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Authors: Cuesta, Pablo | Barabash, Ana | Aurtenetxe, Sara | Garcés, Pilar | López, María Eugenia | Bajo, Ricardo | Llanero-Luque, Marcos | Ancín, Inés | Cabranes, José Antonio | Marcos, Alberto | Sancho, Miguel | Nakamura, Akinori | Maestú, Fernando | Fernandez, Alberto

Article Type: Research Article

Abstract: The apolipoprotein E (APOE) ε4 allele is a genetic risk factor for the development of late-onset Alzheimer's disease (AD), which affects cholinergic system functioning. The association between reduced cholinergic levels and increase of magnetoencephalographic (MEG) low-frequency has been used to explain spectral changes found in AD patients. However, the investigation in predementia stages is scarce. We obtained MEG recordings from 25 aged controls and 36 mild cognitive impairment (MCI) patients during a resting-state condition. According to their APOE genotype, MCIs and controls were subdivided in carriers and non-carriers of the ε4 allele. Sources of spectral variations in these groups were …calculated through beamforming. MCI patients exhibited a significant increase of relative power within the low-frequency domain, accompanied by a power decrease within the high-frequency range. APOEε4 carriers showed an increased relative power in the 4.5–6.5 Hz frequency range over frontal lobes. The power increase observed in controls carrying ε4 was significantly higher as compared with MCI non-carriers, while MCI carriers exhibited the highest relative power within the 4.5–6.5 Hz range. Higher power values within the low-frequency ranges correlated with a poorer cognitive performance in MCIs and controls. Our investigation demonstrates that APOEε4 affects resting-state activity to an extent that makes it more proximate to the pattern observed in early stages of AD. Therefore, a combination of genetic and neurophysiological information might help to detect MCI patients at higher risk of conversion to AD, and asymptomatic subjects at higher risk of developing a manifest cognitive deterioration. Show more

Keywords: Aging, APOEε4, magnetoencephalography, mild cognitive impairment, relative power, source analysis

DOI: 10.3233/JAD-140633

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 259-273, 2015

Authors: Samaranch, Lluís | Cervantes, Sebastián | Barabash, Ana | Alonso, Alvaro | Cabranes, José Antonio | Lamet, Isabel | Ancín, Inés | Lorenzo, Elena | Martínez-Lage, Pablo | Marcos, Alberto | Clarimón, Jordi | Alcolea, Daniel | Lleó, Alberto | Blesa, Rafael | Gómez-Isla, Teresa | Pastor, Pau

Article Type: Research Article

Abstract: Microtubule-associated protein tau (MAPT) and apolipoprotein E (APOE) are involved in the pathogenic mechanisms of Alzheimer's disease (AD). We prospectively followed three longitudinal independent samples (total n = 319) with amnestic mild cognitive impairment (MCI) and analyzed whether MAPT H1/H2 haplotypes and APOE ε4 polymorphisms accelerated the rate of progression from MCI to dementia. At the end of the study, 172 subjects remained cognitively stable, whereas 147 progressed to dementia. APOE ε4 and MAPT H1/H1 were independently associated with an increased rate of progression to dementia in the combined sample. Cox regression models of the combined MCI sample showed that …MAPT H1/H1 carriers had an increased rate of progression to dementia compared with non carriers (Hazard Ratio = 1.45; 95% CI = 1.04–2.02; p = 0.028) and time-to-progression was shortened by 1.37 years. APOE ε4 allele also accelerated progression to dementia (Hazard Ratio = 1.47; 95% CI = 1.06–2.04; p = 0.020) and reduced the time-to-progression by 0.87 years. Additionally, MAPT H1/H1 genotype and APOE ε4 allele had an additive effect in progression to dementia, increasing progression rate to dementia (Hazard Ratio = 2.24, 95% CI = 1.40–3.58; p = 0.001) and shortening time-to-progression to dementia by 2.92 years. Similar results were obtained when only considering progression to AD-type dementia. Our results suggest that both MAPT H1/H1 genotype and APOE ε4 allele lead to a more rapid progression to dementia among MCI subjects, probably mediating an increased rate of amyloid-β and tau brain deposition. Show more

Keywords: Alzheimer's disease, APOE, interaction, genetics, microtubule-associated tau protein, MAPT, mild cognitive impairment

DOI: 10.3233/JAD-2010-101011

Citation: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1065-1071, 2010

Authors: Cuesta, Pablo | Garcés, Pilar | Castellanos, Nazareth P. | López, Maria Eugenia | Aurtenetxe, Sara | Bajo, Ricardo | Pineda-Pardo, José Angel | Bruña, Ricardo | Marín, Antonio García | Delgado, Marisa | Barabash, Ana | Ancín, Inés | Cabranes, Jose Antonio | Fernandez, Alberto | del Pozo, Francisco | Sancho, Miguel | Marcos, Alberto | Nakamura, Akinori | Maestú, Fernando

Article Type: Research Article

Abstract: The apolipoprotein E (APOE) ε4 allele constitutes the major genetic risk for the development of late onset Alzheimer's disease (AD). However, its influence on the neurodegeneration that occurs in early AD remains unresolved. In this study, the resting state magnetoencephalography(MEG) recordings were obtained from 27 aged healthy controls and 36 mild cognitive impairment (MCI) patients. All participants were divided into carriers and non-carriers of the ε4 allele. We have calculated the functional connectivity (FC) in the source space along brain regions estimated using the Harvard-Oxford atlas and in the classical bands. Then, a two way ANOVA analysis (diagnosis and APOE) …was performed in each frequency band. The diagnosis effect consisted of a diminished FC within the high frequency bands in the MCI patients, affecting medial temporal and parietal regions. The APOE effect produced a decreased long range FC in delta band in ε4 carriers. Finally, the interaction effect showed that the FC pattern of the right frontal-temporal region could be reflecting a compensatory/disruption process within the ε4 allele carriers. Several of these results correlated with cognitive decline and neuropsychological performance. The present study characterizes how the APOE ε4 allele and MCI status affect the brain's functional organization by analyzing the FC patterns in MEG resting state in the sources space. Therefore a combination of genetic, neuropsychological, and neurophysiological information might help to detect MCI patients at higher risk of conversion to AD and asymptomatic subjects at higher risk of developing a manifest cognitive deterioration. Show more

Keywords: Aging, APOE ε4, functional connectivity, magnetoencephalography, mild cognitive impairment, source analysis

DOI: 10.3233/JAD-141872

Citation: Journal of Alzheimer's Disease, vol. 44, no. 2, pp. 493-505, 2015