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Cognitive impairment in long-living adults: a genome-wide association study, polygenic risk score model and molecular modeling of the APOE protein

BACKGROUND: Cognitive impairment is an irreversible, aging-associated condition that robs people of their independence. The purpose of this study was to investigate possible causes of this condition and propose preventive options. METHODS: We assessed cognitive status in long-living adults aged 90+...

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Autores principales: Kashtanova, D. A., Mamchur, A. A., Dzhumaniyazova, I. H., Ivanov, M. V., Erema, V. V., Zelenova, E. A., Yakovchik, A. Y., Gusakova, M. S., Rumyantseva, A. M., Terekhov, M. V., Matkava, L. R., Akopyan, A. A., Strazhesko, I. D., Yudin, V. S., Makarov, V. V., Kraevoy, S. A., Tkacheva, O. N., Yudin, S. M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10637623/
https://www.ncbi.nlm.nih.gov/pubmed/37953886
http://dx.doi.org/10.3389/fnagi.2023.1273825
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author Kashtanova, D. A.
Mamchur, A. A.
Dzhumaniyazova, I. H.
Ivanov, M. V.
Erema, V. V.
Zelenova, E. A.
Yakovchik, A. Y.
Gusakova, M. S.
Rumyantseva, A. M.
Terekhov, M. V.
Matkava, L. R.
Akopyan, A. A.
Strazhesko, I. D.
Yudin, V. S.
Makarov, V. V.
Kraevoy, S. A.
Tkacheva, O. N.
Yudin, S. M.
author_facet Kashtanova, D. A.
Mamchur, A. A.
Dzhumaniyazova, I. H.
Ivanov, M. V.
Erema, V. V.
Zelenova, E. A.
Yakovchik, A. Y.
Gusakova, M. S.
Rumyantseva, A. M.
Terekhov, M. V.
Matkava, L. R.
Akopyan, A. A.
Strazhesko, I. D.
Yudin, V. S.
Makarov, V. V.
Kraevoy, S. A.
Tkacheva, O. N.
Yudin, S. M.
author_sort Kashtanova, D. A.
collection PubMed
description BACKGROUND: Cognitive impairment is an irreversible, aging-associated condition that robs people of their independence. The purpose of this study was to investigate possible causes of this condition and propose preventive options. METHODS: We assessed cognitive status in long-living adults aged 90+ (n = 2,559) and performed a genome wide association study using two sets of variables: Mini-Mental State Examination scores as a continuous variable (linear regression) and cognitive status as a binary variable (> 24, no cognitive impairment; <10, impairment) (logistic regression). RESULTS: Both variations yielded the same polymorphisms, including a well-known marker of dementia, rs429358in the APOE gene. Molecular dynamics simulations showed that this polymorphism leads to changes in the structure of alpha helices and the mobility of the lipid-binding domain in the APOE protein. CONCLUSION: These changes, along with higher LDL and total cholesterol levels, could be the mechanism underlying the development of cognitive impairment in older adults. However, this polymorphism is not the only determining factor in cognitive impairment. The polygenic risk score model included 45 polymorphisms (ROC AUC 69%), further confirming the multifactorial nature of this condition. Our findings, particularly the results of PRS modeling, could contribute to the development of early detection strategies for predisposition to cognitive impairment in older adults.
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spelling pubmed-106376232023-11-11 Cognitive impairment in long-living adults: a genome-wide association study, polygenic risk score model and molecular modeling of the APOE protein Kashtanova, D. A. Mamchur, A. A. Dzhumaniyazova, I. H. Ivanov, M. V. Erema, V. V. Zelenova, E. A. Yakovchik, A. Y. Gusakova, M. S. Rumyantseva, A. M. Terekhov, M. V. Matkava, L. R. Akopyan, A. A. Strazhesko, I. D. Yudin, V. S. Makarov, V. V. Kraevoy, S. A. Tkacheva, O. N. Yudin, S. M. Front Aging Neurosci Aging Neuroscience BACKGROUND: Cognitive impairment is an irreversible, aging-associated condition that robs people of their independence. The purpose of this study was to investigate possible causes of this condition and propose preventive options. METHODS: We assessed cognitive status in long-living adults aged 90+ (n = 2,559) and performed a genome wide association study using two sets of variables: Mini-Mental State Examination scores as a continuous variable (linear regression) and cognitive status as a binary variable (> 24, no cognitive impairment; <10, impairment) (logistic regression). RESULTS: Both variations yielded the same polymorphisms, including a well-known marker of dementia, rs429358in the APOE gene. Molecular dynamics simulations showed that this polymorphism leads to changes in the structure of alpha helices and the mobility of the lipid-binding domain in the APOE protein. CONCLUSION: These changes, along with higher LDL and total cholesterol levels, could be the mechanism underlying the development of cognitive impairment in older adults. However, this polymorphism is not the only determining factor in cognitive impairment. The polygenic risk score model included 45 polymorphisms (ROC AUC 69%), further confirming the multifactorial nature of this condition. Our findings, particularly the results of PRS modeling, could contribute to the development of early detection strategies for predisposition to cognitive impairment in older adults. Frontiers Media S.A. 2023-10-26 /pmc/articles/PMC10637623/ /pubmed/37953886 http://dx.doi.org/10.3389/fnagi.2023.1273825 Text en Copyright © 2023 Kashtanova, Mamchur, Dzhumaniyazova, Ivanov, Erema, Zelenova, Yakovchik, Gusakova, Rumyantseva, Terekhov, Matkava, Akopyan, Strazhesko, Yudin, Makarov, Kraevoy, Tkacheva and Yudin. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Aging Neuroscience
Kashtanova, D. A.
Mamchur, A. A.
Dzhumaniyazova, I. H.
Ivanov, M. V.
Erema, V. V.
Zelenova, E. A.
Yakovchik, A. Y.
Gusakova, M. S.
Rumyantseva, A. M.
Terekhov, M. V.
Matkava, L. R.
Akopyan, A. A.
Strazhesko, I. D.
Yudin, V. S.
Makarov, V. V.
Kraevoy, S. A.
Tkacheva, O. N.
Yudin, S. M.
Cognitive impairment in long-living adults: a genome-wide association study, polygenic risk score model and molecular modeling of the APOE protein
title Cognitive impairment in long-living adults: a genome-wide association study, polygenic risk score model and molecular modeling of the APOE protein
title_full Cognitive impairment in long-living adults: a genome-wide association study, polygenic risk score model and molecular modeling of the APOE protein
title_fullStr Cognitive impairment in long-living adults: a genome-wide association study, polygenic risk score model and molecular modeling of the APOE protein
title_full_unstemmed Cognitive impairment in long-living adults: a genome-wide association study, polygenic risk score model and molecular modeling of the APOE protein
title_short Cognitive impairment in long-living adults: a genome-wide association study, polygenic risk score model and molecular modeling of the APOE protein
title_sort cognitive impairment in long-living adults: a genome-wide association study, polygenic risk score model and molecular modeling of the apoe protein
topic Aging Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10637623/
https://www.ncbi.nlm.nih.gov/pubmed/37953886
http://dx.doi.org/10.3389/fnagi.2023.1273825
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