Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non-demented individuals.
biological pathways
magnetic resonance imaging
polygenic risk
preclinical Alzheimer's disease
Journal
Alzheimer's & dementia : the journal of the Alzheimer's Association
ISSN: 1552-5279
Titre abrégé: Alzheimers Dement
Pays: United States
ID NLM: 101231978
Informations de publication
Date de publication:
29 Jul 2024
29 Jul 2024
Historique:
revised:
20
03
2024
received:
31
10
2023
accepted:
03
06
2024
medline:
29
7
2024
pubmed:
29
7
2024
entrez:
29
7
2024
Statut:
aheadofprint
Résumé
Unraveling how Alzheimer's disease (AD) genetic risk is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, is a key step toward precision medicine. We computed pathway-specific genetic risk scores (GRSs) in non-demented individuals and investigated how AD risk variants predict cerebrospinal fluid (CSF) and imaging biomarkers reflecting AD pathology, cardiovascular, white matter integrity, and brain connectivity. CSF amyloidbeta and phosphorylated tau were related to most GRSs. Inflammatory pathways were associated with cerebrovascular disease, whereas quantitative measures of white matter lesion and microstructure integrity were predicted by clearance and migration pathways. Functional connectivity alterations were related to genetic variants involved in signal transduction and synaptic communication. This study reveals distinct genetic risk profiles in association with specific pathophysiological aspects in predementia stages of AD, unraveling the biological substrates of the heterogeneity of AD-associated endophenotypes and promoting a step forward in disease understanding and development of personalized therapies. Polygenic risk for Alzheimer's disease encompasses six biological pathways that can be quantified with pathway-specific genetic risk scores, and differentially relate to cerebrospinal fluid and imaging biomarkers. Inflammatory pathways are mostly related to cerebrovascular burden. White matter health is associated with pathways of clearance and membrane integrity, whereas functional connectivity measures are related to signal transduction and synaptic communication pathways.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : EU/EFPIA Innovative Medicines Initiative Joint Undertaking EPAD
ID : 115736
Informations de copyright
© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
Références
Bellenguez C, Küçükali F, Jansen IE, et al. New insights into the genetic etiology of Alzheimer's disease and related dementias. Nat Genet. 2022;54:412‐436.
Sims R, Hill M, Williams J. The multiplex model of the genetics of Alzheimer's disease. Nat Neurosci. 2020;23:311‐322.
Ferreira D, Nordberg A, Westman E. Biological subtypes of Alzheimer disease: a systematic review and meta‐analysis. Neurology. 2020;94:436‐448.
Dong A, Toledo JB, Honnorat N, et al. Heterogeneity of neuroanatomical patterns in prodromal Alzheimer's disease: links to cognition, progression and biomarkers. Brain. 2017;140:735‐747.
Scheltens P, Blennow K, Breteler MMB, et al. Alzheimer's disease. Lancet. 2016;388:505‐517.
Ten Kate M, Dicks E, Visser PJ, et al. Atrophy subtypes in prodromal Alzheimer's disease are associated with cognitive decline. Brain. 2018;141:3443‐3456.
Mehta D, Jackson R, Paul G, Shi J, Sabbagh M. Why do trials for Alzheimer's disease drugs keep failing? A discontinued drug perspective for 2010‐2015. Expert Opin Investig Drugs. 2017;26:735‐739.
Wesenhagen KEJ, Teunissen CE, Visser PJ, Tijms BM. Cerebrospinal fluid proteomics and biological heterogeneity in Alzheimer's disease: a literature review. Crit Rev Clin Lab Sci. 2020;57:86‐98.
Lam B, Masellis M, Freedman M, Stuss DT, Black SE. Clinical, imaging, and pathological heterogeneity of the Alzheimer's disease syndrome. Alzheimer's Res Ther. 2013;5:1. doi:10.1186/alzrt155
Choi SW, Mak TS‐H, O'Reilly PF. Tutorial: a guide to performing polygenic risk score analyses. Nat Protoc. 2020;15:2759‐2772.
Darst BF, Koscik RL, Racine AM, et al. Pathway‐specific polygenic risk scores as predictors of amyloid‐β deposition and cognitive function in a sample at increased risk for Alzheimer's disease. J Alzheimers Dis. 2017;55:473‐484.
Morris JC, Roe CM, Xiong C, et al. APOEpredicts amyloid‐beta but not tau Alzheimer pathology in cognitively normal aging. Annals of Neurology. 2010;67:122‐131. doi:10.1002/ana.21843
Benson GS, Bauer C, Hausner L, et al. Don't forget about tau: the effects of ApoE4 genotype on Alzheimer's disease cerebrospinal fluid biomarkers in subjects with mild cognitive impairment—data from the dementia competence network. J Neural Transm. 2022;129:477‐486. doi:10.1007/s00702‐022‐02461‐0
Mishra S, Blazey TM, Holtzman DM, et al. Longitudinal brain imaging in preclinical Alzheimer disease: impact of APOE ε4 genotype. Brain. 2018;141:1828‐1839.
Cacciaglia R, Operto G, Falcón C, et al. Genotypic effects of APOE‐ε4 on resting‐state connectivity in cognitively intact individuals support functional brain compensation. Cereb Cortex. 2022;33:2748‐2760. doi:10.1093/cercor/bhac239
Altmann A, Scelsi MA, Shoai M, et al. A comprehensive analysis of methods for assessing polygenic burden on Alzheimer's disease pathology and risk beyond APOE. Brain Commun. 2020;2:fcz047.
Rubinski A, Frerich S, Malik R, et al. Polygenic effect on tau pathology progression in Alzheimer's disease. Ann Neurol. 2023;93:819‐829.
Ahmad S, Bannister C, van der Lee SJ, et al. Disentangling the biological pathways involved in early features of Alzheimer's disease in the Rotterdam Study. Alzheimers Dement. 2018;14:848‐857.
Ritchie CW, Muniz‐Terrera G, Kivipelto M, Solomon A, Tom B, Molinuevo JL. The European Prevention of Alzheimer's Dementia (EPAD) longitudinal cohort study: baseline data release V500.0. J Prev Alzheimers Dis. 2020;7:8‐13.
Solomon A, Kivipelto M, Molinuevo JL, Tom B, Ritchie CW, EPAD Consortium. European Prevention of Alzheimer's Dementia Longitudinal Cohort Study (EPAD LCS): study protocol. BMJ Open. 2019;8:e021017.
Das S, Forer L, Schönherr S, et al. Next‐generation genotype imputation service and methods. Nat Genet. 2016;48:1284‐1287.
Tesi N, van der Lee S, Hulsman M, Holstege H, Reinders MJT. snpXplorer: a web application to explore human SNP‐associations and annotate SNP‐sets. Nucleic Acids Res. 2021;49:W603‐W612.
Raudvere U, Kolberg L, Kuzmin I, et al. g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res. 2019;47:W191‐W198. doi:10.1093/nar/gkz369
Ashburner M, Ball CA, Blake JA, et al. Gene ontology: tool for the unification of biology. Nat Genet. 2000;25:25‐29.
Lin D. An information‐theoretic definition of similarity. ICML. 1998;98:296‐304.
Ingala S, De Boer C, Masselink LA, et al. Application of the ATN classification scheme in a population without dementia: findings from the EPAD cohort. Alzheimers Dement. 2021;17:1189‐1204. doi:10.1002/alz.12292
Lorenzini L, Ingala S, Wink AM, et al. The Open‐Access European Prevention of Alzheimer's Dementia (EPAD) MRI dataset and processing workflow. Neuroimage Clin. 2022;35:103106.
Wolz R, Aljabar P, Hajnal JV, Hammers A, Rueckert D. Alzheimer's Disease Neuroimaging Initiative. LEAP: learning embeddings for atlas propagation. Neuroimage. 2010;49:1316‐1325.
Sudre CH, Cardoso MJ, Bouvy WH, Biessels GJ, Barnes J, Ourselin S. Bayesian model selection for pathological neuroimaging data applied to white matter lesion segmentation. IEEE Trans Med Imaging. 2015;34:2079‐2102.
Pålhaugen L, Sudre CH, Tecelao S, et al. Brain amyloid and vascular risk are related to distinct white matter hyperintensity patterns. J Cereb Blood Flow Metab. 2020; 41:1162‐1174. 10.1177/0271678X20957604
Nickerson LD, Smith SM, Öngür D, Beckmann CF. Using dual regression to investigate network shape and amplitude in functional connectivity analyses. Front Neurosci. 2017;11:115. doi:10.3389/fnins.2017.00115
Yeo BTT, Thomas Yeo BT, Krienen FM, et al. The organization of the human cerebral cortex estimated by intrinsic functional connectivity. J Neurophysiol. 2011;106:1125‐1165. doi:10.1152/jn.00338.2011
Jones DT, Knopman DS, Gunter JL, et al. Cascading network failure across the Alzheimer's disease spectrum. Brain. 2016;139:547‐562.
Wardlaw JM, Smith EE, Biessels GJ, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013;12:822‐838. doi:10.1016/s1474‐4422(13)70124‐8
MacLullich AMJ, Wardlaw JM, Ferguson KJ, Starr JM, Seckl JR, Deary IJ. Enlarged perivascular spaces are associated with cognitive function in healthy elderly men. J Neurol Neurosurg Psychiatry. 2004;75:1519‐1523.
Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. AJR Am J Roentgenol. 1987;149:351‐356.
Hardy J, Bogdanovic N, Winblad B, et al. Pathways to Alzheimer's disease. J Intern Med. 2014;275:296‐303.
Van Cauwenberghe C, Van Broeckhoven C, Sleegers K. The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet Med. 2016;18:421‐430.
Tesi N, Van Der Lee SJ, Hulsman M, et al. Immune response and endocytosis pathways are associated with the resilience against Alzheimer's disease. Alzheimers Dement. 2020;16:332. doi:10.1002/alz.042614
Newcombe EA, Camats‐Perna J, Silva ML, Valmas N, Huat TJ, Medeiros R. Inflammation: the link between comorbidities, genetics, and Alzheimer's disease. J Neuroinflammation. 2018;15:276.
Naj AC, Schellenberg GD, Alzheimer's Disease Genetics Consortium (ADGC). Genomic variants, genes, and pathways of Alzheimer's disease: an overview. Am J Med Genet B Neuropsychiatr Genet. 2017;174:5‐26.
Efthymiou AG, Goate AM. Late onset Alzheimer's disease genetics implicates microglial pathways in disease risk. Mol Neurodegener. 2017;12:43.
Cummings J, Zhou Y, Lee G, Zhong K, Fonseca J, Cheng F. Alzheimer's disease drug development pipeline: 2023. Alzheimers Dement. 2023;9:e12385.
Toledo JB, Habes M, Sotiras A, et al. APOE effect on amyloid‐β PET spatial distribution, deposition rate, and cut‐points. J Alzheimers Dis. 2019;69:783‐793.
Lim YY, Mormino EC. Alzheimer's disease neuroimaging initiative. APOE genotype and early β‐amyloid accumulation in older adults without dementia. Neurology. 2017;89:1028‐1034.
Luckett ES, Abakkouy Y, Reinartz M, et al. Association of Alzheimer's disease polygenic risk scores with amyloid accumulation in cognitively intact older adults. Alzheimers Res Ther. 2022;14:138.
Leonenko G, Shoai M, Bellou E, et al. Genetic risk for Alzheimer disease is distinct from genetic risk for amyloid deposition. Ann Neurol. 2019;86:427‐435.
Belloy ME, Napolioni V, Greicius MD. A quarter century of APOE and Alzheimer's disease: progress to date and the path forward. Neuron. 2019;101:820‐838.
Xicota L, Gyorgy B, Grenier‐Boley B, et al. Association of APOE‐independent Alzheimer disease polygenic risk score with brain amyloid deposition in asymptomatic older adults. Neurology. 2022;99:e462‐e475.
Louwersheimer E, Wolfsgruber S, Espinosa A, et al. Alzheimer's disease risk variants modulate endophenotypes in mild cognitive impairment. Alzheimers Dement. 2016;12:872‐881.
Zettergren A, Lord J, Ashton NJ, et al. Association between polygenic risk score of Alzheimer's disease and plasma phosphorylated tau in individuals from the Alzheimer's disease neuroimaging initiative. Alzheimers Res Ther. 2021;13:17.
Kumar A, Janelidze S, Stomrud E, et al. β‐Amyloid‐dependent and ‐independent genetic pathways regulating CSF tau biomarkers in Alzheimer disease. Neurology. 2022;99:e476‐e487. doi:10.1212/wnl.0000000000200605
Sepulcre J, Grothe MJ, d'Oleire Uquillas F, et al. Neurogenetic contributions to amyloid beta and tau spreading in the human cortex. Nat Med. 2018;24:1910‐1918.
Ising C, Heneka MT. Chronic inflammation: a potential target in tauopathies. Lancet Neurol. 2023;22:371‐373.
Langworth‐Green C, Patel S, Jaunmuktane Z, et al. Chronic effects of inflammation on tauopathies. Lancet Neurol. 2023;22:430‐442.
Altmann A, Aksman LM, Oxtoby NP,… & Oxtoby NP. Towards cascading genetic risk in Alzheimer's disease. Brain. 2024, awae176.
Kim SE, Kim HJ, Jang H, et al. Interaction between Alzheimer's disease and cerebral small vessel disease: a review focused on neuroimaging markers. Int J Mol Sci. 2022;23:10490. doi:10.3390/ijms231810490
Theofilis P, Sagris M, Oikonomou E, et al. Inflammatory mechanisms contributing to endothelial dysfunction. Biomedicines. 2021;9:781. doi:10.3390/biomedicines9070781
Harrison JR, Foley SF, Baker E, et al. Pathway‐specific polygenic scores for Alzheimer's disease are associated with changes in brain structure in younger and older adults. Brain Commun. 2023;5:fcad229.
Prins ND, Scheltens P. White matter hyperintensities, cognitive impairment and dementia: an update. Nat Rev Neurol. 2015;11:157‐165.
Sabayan B, Westendorp RGJ. Neurovascular‐glymphatic dysfunction and white matter lesions. GeroScience. 2021;43:1635‐1642.
Williams VJ, Leritz EC, Shepel J, et al. Interindividual variation in serum cholesterol is associated with regional white matter tissue integrity in older adults. Hum Brain Mapp. 2013;34:1826‐1841.
Sharp FR, DeCarli CS, Jin L‐W, Zhan X. White matter injury, cholesterol dysmetabolism, and APP/Abeta dysmetabolism interact to produce Alzheimer's disease (AD) neuropathology: a hypothesis and review. Front Aging Neurosci. 2023;15:1096206.
Lorenzini L, Ingala S, Collij LE, Wottschel V, Haller S, Blennow K,… & Wink AM. Eigenvector centrality dynamics are related to Alzheimer.s disease pathological changes in non-demented individuals. Brain communications. 2023;5(3):fcad088.
Damoiseaux JS, Beckmann CF, Arigita EJS, et al. Reduced resting‐state brain activity in the “default network” in normal aging. Cereb Cortex. 2007;18:1856‐1864.
Bero AW, Yan P, Roh JH, et al. Neuronal activity regulates the regional vulnerability to amyloid‐β deposition. Nat Neurosci. 2011;14:750‐756.
Choi SW, García‐González J, Ruan Y, et al. PRSet: pathway‐based polygenic risk score analyses and software. PLoS Genet. 2023;19:e1010624.
Blumenfeld J, Yip O, Kim MJ, Huang Y. Cell type‐specific roles of APOE4 in Alzheimer disease. Nat Rev Neurosci. 2024;25:91‐110.
Yang H‐S, Teng L, Kang D, et al. Cell‐type‐specific Alzheimer's disease polygenic risk scores are associated with distinct disease processes in Alzheimer's disease. Nat Commun. 2023;14:7659.