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White matter microstructure is altered in cognitively normal middle-aged APOE-ε4 homozygotes.
Alzheimers Res Ther 2018; 10(1):48AR

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.

Authors+Show Affiliations

Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, C/ Wellington, 30, 08005, Barcelona, Spain.Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, C/ Wellington, 30, 08005, Barcelona, Spain.Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, C/ Wellington, 30, 08005, Barcelona, Spain.Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, C/ Wellington, 30, 08005, Barcelona, Spain. Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain.Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, C/ Wellington, 30, 08005, Barcelona, Spain.Barcelona Supercomputing Center, Barcelona, Catalonia, Spain.Barcelona Supercomputing Center, Barcelona, Catalonia, Spain.Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain.Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain. Departament de Ciències Fisiològiques II, Escola de Medicina, Universitat de Barcelona, Barcelona, Catalonia, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain. Centre Mèdic Diagnòstic Alomar, Barcelona, Spain.Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, C/ Wellington, 30, 08005, Barcelona, Spain. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain. CIBER Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain.Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, C/ Wellington, 30, 08005, Barcelona, Spain. jdgispert@barcelonabeta.org. Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain. jdgispert@barcelonabeta.org.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29793545

Citation

Operto, Grégory, et al. "White Matter Microstructure Is Altered in Cognitively Normal Middle-aged APOE-ε4 Homozygotes." Alzheimer's Research & Therapy, vol. 10, no. 1, 2018, p. 48.
Operto G, Cacciaglia R, Grau-Rivera O, et al. White matter microstructure is altered in cognitively normal middle-aged APOE-ε4 homozygotes. Alzheimers Res Ther. 2018;10(1):48.
Operto, G., Cacciaglia, R., Grau-Rivera, O., Falcon, C., Brugulat-Serrat, A., Ródenas, P., ... Gispert, J. D. (2018). White matter microstructure is altered in cognitively normal middle-aged APOE-ε4 homozygotes. Alzheimer's Research & Therapy, 10(1), p. 48. doi:10.1186/s13195-018-0375-x.
Operto G, et al. White Matter Microstructure Is Altered in Cognitively Normal Middle-aged APOE-ε4 Homozygotes. Alzheimers Res Ther. 2018 05 24;10(1):48. PubMed PMID: 29793545.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - White matter microstructure is altered in cognitively normal middle-aged APOE-ε4 homozygotes. AU - Operto,Grégory, AU - Cacciaglia,Raffaele, AU - Grau-Rivera,Oriol, AU - Falcon,Carles, AU - Brugulat-Serrat,Anna, AU - Ródenas,Pablo, AU - Ramos,Rubén, AU - Morán,Sebastián, AU - Esteller,Manel, AU - Bargalló,Nuria, AU - Molinuevo,José Luis, AU - Gispert,Juan Domingo, AU - ,, Y1 - 2018/05/24/ PY - 2018/01/16/received PY - 2018/04/24/accepted PY - 2018/5/26/entrez PY - 2018/5/26/pubmed PY - 2019/8/3/medline KW - Aging KW - Apolipoprotein E KW - Cognitively normal subjects KW - Diffusion tensor imaging KW - White matter integrity SP - 48 EP - 48 JF - Alzheimer's research & therapy JO - Alzheimers Res Ther VL - 10 IS - 1 N2 - 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. SN - 1758-9193 UR - https://www.unboundmedicine.com/medline/citation/29793545/White_matter_microstructure_is_altered_in_cognitively_normal_middle_aged_APOE_ε4_homozygotes_ L2 - https://alzres.biomedcentral.com/articles/10.1186/s13195-018-0375-x DB - PRIME DP - Unbound Medicine ER -