White matter microstructure is altered in cognitively normal middle-aged APOE-ε4 homozygotes
Abstract Background The ε4 allele of the apolipoprotein E gene (APOE-ε4) is the strongest genetic factor for late-onset Alzheimer’s disease. During middle age, cognitively healthy APOE-ε4 carriers already show several brain alterations that resemble those of Alzheimer's disease (AD), but to a s...
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doaj-deeb308a4fec42c5a252aee6fd117ebb2020-11-25T00:37:35ZengBMCAlzheimer’s Research & Therapy1758-91932018-05-0110111810.1186/s13195-018-0375-xWhite matter microstructure is altered in cognitively normal middle-aged APOE-ε4 homozygotesGrégory Operto0Raffaele Cacciaglia1Oriol Grau-Rivera2Carles Falcon3Anna Brugulat-Serrat4Pablo Ródenas5Rubén Ramos6Sebastián Morán7Manel Esteller8Nuria Bargalló9José Luis Molinuevo10Juan Domingo Gispert11for the ALFA StudyBarcelonaβeta Brain Research Center, Pasqual Maragall FoundationBarcelonaβeta Brain Research Center, Pasqual Maragall FoundationBarcelonaβeta Brain Research Center, Pasqual Maragall FoundationBarcelonaβeta Brain Research Center, Pasqual Maragall FoundationBarcelonaβeta Brain Research Center, Pasqual Maragall FoundationBarcelona Supercomputing CenterBarcelona Supercomputing CenterCancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L’HospitaletCancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L’HospitaletInstitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)Barcelonaβeta Brain Research Center, Pasqual Maragall FoundationBarcelonaβeta Brain Research Center, Pasqual Maragall FoundationAbstract Background The ε4 allele of the apolipoprotein E gene (APOE-ε4) is the strongest genetic factor for late-onset Alzheimer’s disease. During middle age, cognitively healthy APOE-ε4 carriers already show several brain alterations that resemble those of Alzheimer's disease (AD), but to a subtler degree. These include microstructural white matter (WM) changes that have been proposed as one of the earliest structural events in the AD cascade. However, previous studies have focused mainly on comparison of APOE-ε4 carriers vs noncarriers. Therefore, the extent and magnitude of the brain alterations in healthy ε4 homozygotes, who are the individuals at highest risk, remain to be characterized in detail. Methods We examined mean, axial, and radial water diffusivity (MD, AxD, and RD, respectively) and fractional anisotropy in the WM as measured by diffusion-weighted imaging in 532 cognitively healthy middle-aged participants from the ALFA study (ALzheimer and FAmilies) cohort, a single-site population-based study enriched for AD risk (68 APOE-ε4 homozygotes, 207 heterozygotes, and 257 noncarriers). We examined the impact of age and APOE genotype on these parameters using tract-based spatial statistics. Results Healthy APOE-ε4 homozygotes display increased WM diffusivity in regions known to be affected by AD. The effects in AxD were much smaller than in RD, suggesting a disruption of the myelin sheath rather than pure axonal damage. Conclusions These findings could be interpreted as the result of the reduced capacity of the ε4 isoform of the APOE protein to keep cholesterol homeostasis in the brain. Because cerebral lipid metabolism is strongly related to the pathogenesis of AD, our results shed light on the possible mechanisms through which the APOE-ε4 genotype is associated with an increased risk of AD.http://link.springer.com/article/10.1186/s13195-018-0375-xDiffusion tensor imagingApolipoprotein EWhite matter integrityAgingCognitively normal subjects |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Grégory Operto Raffaele Cacciaglia Oriol Grau-Rivera Carles Falcon Anna Brugulat-Serrat Pablo Ródenas Rubén Ramos Sebastián Morán Manel Esteller Nuria Bargalló José Luis Molinuevo Juan Domingo Gispert for the ALFA Study |
spellingShingle |
Grégory Operto Raffaele Cacciaglia Oriol Grau-Rivera Carles Falcon Anna Brugulat-Serrat Pablo Ródenas Rubén Ramos Sebastián Morán Manel Esteller Nuria Bargalló José Luis Molinuevo Juan Domingo Gispert for the ALFA Study White matter microstructure is altered in cognitively normal middle-aged APOE-ε4 homozygotes Alzheimer’s Research & Therapy Diffusion tensor imaging Apolipoprotein E White matter integrity Aging Cognitively normal subjects |
author_facet |
Grégory Operto Raffaele Cacciaglia Oriol Grau-Rivera Carles Falcon Anna Brugulat-Serrat Pablo Ródenas Rubén Ramos Sebastián Morán Manel Esteller Nuria Bargalló José Luis Molinuevo Juan Domingo Gispert for the ALFA Study |
author_sort |
Grégory Operto |
title |
White matter microstructure is altered in cognitively normal middle-aged APOE-ε4 homozygotes |
title_short |
White matter microstructure is altered in cognitively normal middle-aged APOE-ε4 homozygotes |
title_full |
White matter microstructure is altered in cognitively normal middle-aged APOE-ε4 homozygotes |
title_fullStr |
White matter microstructure is altered in cognitively normal middle-aged APOE-ε4 homozygotes |
title_full_unstemmed |
White matter microstructure is altered in cognitively normal middle-aged APOE-ε4 homozygotes |
title_sort |
white matter microstructure is altered in cognitively normal middle-aged apoe-ε4 homozygotes |
publisher |
BMC |
series |
Alzheimer’s Research & Therapy |
issn |
1758-9193 |
publishDate |
2018-05-01 |
description |
Abstract Background The ε4 allele of the apolipoprotein E gene (APOE-ε4) is the strongest genetic factor for late-onset Alzheimer’s disease. During middle age, cognitively healthy APOE-ε4 carriers already show several brain alterations that resemble those of Alzheimer's disease (AD), but to a subtler degree. These include microstructural white matter (WM) changes that have been proposed as one of the earliest structural events in the AD cascade. However, previous studies have focused mainly on comparison of APOE-ε4 carriers vs noncarriers. Therefore, the extent and magnitude of the brain alterations in healthy ε4 homozygotes, who are the individuals at highest risk, remain to be characterized in detail. Methods We examined mean, axial, and radial water diffusivity (MD, AxD, and RD, respectively) and fractional anisotropy in the WM as measured by diffusion-weighted imaging in 532 cognitively healthy middle-aged participants from the ALFA study (ALzheimer and FAmilies) cohort, a single-site population-based study enriched for AD risk (68 APOE-ε4 homozygotes, 207 heterozygotes, and 257 noncarriers). We examined the impact of age and APOE genotype on these parameters using tract-based spatial statistics. Results Healthy APOE-ε4 homozygotes display increased WM diffusivity in regions known to be affected by AD. The effects in AxD were much smaller than in RD, suggesting a disruption of the myelin sheath rather than pure axonal damage. Conclusions These findings could be interpreted as the result of the reduced capacity of the ε4 isoform of the APOE protein to keep cholesterol homeostasis in the brain. Because cerebral lipid metabolism is strongly related to the pathogenesis of AD, our results shed light on the possible mechanisms through which the APOE-ε4 genotype is associated with an increased risk of AD. |
topic |
Diffusion tensor imaging Apolipoprotein E White matter integrity Aging Cognitively normal subjects |
url |
http://link.springer.com/article/10.1186/s13195-018-0375-x |
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