, Gyungah R</creatorcontrib><collection>PubMed</collection><jtitle>Alzheimer's & dementia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Panitch, Rebecca</au><au>Hu, Junming</au><au>Farrer, Lindsay A.</au><au>Jun, Gyungah R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Multivariate analysis of blood and brain transcriptome in Alzheimer’s reveals unique APOE ε4‐related immune pathways</atitle><jtitle>Alzheimer's & dementia</jtitle><addtitle>Alzheimers Dement</addtitle><date>2021-12</date><risdate>2021</risdate><volume>17</volume><spage>e054237</spage><epage>n/a</epage><pages>e054237-n/a</pages><issn>1552-5260</issn><eissn>1552-5279</eissn><abstract>Background
While Alzheimer’s disease (AD) is generally considered a brain disease, plasma levels of AD‐related proteins including amyloid‐β, phosphorylated tau, and neurofilament light chain are associated with neurodegeneration and neuroinflammation. The APOE ε4 allele has shown cerebrovascular effects including acceleration of blood brain barrier (BBB) breakdown.
Method
We evaluated differential expression (DE) of previously established AD genes in brains obtained from 344 pathologically confirmed AD cases and 232 controls and in blood obtained from 112 clinically diagnosed AD cases and 67 controls from the Religious Orders Study and Memory and Aging Project. We analyzed DE between AD and controls in the blood and brain jointly using O’Brien’s multivariate approach in the total sample and APOE genotype groups (ε2/ε3, ε3/ε3, ε3/ε4). To identify biologically important pathways, gene set enrichment analysis was performed within APOE genotype groups using DE results for all genes ranked by Z‐score from the combined blood and brain analyses. Pathway results were corrected by the false‐discovery rate (FDR).
Result
Nominally significant (P<0.05) DE was observed in both brain and blood for INDPP5D (upregulated) and HLA‐DQA1 (downregulated). Gene‐set enrichment analysis revealed 21 significant pathways (FDR‐adjusted P<0.05) in at least one APOE genotype subgroup. Ten pathways were significantly enriched in the ε3/ε4 group and six of these were unique to these subjects (apoptosis, estrogen response late, hypoxia, il6/jak/stat3 signaling, inflammatory response, and p53 pathway). The other four pathways (allograft rejection, interferon gamma response, peroxisome, and TNFA signaling via NFKB) were enriched for AD upregulated genes from the ε3/ε4 group and different from AD downregulated genes identified in APOE ε4‐ subjects.
Conclusion
Expression profiles from two AD genes involved in immune function, INPP5D and HLA‐DQA1, were consistent in both blood and brain. The same immune related pathways are enriched in AD upregulated genes in APOE ε4+ subjects and in AD downregulated genes in ε4‐ subjects. These results suggest that the ε4 allele contributes to a unique expression profile in both blood and brain, potentially related to ε4’s effect on the cerebrovasculature.</abstract><cop>United States</cop><pmid>35109177</pmid><doi>10.1002/alz.054237</doi><tpages>1</tpages></addata></record> |
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| source | Wiley Online Library Journals Frontfile Complete |
| title | Multivariate analysis of blood and brain transcriptome in Alzheimer’s reveals unique APOE ε4‐related immune pathways |
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