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4. Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease

Author

Desikan, Rahul S, Schork, Andrew J, Wang, Yunpeng, Thompson, Wesley K, Dehghan, Abbas, Ridker, Paul M, Chasman, Daniel I, McEvoy, Linda K, Holland, Dominic, Chen, Chi-Hua, Karow, David S, Brewer, James B, Hess, Christopher P, Williams, Julie, Sims, Rebecca, O'Donovan, Michael C, Choi, Seung Hoan, Bis, Joshua C, Ikram, M Arfan, Gudnason, Vilmundur, DeStefano, Anita L, van der Lee, Sven J, Psaty, Bruce M, van Duijn, Cornelia M, Launer, Lenore, Seshadri, Sudha, Pericak-Vance, Margaret A, Mayeux, Richard, Haines, Jonathan L, Farrer, Lindsay A, Hardy, John, Ulstein, Ingun Dina, Aarsland, Dag, Fladby, Tormod, White, Linda R, Sando, Sigrid B, Rongve, Arvid, Witoelar, Aree, Djurovic, Srdjan, Hyman, Bradley T, Snaedal, Jon, Steinberg, Stacy, Stefansson, Hreinn, Stefansson, Kari, Schellenberg, Gerard D, Andreassen, Ole A, and Dale, Anders M

Subjects
Epidemiology, Health Sciences, Alzheimer's Disease, Neurodegenerative, Prevention, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Genetics, Human Genome, Dementia, Acquired Cognitive Impairment, Cardiovascular, Brain Disorders, 2.1 Biological and endogenous factors, Aged, Aged, 80 and over, Alzheimer Disease, Biomarkers, Brain, C-Reactive Protein, Dyslipidemias, Female, Genome-Wide Association Study, Humans, Inflammation, Lipids, Male, Multifactorial Inheritance, Peroxisomal Bifunctional Enzyme, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Sulfotransferases, inflammation, lipids, Inflammation working group, IGAP and DemGene Investigators, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Public Health and Health Services, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences, Sports science and exercise
Abstract

BackgroundEpidemiological findings suggest a relationship between Alzheimer disease (AD), inflammation, and dyslipidemia, although the nature of this relationship is not well understood. We investigated whether this phenotypic association arises from a shared genetic basis.Methods and resultsUsing summary statistics (P values and odds ratios) from genome-wide association studies of >200 000 individuals, we investigated overlap in single-nucleotide polymorphisms associated with clinically diagnosed AD and C-reactive protein (CRP), triglycerides, and high- and low-density lipoprotein levels. We found up to 50-fold enrichment of AD single-nucleotide polymorphisms for different levels of association with C-reactive protein, low-density lipoprotein, high-density lipoprotein, and triglyceride single-nucleotide polymorphisms using a false discovery rate threshold

Published
2015

5. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk

Author

Jansen, Iris E., Savage, Jeanne E., Watanabe, Kyoko, Bryois, Julien, Williams, Dylan M., Steinberg, Stacy, Sealock, Julia, Karlsson, Ida K., Hägg, Sara, Athanasiu, Lavinia, Voyle, Nicola, Proitsi, Petroula, Witoelar, Aree, Stringer, Sven, Aarsland, Dag, Almdahl, Ina S., Andersen, Fred, Bergh, Sverre, Bettella, Francesco, Bjornsson, Sigurbjorn, Brækhus, Anne, Bråthen, Geir, de Leeuw, Christiaan, Desikan, Rahul S., Djurovic, Srdjan, Dumitrescu, Logan, Fladby, Tormod, Hohman, Timothy J., Jonsson, Palmi V., Kiddle, Steven J., Rongve, Arvid, Saltvedt, Ingvild, Sando, Sigrid B., Selbæk, Geir, Shoai, Maryam, Skene, Nathan G., Snaedal, Jon, Stordal, Eystein, Ulstein, Ingun D., Wang, Yunpeng, White, Linda R., Hardy, John, Hjerling-Leffler, Jens, Sullivan, Patrick F., van der Flier, Wiesje M., Dobson, Richard, Davis, Lea K., Stefansson, Hreinn, Stefansson, Kari, Pedersen, Nancy L., Ripke, Stephan, Andreassen, Ole A., and Posthuma, Danielle

Published
2019
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6. A multinational study distinguishing Alzheimer's and healthy patients using cerebrospinal fluid tau/Aβ42 cutoff with concordance to amyloid positron emission tomography imaging

Author

Mo, Yi, Stromswold, Julie, Wilson, Kimberly, Holder, Daniel, Sur, Cyrille, Laterza, Omar, Savage, Mary J., Struyk, Arie, Scheltens, Philip, Teunissen, Charlotte E., Burke, James, Macaulay, S. Lance, Bråthen, Geir, Sando, Sigrid Botne, White, Linda R., Weiss, Christy, Cowes, Arturo, Bush, Michele M., DeSilva, Ganga, Darby, David G., Rainey-Smith, Stephanie R., Surls, Jackie, Sagini, Eileen, Tanen, Michael, Altman, Amy, Luthman, Johan, and Egan, Michael F.

Published
2017
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7. Author Correction: Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk

Author

Jansen, Iris E., Savage, Jeanne E., Watanabe, Kyoko, Bryois, Julien, Williams, Dylan M., Steinberg, Stacy, Sealock, Julia, Karlsson, Ida K., Hägg, Sara, Athanasiu, Lavinia, Voyle, Nicola, Proitsi, Petroula, Witoelar, Aree, Stringer, Sven, Aarsland, Dag, Almdahl, Ina S., Andersen, Fred, Bergh, Sverre, Bettella, Francesco, Bjornsson, Sigurbjorn, Brækhus, Anne, Bråthen, Geir, de Leeuw, Christiaan, Desikan, Rahul S., Djurovic, Srdjan, Dumitrescu, Logan, Fladby, Tormod, Hohman, Timothy J., Jonsson, Palmi V., Kiddle, Steven J., Rongve, Arvid, Saltvedt, Ingvild, Sando, Sigrid B., Selbæk, Geir, Shoai, Maryam, Skene, Nathan G., Snaedal, Jon, Stordal, Eystein, Ulstein, Ingun D., Wang, Yunpeng, White, Linda R., Hardy, John, Hjerling-Leffler, Jens, Sullivan, Patrick F., van der Flier, Wiesje M., Dobson, Richard, Davis, Lea K., Stefansson, Hreinn, Stefansson, Kari, Pedersen, Nancy L., Ripke, Stephan, Andreassen, Ole A., and Posthuma, Danielle

Published
2020
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9. Meta-analysis of Alzheimer’s disease on 9,751 samples from Norway and IGAP study identifies four risk loci

Author

Witoelar, Aree, Rongve, Arvid, Almdahl, Ina S., Ulstein, Ingun D., Engvig, Andreas, White, Linda R., Selbæk, Geir, Stordal, Eystein, Andersen, Fred, Brækhus, Anne, Saltvedt, Ingvild, Engedal, Knut, Hughes, Timothy, Bergh, Sverre, Bråthen, Geir, Bogdanovic, Nenad, Bettella, Francesco, Wang, Yunpeng, Athanasiu, Lavinia, Bahrami, Shahram, Le Hellard, Stephanie, Giddaluru, Sudheer, Dale, Anders M., Sando, Sigrid B., Steinberg, Stacy, Stefansson, Hreinn, Snaedal, Jon, Desikan, Rahul S., Stefansson, Kari, Aarsland, Dag, Djurovic, Srdjan, Fladby, Tormod, and Andreassen, Ole A.

Published
2018
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10. The relevance of cerebrospinal fluid α-synuclein levels to sporadic and familial Alzheimer’s disease

Author

Twohig, Daniel, Rodriguez-Vieitez, Elena, Sando, Sigrid B., Berge, Guro, Lauridsen, Camilla, Møller, Ina, Grøntvedt, Gøril R., Bråthen, Geir, Patra, Kalicharan, Bu, Guojun, Benzinger, Tammie L. S., Karch, Celeste M., Fagan, Anne, Morris, John C., Bateman, Randall J., Nordberg, Agneta, White, Linda R., Nielsen, Henrietta M., and for the Dominantly Inherited Alzheimer Network (DIAN)

Published
2018
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11. Safety and efficacy of plasma transfusion from exercise-trained donors in patients with early Alzheimer’s disease: protocol for the ExPlas study

Author

Tari, Atefe R, primary, Berg, Helene Haugen, additional, Videm, Vibeke, additional, Bråthen, Geir, additional, White, Linda R, additional, Røsbjørgen, Ragnhild Nyhus, additional, Scheffler, Katja, additional, Dalen, Havard, additional, Holte, Espen, additional, Haberg, Asta K, additional, Selbaek, Geir, additional, Lydersen, Stian, additional, Duezel, Emrah, additional, Bergh, Sverre, additional, Logan-Halvorsrud, Kjell Rune, additional, Sando, Sigrid Botne, additional, and Wisløff, Ulrik, additional

Published
2022
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14. Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case–control study

Author

Ross, Owen A, Soto-Ortolaza, Alexandra I, Heckman, Michael G, Aasly, Jan O, Abahuni, Nadine, Annesi, Grazia, Bacon, Justin A, Bardien, Soraya, Bozi, Maria, Brice, Alexis, Brighina, Laura, Van Broeckhoven, Christine, Carr, Jonathan, Chartier-Harlin, Marie-Christine, Dardiotis, Efthimios, Dickson, Dennis W, Diehl, Nancy N, Elbaz, Alexis, Ferrarese, Carlo, Ferraris, Alessandro, Fiske, Brian, Gibson, J Mark, Gibson, Rachel, Hadjigeorgiou, Georgios M, Hattori, Nobutaka, Ioannidis, John PA, Jasinska-Myga, Barbara, Jeon, Beom S, Kim, Yun Joong, Klein, Christine, Kruger, Rejko, Kyratzi, Elli, Lesage, Suzanne, Lin, Chin-Hsien, Lynch, Timothy, Maraganore, Demetrius M, Mellick, George D, Mutez, Eugénie, Nilsson, Christer, Opala, Grzegorz, Park, Sung Sup, Puschmann, Andreas, Quattrone, Aldo, Sharma, Manu, Silburn, Peter A, Sohn, Young Ho, Stefanis, Leonidas, Tadic, Vera, Theuns, Jessie, Tomiyama, Hiroyuki, Uitti, Ryan J, Valente, Enza Maria, van de Loo, Simone, Vassilatis, Demetrios K, Vilariño-Güell, Carles, White, Linda R, Wirdefeldt, Karin, Wszolek, Zbigniew K, Wu, Ruey-Meei, and Farrer, Matthew J

Published
2011
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26. Population-specific frequencies for LRRK2 susceptibility variants in the genetic epidemiology of Parkinsonʼs disease (GEO-PD) consortium

Author

Heckman, Michael G., Soto-Ortolaza, Alexandra I., Aasly, Jan O., Abahuni, Nadine, Annesi, Grazia, Bacon, Justin A., Bardien, Soraya, Bozi, Maria, Brice, Alexis, Brighina, Laura, Carr, Jonathan, Chartier-Harlin, Marie-Christine, Dardiotis, Efthimios, Dickson, Dennis W., Diehl, Nancy N., Elbaz, Alexis, Ferrarese, Carlo, Fiske, Brian, Gibson, Mark J., Gibson, Rachel, Hadjigeorgiou, Georgios M., Hattori, Nobutaka, Ioannidis, John P.A., Boczarska-Jedynak, Magdalena, Jasinska-Myga, Barbara, Jeon, Beom S., Kim, Yun Joong, Klein, Christine, Kruger, Rejko, Kyratzi, Elli, Lesage, Suzanne, Lin, Chin-Hsien, Lynch, Timothy, Maraganore, Demetrius M., Mellick, George D., Mutez, Eugénie, Nilsson, Christer, Opala, Grzegorz, Park, Sung Sup, Petrucci, Simona, Puschmann, Andreas, Quattrone, Aldo, Sharma, Manu, Silburn, Peter A., Sohn, Young Ho, Stefanis, Leonidas, Tadic, Vera, Theuns, Jessie, Tomiyama, Hiroyuki, Uitti, Ryan J., Valente, Enza Maria, Van Broeckhoven, Christine, van de Loo, Simone, Vassilatis, Demetrios K., Vilariño-Güell, Carles, White, Linda R., Wirdefeldt, Karin, Wszolek, Zbigniew K., Wu, Ruey-Meei, Hentati, Faycal, Farrer, Matthew J., and Ross, Owen A.

Published
2013
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29. Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinsonʼs disease

Author

Aasly, Jan O., Vilariño-Güell, Carles, Dachsel, Justus C., Webber, Philip J., West, Andrew B., Haugarvoll, Kristoffer, Johansen, Krisztina K., Toft, Mathias, Nutt, John G., Payami, Haydeh, Kachergus, Jennifer M., Lincoln, Sarah J., Felic, Amela, Wider, Christian, Soto-Ortolaza, Alexandra I., Cobb, Stephanie A., White, Linda R., Ross, Owen A., and Farrer, Matthew J.

Published
2010
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30. The protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants

Author

Heckman, Michael G., Elbaz, Alexis, Soto-Ortolaza, Alexandra I., Serie, Daniel J., Aasly, Jan O., Annesi, Grazia, Auburger, Georg, Bacon, Justin A., Boczarska-Jedynak, Magdalena, Bozi, Maria, Brighina, Laura, Chartier-Harlin, Marie-Christine, Dardiotis, Efthimios, Destée, Alain, Ferrarese, Carlo, Ferraris, Alessandro, Fiske, Brian, Gispert, Suzana, Hadjigeorgiou, Georgios M., Hattori, Nobutaka, Ioannidis, John P.A., Jasinska-Myga, Barbara, Jeon, Beom S., Kim, Yun Joong, Klein, Christine, Kruger, Rejko, Kyratzi, Elli, Lin, Chin-Hsien, Lohmann, Katja, Loriot, Marie-Anne, Lynch, Timothy, Mellick, George D., Mutez, Eugénie, Opala, Grzegorz, Park, Sung Sup, Petrucci, Simona, Quattrone, Aldo, Sharma, Manu, Silburn, Peter A., Sohn, Young Ho, Stefanis, Leonidas, Tadic, Vera, Tomiyama, Hiroyuki, Uitti, Ryan J., Valente, Enza Maria, Vassilatis, Demetrios K., Vilariño-Güell, Carles, White, Linda R., Wirdefeldt, Karin, Wszolek, Zbigniew K., Wu, Ruey-Meei, Xiromerisiou, Georgia, Maraganore, Demetrius M., Farrer, Matthew J., and Ross, Owen A.

Published
2014
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33. ELAVL4, PARK10, and the Celts

Author

Haugarvoll, Kristoffer, Toft, Mathias, Ross, Owen A., Stone, Jeremy T., Heckman, Michael G., White, Linda R., Lynch, Timothy, Gibson, John Mark, Wszolek, Zbigniew K., Uitti, Ryan J., Aasly, Jan O., and Farrer, Matthew J.

Published
2007
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39. APOE ε4 lowers age at onset and is a high risk factor for Alzheimer's disease; A case control study from central Norway

Author

Saltvedt Ingvild, Sletvold Olav, Hutton Michael L, Cannon Ashley, Melquist Stacey, Sando Sigrid B, White Linda R, Lydersen Stian, and Aasly Jan O

Subjects
Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background The objective of this study was to analyze factors influencing the risk and timing of Alzheimer's disease (AD) in central Norway. The APOE ε4 allele is the only consistently identified risk factor for late onset Alzheimer's disease (LOAD). We have described the allele frequencies of the apolipoprotein E gene (APOE) in a large population of patients with AD compared to the frequencies in a cognitively-normal control group, and estimated the effect of the APOE ε4 allele on the risk and the age at onset of AD in this population. Methods 376 patients diagnosed with AD and 561 cognitively-normal control individuals with no known first degree relatives with dementia were genotyped for the APOE alleles. Allele frequencies and genotypes in patients and control individuals were compared. Odds Ratio for developing AD in different genotypes was calculated. Results Odds Ratio (OR) for developing AD was significantly increased in carriers of the APOE ε4 allele compared to individuals with the APOE ε3/ε3 genotype. Individuals carrying APOE ε4/ε4 had OR of 12.9 for developing AD, while carriers of APOE ε2/ε4 and APOE ε3/ε4 had OR of 3.2 and 4.2 respectively. The effect of the APOE ε4 allele was weaker with increasing age. Carrying the APOE ε2 allele showed no significant protective effect against AD and did not influence age at onset of the disease. Onset in LOAD patients was significantly reduced in a dose dependent manner from 78.4 years in patients without the APOE ε4 allele, to 75.3 in carriers of one APOE ε4 allele and 72.9 in carriers of two APOE ε4 alleles. Age at onset in early onset AD (EOAD) was not influenced by APOE ε4 alleles. Conclusion APOE ε4 is a very strong risk factor for AD in the population of central Norway, and lowers age at onset of LOAD significantly.

Published
2008
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40. Angiotensin-converting enzyme gene insertion/deletion polymorphism in migraine patients

Author

White Linda R, Bovim Gunnar, Stovner Lars J, Tronvik Erling, Gladwin Amanda J, Owen Kathryn, and Schrader Harald

Subjects
Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background The main objective of this study was to investigate the angiotensin converting enzyme (ACE) genotype as a possible risk factor for migraine (both with and without aura) compared to controls. We also wanted to examine whether a clinical response to an ACE inhibitor, lisinopril, or an angiotensin II receptor blocker, candesartan, in migraine prophylaxis was related to ACE genotype. Methods 347 migraine patients aged 18–68 (155 migraine without aura (MoA), 187 migraine with aura (MwA) and 5 missing aura subgroup data) and 403 healthy non-migrainous controls > 40 years of age were included in the study. A polymerase chain reaction (PCR) was performed on the genomic DNA samples to obtain the ACE insertion (I)/deletion(D) polymorphisms. Results No significant differences between migraine patients and controls were found with regard to ACE genotype and allele distributions. Furthermore, there was no significant difference between the controls and the MwA or MoA subgroups. Conclusion In our sample there is no association between ACE genotype or allele frequency and migraine. In addition, ACE genotype in our experience did not predict the clinical response to lisinopril or candesartan used as migraine prophylactics.

Published
2008
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41. Plasma Apolipoprotein E Monomer and Dimer Profile and Relevance to Alzheimer's Disease

Author

Patra, Kalicharan, Giannisis, Andreas, Edlund, Anna K., Sando, Sigrid Botne, Lauridsen, Camilla, Berge, Guro, Grøntvedt, Gøril Rolfseng, Bråthen, Geir, White, Linda R., Nielsen, Henrietta M., Patra, Kalicharan, Giannisis, Andreas, Edlund, Anna K., Sando, Sigrid Botne, Lauridsen, Camilla, Berge, Guro, Grøntvedt, Gøril Rolfseng, Bråthen, Geir, White, Linda R., and Nielsen, Henrietta M.

Abstract

The APOE epsilon 4 gene variant is the strongest genetic risk factor for Alzheimer's disease (AD), whereas APOE epsilon 3 conventionally is considered as 'risk neutral' although APOE epsilon 3-carriers also develop AD. Previous studies have shown that the apolipoprotein E3 (apoE3) isoform occurs as monomers, homodimers and heterodimers with apolipoprotein A-II in human body fluids and brain tissue, but the relevance of a plasma apoE3 monomer/dimer profile to AD is unknown. Here we assessed the distribution of monomers, homodimers and heterodimers in plasma from control subjects and patients with mild cognitive impairment (MCI) and AD with either a homozygous APOE epsilon 3 (n = 31 control subjects, and n = 14 MCI versus n = 5 AD patients) or APOE epsilon 4 genotype (n = 1 control subject, n = 21 MCI and n = 7 AD patients). Total plasma apoE levels were lower in APOE epsilon 4-carriers and overall correlated significantly to CSF A beta(42), p(Thr181)-tau and t-tau levels. Apolipoprotein E dimers were only observed in the APOE epsilon 3-carriers and associated with total plasma apoE levels, negatively correlated to apoE monomers, but were unrelated to plasma homocysteine levels. Importantly, the APOE epsilon 3-carrying AD patients versus controls exhibited a significant decrease in apoE homodimers (17.8 +/- 9.6% versus 26.7 +/- 6.3%, p = 0.025) paralleled by an increase in apoE monomers (67.8 +/- 18.3% versus 48.5 +/- 11.2%, p = 0.008). In the controls, apoE monomers and heterodimers were significantly associated with plasma triglycerides; the apoE heterodimers were also associated with levels of high-density lipoprotein cholesterol. The physiological relevance of apoE dimer formation needs to be further investigated, though the distribution of apoE in monomers and dimers appears to be of relevance to AD in APOE epsilon 3 subjects.

Published
2019
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42. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk

Author

Jansen, Iris E, Savage, Jeanne E, Watanabe, Kyoko, Bryois, Julien, Williams, Dylan M, Steinberg, Stacy, Sealock, Julia, Karlsson, Ida K, Hägg, Sara, Athanasiu, Lavinia, Voyle, Nicola, Proitsi, Petroula, Witoelar, Aree, Stringer, Sven, Aarsland, Dag, Almdahl, Ina S, Andersen, Fred, Bergh, Sverre, Bettella, Francesco, Bjornsson, Sigurbjorn, Brækhus, Anne, Bråthen, Geir, de Leeuw, Christiaan, Desikan, Rahul S, Djurovic, Srdjan, Dumitrescu, Logan, Fladby, Tormod, Hohman, Timothy J, Jonsson, Palmi V, Kiddle, Steven J, Rongve, Arvid, Saltvedt, Ingvild, Sando, Sigrid B, Selbæk, Geir, Shoai, Maryam, Skene, Nathan G, Snaedal, Jon, Stordal, Eystein, Ulstein, Ingun D, Wang, Yunpeng, White, Linda R, Hardy, John, Hjerling-Leffler, Jens, Sullivan, Patrick F, van der Flier, Wiesje M, Dobson, Richard, Davis, Lea K, Stefansson, Hreinn, Stefansson, Kari, Pedersen, Nancy L, Ripke, Stephan, Andreassen, Ole A, Posthuma, Danielle, Jansen, Iris E, Savage, Jeanne E, Watanabe, Kyoko, Bryois, Julien, Williams, Dylan M, Steinberg, Stacy, Sealock, Julia, Karlsson, Ida K, Hägg, Sara, Athanasiu, Lavinia, Voyle, Nicola, Proitsi, Petroula, Witoelar, Aree, Stringer, Sven, Aarsland, Dag, Almdahl, Ina S, Andersen, Fred, Bergh, Sverre, Bettella, Francesco, Bjornsson, Sigurbjorn, Brækhus, Anne, Bråthen, Geir, de Leeuw, Christiaan, Desikan, Rahul S, Djurovic, Srdjan, Dumitrescu, Logan, Fladby, Tormod, Hohman, Timothy J, Jonsson, Palmi V, Kiddle, Steven J, Rongve, Arvid, Saltvedt, Ingvild, Sando, Sigrid B, Selbæk, Geir, Shoai, Maryam, Skene, Nathan G, Snaedal, Jon, Stordal, Eystein, Ulstein, Ingun D, Wang, Yunpeng, White, Linda R, Hardy, John, Hjerling-Leffler, Jens, Sullivan, Patrick F, van der Flier, Wiesje M, Dobson, Richard, Davis, Lea K, Stefansson, Hreinn, Stefansson, Kari, Pedersen, Nancy L, Ripke, Stephan, Andreassen, Ole A, and Posthuma, Danielle

Abstract

Alzheimer's disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.

Published
2019
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48. Genetic meta-analysis identifies 9 novel loci and functional pathways for Alzheimer’s disease risk

Author

Jansen, Iris E, primary, Savage, Jeanne E, additional, Watanabe, Kyoko, additional, Bryois, Julien, additional, Williams, Dylan M, additional, Steinberg, Stacy, additional, Sealock, Julia, additional, Karlsson, Ida K, additional, Hägg, Sara, additional, Athanasiu, Lavinia, additional, Voyle, Nicola, additional, Proitsi, Petroula, additional, Witoelar, Aree, additional, Stringer, Sven, additional, Aarsland, Dag, additional, Almdahl, Ina S, additional, Andersen, Fred, additional, Bergh, Sverre, additional, Bettella, Francesco, additional, Bjornsson, Sigurbjorn, additional, Brækhus, Anne, additional, Bråthen, Geir, additional, de Leeuw, Christiaan, additional, Desikan, Rahul S, additional, Djurovic, Srdjan, additional, Dumitrescu, Logan, additional, Fladby, Tormod, additional, Homan, Timothy, additional, Jonsson, Palmi V, additional, Kiddle, Steven J, additional, Rongve, K Arvid, additional, Saltvedt, Ingvild, additional, Sando, Sigrid B., additional, Selbæk, Geir, additional, Skenne, Nathan, additional, Snaedal, Jon, additional, Stordal, Eystein, additional, Ulstein, Ingun D., additional, Wang, Yunpeng, additional, White, Linda R, additional, Hjerling-Leffler, Jens, additional, Sullivan, Patrick F, additional, van der Flier, Wiesje M, additional, Dobson, Richard, additional, Davis, Lea K., additional, Stefansson, Hreinn, additional, Stefansson, Kari, additional, Pedersen, Nancy L, additional, Ripke, Stephan, additional, Andreassen, Ole A, additional, and Posthuma, Danielle, additional

Published
2018
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49. Assessment of kallikrein 6 as a cross-sectional and longitudinal biomarker for Alzheimer's disease

Author

Patra, Kalicharan, Soosaipillai, Antoninus, Sando, Sigrid Botne, Lauridsen, Camilla, Berge, Guro, Møller, Ina, Grontvedt, Gøril Rolfseng, Bråthen, Geir, Begcevic, Ilijana, Moussaud, Simon, Minthon, Lennart, Hansson, Oskar, Diamandis, Eleftherios P., White, Linda R., Nielsen, Henrietta M., Patra, Kalicharan, Soosaipillai, Antoninus, Sando, Sigrid Botne, Lauridsen, Camilla, Berge, Guro, Møller, Ina, Grontvedt, Gøril Rolfseng, Bråthen, Geir, Begcevic, Ilijana, Moussaud, Simon, Minthon, Lennart, Hansson, Oskar, Diamandis, Eleftherios P., White, Linda R., and Nielsen, Henrietta M.

Abstract

Background: Kallikrein 6 (KLK6) is known to be an age-related protease expressed at high levels in the central nervous system. It was previously shown to be involved in proteolysis of extracellular proteins implicated in neurodegenerative diseases such as Alzheimer's disease (AD), prompting validation of KLK6 as a potential biomarker of disease. However, analyses of both plasma and cerebrospinal fluid (CSF) levels of KLK6 in patients with AD have been inconclusive. We present a detailed analysis of KLK6 in plasma and CSF in two separate cohorts in a cross-sectional and a longitudinal clinical setting. Methods: The cross-sectional cohort included control subjects without dementia and patients with AD, and the longitudinal cohort included patients with MCI and patients with AD followed over a 2-year period. Plasma and CSF levels of KLK6 were quantified by use of a previously developed and validated enzyme-linked immunosorbent assay. Statistical analyses were performed to compare KLK6 levels between diagnostic groups and to identify potential associations between KLK6 level, age, apolipoprotein E (APOE) genotype, total apoE level and the classical CSF AD biomarkers. Results: In the cross-sectional setting, KLK6 levels in plasma but not in CSF were significantly higher in the AD group than in control subjects. CSF but not plasma KLK6 levels were positively correlated with age in both the cross-sectional and longitudinal settings. In both cohorts, the CSF KLK6 levels were significantly and positively correlated with the CSF levels of core AD biomarkers. Total plasma and CSF apoE levels were positively associated with KLK6 in the cross-sectional study. Finally, during the 2-year monitoring period of the longitudinal cohort, CSF KLK6 levels increased with disease progression over time in the investigated patient groups. Conclusions: In two separate cohorts we have confirmed the previously reported correlation between age and CSF levels of KLK6. Increased plasma KLK6 levels

Published
2018
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