Risk of Alzheimer's disease and genetically predicted levels of 1400 plasma metabolites: a Mendelian randomization study.
Alzheimer’s disease
Genome-wide association study
Mendelian randomization
Metabolic pathway
Plasma metabolites
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
30 10 2024
30 10 2024
Historique:
received:
29
03
2024
accepted:
28
10
2024
medline:
31
10
2024
pubmed:
31
10
2024
entrez:
31
10
2024
Statut:
epublish
Résumé
Alzheimer's disease (AD) is a metabolic disorder. Discovering the metabolic products involved in the development of AD may help not only in the early detection and prevention of AD but also in understanding its pathogenesis and treatment. This study investigated the causal association between the latest large-scale plasma metabolites (1091 metabolites and 309 metabolite ratios) and AD. Through the application of Mendelian randomization analysis methods such as inverse-variance weighted (IVW), MR-Egger, and weighted median models, 66 metabolites and metabolite ratios were identified as potentially having a causal association with AD, with 13 showing significant causal associations. During the replication validation phase, six metabolites and metabolite ratios were confirmed for their roles in AD: N-lactoyl tyrosine, argininate, and the adenosine 5'-monophosphate to flavin adenine dinucleotide ratio were found to exhibit protective effects against AD. In contrast, ergothioneine, piperine, and 1,7-dimethyluric acid were identified as contributing to an increased risk of AD. Among them, argininate showed a significant effect against AD. Replication and sensitivity analyses confirmed the robustness of these findings. Metabolic pathway analysis linked "Vitamin B6 metabolism" to AD risk. No genetic correlations were found, but colocalization analysis indicated potential AD risk elevation through top SNPs in APOE and PSEN2 genes. This provides novel insights into AD's etiology from a metabolomic viewpoint, suggesting both protective and risk metabolites.
Identifiants
pubmed: 39478193
doi: 10.1038/s41598-024-77921-6
pii: 10.1038/s41598-024-77921-6
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
26078Subventions
Organisme : Key Research and Development Project of the Jilin Provincial Department of Science and Technology
ID : 20220203153SF
Organisme : Qihuang scholar in the National Support Program for Leading Talents of Traditional Chinese Medicine
ID : [2018] No. 12
Organisme : Key Project of National Natural Science Foundation of China
ID : 82130119
Informations de copyright
© 2024. The Author(s).
Références
Gustavsson, A. et al. Global estimates on the number of persons across the Alzheimer’s disease continuum. Alzheimers Dement. 19, 658–670 (2023).
pubmed: 35652476
doi: 10.1002/alz.12694
Afsar, A., Chacon Castro, M. D. C., Soladogun, A. S. & Zhang, L. Recent development in the understanding of molecular and cellular mechanisms underlying the etiopathogenesis of Alzheimer’s disease. Int. J. Mol. Sci. 24, 7258 (2023).
pubmed: 37108421
pmcid: 10138573
doi: 10.3390/ijms24087258
Guo, T. et al. Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease. Mol. Neurodegener. 15, 40 (2020).
pubmed: 32677986
pmcid: 7364557
doi: 10.1186/s13024-020-00391-7
Cunnane, S. C. et al. Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing. Nat. Rev. Drug Discov. 19, 609–633 (2020).
pubmed: 32709961
pmcid: 7948516
doi: 10.1038/s41573-020-0072-x
Van Der Velpen, V. et al. Systemic and central nervous system metabolic alterations in Alzheimer’s disease. Alzheimers Res. Ther. 11, 93 (2019).
pubmed: 31779690
pmcid: 6883620
doi: 10.1186/s13195-019-0551-7
Kim, M. et al. Primary fatty amides in plasma associated with brain amyloid burden, hippocampal volume, and memory in the European Medical Information Framework for Alzheimer’s disease biomarker discovery cohort. Alzheimers Dement. 15, 817–827 (2019).
pubmed: 31078433
doi: 10.1016/j.jalz.2019.03.004
Varma, V. R. et al. Brain and blood metabolite signatures of pathology and progression in Alzheimer disease: A targeted metabolomics study. PLoS Med. 15, e1002482 (2018).
pubmed: 29370177
pmcid: 5784884
doi: 10.1371/journal.pmed.1002482
Zhu, J. et al. Associations between genetically predicted plasma protein levels and Alzheimer’s disease risk: a study using genetic prediction models. Alzheimers Res. Ther. 16, 8 (2024).
pubmed: 38212844
pmcid: 10782590
doi: 10.1186/s13195-023-01378-4
Sekula, P., Del Greco, M. F., Pattaro, C. & Köttgen, A. Mendelian randomization as an approach to assess causality using observational data. J. Am. Soc. Nephrol. 27, 3253–3265 (2016).
pubmed: 27486138
pmcid: 5084898
doi: 10.1681/ASN.2016010098
Burgess, S., Timpson, N. J., Ebrahim, S. & Davey Smith, G. Mendelian randomization: where are we now and where are we going? Int. J. Epidemiol. 44, 379–388 (2015).
pubmed: 26085674
doi: 10.1093/ije/dyv108
Richmond, R. C. & Davey Smith, G. Mendelian randomization: Concepts and scope. Cold Spring Harb. Perspect. Med. 12, a040501 (2022).
pubmed: 34426474
pmcid: 8725623
doi: 10.1101/cshperspect.a040501
Davey Smith, G. & Hemani, G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum. Mol. Genet. 23, R89–R98 (2014).
pubmed: 25064373
pmcid: 4170722
doi: 10.1093/hmg/ddu328
Slob, E. A. W. & Burgess, S. A comparison of robust Mendelian randomization methods using summary data. Genet. Epidemiol. 44, 313–329 (2020).
pubmed: 32249995
pmcid: 7317850
doi: 10.1002/gepi.22295
Zhai, M. et al. Genetic insights into the association and causality between blood metabolites and Alzheimer’s disease. J. Alzheimer’s Dis. 98, 885–896 (2024).
doi: 10.3233/JAD-230985
Chen, H. et al. Assessing causal relationship between human blood metabolites and five neurodegenerative diseases with GWAS summary statistics. Front. Neurosci. 15, 680104 (2021).
pubmed: 34955704
pmcid: 8695771
doi: 10.3389/fnins.2021.680104
Chen, Y. et al. Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases. Nat. Genet. 55, 44–53 (2023).
pubmed: 36635386
pmcid: 7614162
doi: 10.1038/s41588-022-01270-1
Pedrazini, M. C., Martinez, E. F., dos Santos, V. A. B. & Groppo, F. C. L-arginine: Its role in human physiology, in some diseases and mainly in viral multiplication as a narrative literature review. Future J. Pharm. Sci. 10, 99 (2024).
doi: 10.1186/s43094-024-00673-7
Yi, J. et al. L-arginine and Alzheimer’s disease. Int. J. Clin. Exp. Pathol. 2, 211–238 (2009).
pubmed: 19079617
Liu, P. et al. Altered arginine metabolism in Alzheimer’s disease brains. Neurobiol. Aging. 35, 1992–2003 (2014).
pubmed: 24746363
doi: 10.1016/j.neurobiolaging.2014.03.013
Mamsa, S. S. A. & Meloni, B. P. Arginine and arginine-rich peptides as modulators of protein aggregation and cytotoxicity associated with Alzheimer’s disease. Front. Mol. Neurosci. 14, 759729 (2021).
pubmed: 34776866
pmcid: 8581540
doi: 10.3389/fnmol.2021.759729
Ibáñez, C. et al. Toward a predictive model of Alzheimer’s disease progression using capillary electrophoresis-mass spectrometry metabolomics. Anal. Chem. 84, 8532–8540 (2012).
pubmed: 22967182
doi: 10.1021/ac301243k
Fonar, G. et al. Intracerebroventricular administration of L-arginine improves spatial memory acquisition in triple transgenic mice via reduction of oxidative stress and apoptosis. Transl. Neurosci. 9, 43–53 (2018).
pubmed: 29876138
pmcid: 5984558
doi: 10.1515/tnsci-2018-0009
Sarı, İ. et al. Changes in arginine metabolism in advanced Alzheimer’s patients: Experimental and theoretical analyses. J. Mol. Struct. 1282, 135254 (2023).
doi: 10.1016/j.molstruc.2023.135254
Geravand, S., Karami, M., Sahraei, H. & Rahimi, F. Protective effects of L-arginine on Alzheimer’s disease: Modulating hippocampal nitric oxide levels and memory deficits in aluminum chloride-induced rat model. Eur. J. Pharmacol. 958, 176030 (2023).
pubmed: 37660966
doi: 10.1016/j.ejphar.2023.176030
Zinellu, A., Tommasi, S., Sedda, S. & Mangoni, A. A. Circulating arginine metabolites in Alzheimer’s disease and vascular dementia: A systematic review and meta-analysis. Ageing Res. Rev. 92, 102139 (2023).
pubmed: 38007048
doi: 10.1016/j.arr.2023.102139
Tain, Y. & Hsu, C. Toxic dimethylarginines: Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). Toxins. 9, 92 (2017).
pubmed: 28272322
pmcid: 5371847
doi: 10.3390/toxins9030092
Guo, X., Xing, Y. & Jin, W. Role of ADMA in the pathogenesis of microvascular complications in type 2 diabetes mellitus. Front. Endocrinol. 14, 1183586 (2023).
doi: 10.3389/fendo.2023.1183586
Cheah, I. K., Feng, L., Tang, R. M. Y., Lim, K. H. C. & Halliwell, B. Ergothioneine levels in an elderly population decrease with age and incidence of cognitive decline; a risk factor for neurodegeneration? Biochem. Biophys. Res. Commun. 478, 162–167 (2016).
pubmed: 27444382
doi: 10.1016/j.bbrc.2016.07.074
Wu, L. Y. et al. Low plasma ergothioneine levels are associated with neurodegeneration and cerebrovascular disease in dementia. Free Radic. Biol. Med. 177, 201–211 (2021).
pubmed: 34673145
doi: 10.1016/j.freeradbiomed.2021.10.019
Wijesinghe, P. et al. Ergothioneine, a dietary antioxidant improves amyloid beta clearance in the neuroretina of a mouse model of Alzheimer’s disease. Front. Neurosci. 17, 1107436 (2023).
pubmed: 36998724
pmcid: 10043244
doi: 10.3389/fnins.2023.1107436
Liang, C. H., Huang, P. C., Mau, J. L. & Chiang, S. S. Effect of the king oyster culinary-medicinal mushroom Pleurotus eryngii (Agaricomycetes) basidiocarps powder to ameliorate memory and learning deficit in ability in Aβ-induced Alzheimer’s disease C57BL/6J mice model. Int. J. Med. Mushrooms. 22, 145–159 (2020).
pubmed: 32479003
doi: 10.1615/IntJMedMushrooms.2020033766
Song, T. Y. et al. Ergothioneine and melatonin attenuate oxidative stress and protect against learning and memory deficits in C57BL/6J mice treated with D-galactose. Free Radic. Res. 48, 1049–1060 (2014).
pubmed: 24797165
doi: 10.3109/10715762.2014.920954
Nakamichi, N. et al. Oral administration of the food-derived hydrophilic antioxidant ergothioneine enhances object recognition memory in mice. Curr. Mol. Pharmacol. 14, 220–233 (2020).
doi: 10.2174/1874467213666200212102710
Teruya, T., Chen, Y. J., Kondoh, H., Fukuji, Y. & Yanagida, M. Whole-blood metabolomics of dementia patients reveal classes of disease-linked metabolites. Proc. Natl. Acad. Sci. 118, e2022857118 (2021).
Imran, M., Samal, M., Qadir, D. A., Ali, A. & Mir, S. R. A critical review on the extraction and pharmacotherapeutic activity of piperine. Polym. Med. 52, 31–36 (2022).
doi: 10.17219/pim/145512
Wang, C. et al. Piperine regulates glycogen synthase kinase-3β-related signaling and attenuates cognitive decline in D-galactose-induced aging mouse model. J. Nutr. Biochem. 75, 108261 (2020).
pubmed: 31710934
doi: 10.1016/j.jnutbio.2019.108261
Kumar, S. et al. Downregulation of candidate gene expression and neuroprotection by piperine in Streptozotocin-induced hyperglycemia and memory impairment in rats. Front. Pharmacol. 11, 595471 (2021).
pubmed: 33737876
pmcid: 7962412
doi: 10.3389/fphar.2020.595471
Gracia-Lor, E. et al. Estimation of caffeine intake from analysis of caffeine metabolites in wastewater. Sci. Total Environ. 609, 1582–1588 (2017).
pubmed: 28810510
doi: 10.1016/j.scitotenv.2017.07.258
Heckman, M. A., Weil, J. & De Mejia, E. G. Caffeine (1, 3, 7-trimethylxanthine) in foods: a comprehensive review on consumption, functionality, safety, and regulatory matters. J. Food Sci. 75, R77–R87 (2010).
pubmed: 20492310
doi: 10.1111/j.1750-3841.2010.01561.x
Yelanchezian, M. et al. Neuroprotective effect of caffeine in Alzheimer’s disease. Molecules. 27, 3737 (2022).
doi: 10.3390/molecules27123737
Larsson, S. C., Woolf, B. & Gill, D. Plasma caffeine levels and risk of Alzheimer’s disease and Parkinson’s disease: Mendelian randomization study. Nutrients. 14, 1697 (2022).
pubmed: 35565667
pmcid: 9102212
doi: 10.3390/nu14091697
Yin, F., Sancheti, H., Patil, I. & Cadenas, E. Energy metabolism and inflammation in brain aging and Alzheimer’s disease. Free Radic. Biol. Med. 100, 108–122 (2016).
pubmed: 27154981
pmcid: 5094909
doi: 10.1016/j.freeradbiomed.2016.04.200
Bai, R., Guo, J., Ye, X. Y., Xie, Y. & Xie, T. Oxidative stress: The core pathogenesis and mechanism of Alzheimer’s disease. Ageing Res. Rev. 77, 101619 (2022).
pubmed: 35395415
doi: 10.1016/j.arr.2022.101619
Herzig, S. & Shaw, R. J. AMPK: Guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell. Biol. 19, 121–135 (2018).
pubmed: 28974774
doi: 10.1038/nrm.2017.95
Srinivasan, M. P. et al. Activation of AMP-activated protein kinase attenuates ethanol-induced ER/oxidative stress and lipid phenotype in human pancreatic acinar cells. Biochem. Pharmacol. 180, 114174 (2020).
pubmed: 32717227
pmcid: 7651864
doi: 10.1016/j.bcp.2020.114174
Zhong, X. et al. Flavin adenine dinucleotide ameliorates hypertensive vascular remodeling via activating short chain acyl-CoA dehydrogenase. Life Sci. 258, 118156 (2020).
pubmed: 32735886
doi: 10.1016/j.lfs.2020.118156
Stach, K., Stach, W. & Augoff, K. Vitamin B6 in health and disease. Nutrients. 13, 3229 (2021).
pubmed: 34579110
pmcid: 8467949
doi: 10.3390/nu13093229
Przybelski, A. G., Bendlin, B. B., Jones, J. E., Vogt, N. M. & Przybelski, R. J. Vitamin B6 and vitamin D deficiency co-occurrence in geriatric memory patients. Alzheimers Dement. Diagn. Assess. Dis. Monit. 16, e12525 (2024).
Zhuo, J. M., Wang, H. & Praticò, D. Is hyperhomocysteinemia an Alzheimer’s disease (AD) risk factor, an AD marker, or neither? Trends Pharmacol. Sci. 32, 562–571 (2011).
pubmed: 21684021
pmcid: 3159702
doi: 10.1016/j.tips.2011.05.003
Annerbo, S., Wahlund, L. O. & Lökk, J. The significance of thyroid-stimulating hormone and homocysteine in the development of Alzheimer’s disease in mild cognitive impairment: a 6-year follow-up study. Am. J. Alzheimers Dis. Dementiasr. 21, 182–188 (2006).
doi: 10.1177/1533317506289282
Seshadri, S. et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N. Engl. J. Med. 346, 476–483 (2002).
pubmed: 11844848
doi: 10.1056/NEJMoa011613
Hu, Q., Teng, W., Li, J., Hao, F. & Wang, N. Homocysteine and Alzheimer’s disease: Evidence for a causal link from Mendelian randomization. J. Alzheimers Dis. 52, 747–756 (2016).
pubmed: 27031476
doi: 10.3233/JAD-150977
Serrano-Pozo, A., Das, S. & Hyman, B. T. APOE and Alzheimer’s disease: advances in genetics, pathophysiology, and therapeutic approaches. Lancet Neurol. 20, 68–80 (2021).
pubmed: 33340485
pmcid: 8096522
doi: 10.1016/S1474-4422(20)30412-9
Martens, Y. A. et al. ApoE cascade Hypothesis in the pathogenesis of Alzheimer’s disease and related dementias. Neuron. 110, 1304–1317 (2022).
pubmed: 35298921
pmcid: 9035117
doi: 10.1016/j.neuron.2022.03.004
Koutsodendris, N., Nelson, M. R., Rao, A. & Huang, Y. Apolipoprotein E and Alzheimer’s disease: Findings, hypotheses, and potential mechanisms. Annu. Rev. Pathol. Mech. Dis. 17, 73–99 (2022).
doi: 10.1146/annurev-pathmechdis-030421-112756
Qi, G. et al. ApoE4 impairs neuron-astrocyte coupling of fatty acid metabolism. Cell. Rep. 34, 108572 (2021).
pubmed: 33406436
pmcid: 7837265
doi: 10.1016/j.celrep.2020.108572
Proitsi, P. et al. Association of blood lipids with alzheimer’s disease: A comprehensive lipidomics analysis. Alzheimers Dement. J. Alzheimers Assoc. 13, 140–151 (2017).
doi: 10.1016/j.jalz.2016.08.003
Shahidi, F. & Ambigaipalan, P. Omega-3 polyunsaturated fatty acids and their health benefits. Annu. Rev. Food Sci. Technol. 9, 345–381 (2018).
pubmed: 29350557
doi: 10.1146/annurev-food-111317-095850
Honda, T. et al. Serum elaidic acid concentration and risk of dementia: The Hisayama study. Neurology. 93, e2053–e2064 (2019).
pubmed: 31645469
doi: 10.1212/WNL.0000000000008464
Shinto, L. H. et al. ω-3 PUFA for secondary prevention of white matter lesions and neuronal integrity breakdown in older adults: A randomized clinical trial. JAMA Netw. Open. 7, e2426872 (2024).
pubmed: 39088212
pmcid: 11294966
doi: 10.1001/jamanetworkopen.2024.26872
Andrade-Guerrero, J. et al. Alzheimer’s disease: An updated overview of its genetics. Int. J. Mol. Sci. 24, 3754 (2023).
pubmed: 36835161
pmcid: 9966419
doi: 10.3390/ijms24043754
Fedeli, C., Filadi, R., Rossi, A., Mammucari, C. & Pizzo, P. PSEN2 (presenilin 2) mutants linked to familial Alzheimer disease impair autophagy by altering Ca2 + homeostasis. Autophagy. 15, 2044–2062 (2019).
pubmed: 30892128
pmcid: 6844518
doi: 10.1080/15548627.2019.1596489
Van Cauwenberghe, C., Van Broeckhoven, C. & Sleegers, K. The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet. Med. 18, 421–430 (2016).
pubmed: 26312828
doi: 10.1038/gim.2015.117
Wishart, D. S. et al. HMDB 4.0: The human metabolome database for 2018. Nucleic Acids Res. 46, D608–D617 (2018).
pubmed: 29140435
doi: 10.1093/nar/gkx1089
Kanehisa, M. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28, 27–30 (2000).
pubmed: 10592173
pmcid: 102409
doi: 10.1093/nar/28.1.27
Bowden, J., Davey Smith, G. & Burgess, S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int. J. Epidemiol. 44, 512–525 (2015).
pubmed: 26050253
pmcid: 4469799
doi: 10.1093/ije/dyv080
Verbanck, M., Chen, C. Y., Neale, B. & Do, R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat. Genet. 50, 693–698 (2018).
pubmed: 29686387
pmcid: 6083837
doi: 10.1038/s41588-018-0099-7
Burgess, S., Bowden, J., Fall, T., Ingelsson, E. & Thompson, S. G. Sensitivity analyses for robust causal inference from Mendelian randomization analyses with multiple genetic variants. Epidemiology. 28, 30–42 (2017).
pubmed: 27749700
doi: 10.1097/EDE.0000000000000559
Jin, Q. et al. The causality between intestinal flora and allergic diseases: Insights from a bi-directional two-sample Mendelian randomization analysis. Front. Immunol. 14, 1121273 (2023).
pubmed: 36969260
pmcid: 10033526
doi: 10.3389/fimmu.2023.1121273
Gay, N. R. et al. Impact of admixture and ancestry on eQTL analysis and GWAS colocalization in GTEx. Genome Biol. 21, 233 (2020).
pubmed: 32912333
pmcid: 7488497
doi: 10.1186/s13059-020-02113-0
Giambartolomei, C. et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 10, e1004383 (2014).
pubmed: 24830394
pmcid: 4022491
doi: 10.1371/journal.pgen.1004383
Zuber, V. et al. Combining evidence from Mendelian randomization and colocalization: Review and comparison of approaches. Am. J. Hum. Genet. 109, 767–782 (2022).
pubmed: 35452592
pmcid: 7612737
doi: 10.1016/j.ajhg.2022.04.001
Jonsson, T. et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature. 488, 96–99 (2012).
pubmed: 22801501
doi: 10.1038/nature11283
Arber, C. et al. Familial Alzheimer’s disease mutations in PSEN1 lead to premature human stem cell neurogenesis. Cell. Rep. 34, 108615 (2021).
pubmed: 33440141
pmcid: 7809623
doi: 10.1016/j.celrep.2020.108615
Cacace, R., Sleegers, K. & Van Broeckhoven, C. Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimers Dement. 12, 733–748 (2016).
pubmed: 27016693
doi: 10.1016/j.jalz.2016.01.012
The VA Million Veteran Program. Multi-trait association studies discover pleiotropic loci between Alzheimer’s disease and cardiometabolic traits. Alzheimers Res. Ther. 13, 34 (2021).
doi: 10.1186/s13195-021-00773-z
O’Connor, L. J. & Price, A. L. Distinguishing genetic correlation from causation across 52 diseases and complex traits. Nat. Genet. 50, 1728–1734 (2018).
pubmed: 30374074
pmcid: 6684375
doi: 10.1038/s41588-018-0255-0
Reay, W. R. et al. Genetic estimates of correlation and causality between blood-based biomarkers and psychiatric disorders. Sci. Adv. 8, eabj8969 (2022).
pubmed: 35385317
pmcid: 8986101
doi: 10.1126/sciadv.abj8969