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Disrupted excitation-inhibition balance in cognitively normal individuals at risk of Alzheimer’s disease
BACKGROUND: Sex differences impact Alzheimer’s disease (AD) neuropathology, but cell-to-network level dysfunctions in the prodromal phase are unclear. Alterations in hippocampal excitation-inhibition balance (EIB) have recently been linked to early AD pathology. OBJECTIVE: Examine how AD risk factor...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10473582/ https://www.ncbi.nlm.nih.gov/pubmed/37662359 http://dx.doi.org/10.1101/2023.08.21.554061 |
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author | Fortel, Igor Zhan., Liang Ajilore., Olusola Wu, Yichao Mackin, Scott Leow, Alex |
author_facet | Fortel, Igor Zhan., Liang Ajilore., Olusola Wu, Yichao Mackin, Scott Leow, Alex |
author_sort | Fortel, Igor |
collection | PubMed |
description | BACKGROUND: Sex differences impact Alzheimer’s disease (AD) neuropathology, but cell-to-network level dysfunctions in the prodromal phase are unclear. Alterations in hippocampal excitation-inhibition balance (EIB) have recently been linked to early AD pathology. OBJECTIVE: Examine how AD risk factors (age, APOE-ɛ4, amyloid-β) relate to hippocampal EIB in cognitively normal males and females using connectome-level measures. METHODS: Individuals from the OASIS-3 cohort (age 42–95) were studied (N = 437), with a subset aged 65+ undergoing neuropsychological testing (N = 231). RESULTS: In absence of AD risk factors (APOE-ɛ4/Aβ+), whole-brain EIB decreases with age more significantly in males than females (p = 0.021, β = −0.007). Regression modeling including APOE-ɛ4 allele carriers (Aβ-) yielded a significant positive AGE-by-APOE interaction in the right hippocampus for females only (p = 0.013, β = 0.014), persisting with inclusion of Aβ+ individuals (p = 0.012, β = 0.014). Partial correlation analyses of neuropsychological testing showed significant associations with EIB in females: positive correlations between right hippocampal EIB with categorical fluency and whole-brain EIB with the trail-making test (p < 0.05). CONCLUSION: Sex differences in EIB emerge during normal aging and progresses differently with AD risk. Results suggest APOE-ɛ4 disrupts hippocampal balance more than amyloid in females. Increased excitation correlates positively with neuropsychological performance in the female group, suggesting a duality in terms of potential beneficial effects prior to cognitive impairment. This underscores the translational relevance of APOE-ɛ4 related hyperexcitation in females, potentially informing therapeutic targets or early interventions to mitigate AD progression in this vulnerable population. |
format | Online Article Text |
id | pubmed-10473582 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Cold Spring Harbor Laboratory |
record_format | MEDLINE/PubMed |
spelling | pubmed-104735822023-09-02 Disrupted excitation-inhibition balance in cognitively normal individuals at risk of Alzheimer’s disease Fortel, Igor Zhan., Liang Ajilore., Olusola Wu, Yichao Mackin, Scott Leow, Alex bioRxiv Article BACKGROUND: Sex differences impact Alzheimer’s disease (AD) neuropathology, but cell-to-network level dysfunctions in the prodromal phase are unclear. Alterations in hippocampal excitation-inhibition balance (EIB) have recently been linked to early AD pathology. OBJECTIVE: Examine how AD risk factors (age, APOE-ɛ4, amyloid-β) relate to hippocampal EIB in cognitively normal males and females using connectome-level measures. METHODS: Individuals from the OASIS-3 cohort (age 42–95) were studied (N = 437), with a subset aged 65+ undergoing neuropsychological testing (N = 231). RESULTS: In absence of AD risk factors (APOE-ɛ4/Aβ+), whole-brain EIB decreases with age more significantly in males than females (p = 0.021, β = −0.007). Regression modeling including APOE-ɛ4 allele carriers (Aβ-) yielded a significant positive AGE-by-APOE interaction in the right hippocampus for females only (p = 0.013, β = 0.014), persisting with inclusion of Aβ+ individuals (p = 0.012, β = 0.014). Partial correlation analyses of neuropsychological testing showed significant associations with EIB in females: positive correlations between right hippocampal EIB with categorical fluency and whole-brain EIB with the trail-making test (p < 0.05). CONCLUSION: Sex differences in EIB emerge during normal aging and progresses differently with AD risk. Results suggest APOE-ɛ4 disrupts hippocampal balance more than amyloid in females. Increased excitation correlates positively with neuropsychological performance in the female group, suggesting a duality in terms of potential beneficial effects prior to cognitive impairment. This underscores the translational relevance of APOE-ɛ4 related hyperexcitation in females, potentially informing therapeutic targets or early interventions to mitigate AD progression in this vulnerable population. Cold Spring Harbor Laboratory 2023-08-22 /pmc/articles/PMC10473582/ /pubmed/37662359 http://dx.doi.org/10.1101/2023.08.21.554061 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator. |
spellingShingle | Article Fortel, Igor Zhan., Liang Ajilore., Olusola Wu, Yichao Mackin, Scott Leow, Alex Disrupted excitation-inhibition balance in cognitively normal individuals at risk of Alzheimer’s disease |
title | Disrupted excitation-inhibition balance in cognitively normal individuals at risk of Alzheimer’s disease |
title_full | Disrupted excitation-inhibition balance in cognitively normal individuals at risk of Alzheimer’s disease |
title_fullStr | Disrupted excitation-inhibition balance in cognitively normal individuals at risk of Alzheimer’s disease |
title_full_unstemmed | Disrupted excitation-inhibition balance in cognitively normal individuals at risk of Alzheimer’s disease |
title_short | Disrupted excitation-inhibition balance in cognitively normal individuals at risk of Alzheimer’s disease |
title_sort | disrupted excitation-inhibition balance in cognitively normal individuals at risk of alzheimer’s disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10473582/ https://www.ncbi.nlm.nih.gov/pubmed/37662359 http://dx.doi.org/10.1101/2023.08.21.554061 |
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