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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Main Authors: 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
Format: Article
Language:English
Published: BMC 2018-05-01
Series:Alzheimer’s Research & Therapy
Subjects:
Online Access:http://link.springer.com/article/10.1186/s13195-018-0375-x
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spelling 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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