Effects of <i>APOE</i>‐ε4 allele load on brain morphology in a cohort of middle‐aged healthy individuals with enriched genetic risk for Alzheimer's disease

Cacciaglia, Raffaele; Molinuevo, José Luís; Falcón, Carles; Brugulat‐Serrat, Anna; Sánchez‐Benavides, Gonzalo; Gramunt, Nina; Esteller, Manel; Morán, Sebastian; Minguillón, Carolina; Fauria, Karine; Gispert, Juan Domingo

doi:10.1016/j.jalz.2018.01.016

Cited by 105 publications

(99 citation statements)

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“…A subset of 608 participants was selected to participate in the present study (http://clinicaltrials.gov Identifier: NCT02198586) that was approved by the Ethics Committee of the “Parc de Salut Mar” (Barcelona, Spain; MRI/FBB2014v1.0). A detailed description of the inclusion criteria can be found in (Cacciaglia, Molinuevo, Falcón, et al, ) but in brief, those subjects who were carriers of APOE‐ε4 and APOE‐ε2 , and those with family history of AD were prioritized. All participants accepted the study procedures by signing the informed consent.…”

Section: Methodsmentioning

confidence: 99%

White matter hyperintensities mediate gray matter volume and processing speed relationship in cognitively unimpaired participants

Brugulat‐Serrat

Salvadó

Operto

et al. 2019

Human Brain Mapping

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White matter hyperintensities (WMH) have been extensively associated with cognitive impairment and reductions in gray matter volume (GMv) independently. This study explored whether WMH lesion volume mediates the relationship between cerebral patterns of GMv and cognition in 521 (mean age 57.7 years) cognitively unimpaired middle‐aged individuals. Episodic memory (EM) was measured with the Memory Binding Test and executive functions (EF) using five WAIS‐IV subtests. WMH were automatically determined from T2 and FLAIR sequences and characterized using diffusion‐weighted imaging (DWI) parameters. WMH volume was entered as a mediator in a voxel‐wise mediation analysis relating GMv and cognitive performance (with both EM and EF composites and the individual tests independently). The mediation model was corrected by age, sex, education, number of Apolipoprotein E (APOE)‐ε4 alleles and total intracranial volume. We found that even at very low levels of WMH burden in the cohort (median volume of 3.2 mL), higher WMH lesion volume was significantly associated with a widespread pattern of lower GMv in temporal, frontal, and cerebellar areas. WMH mediated the relationship between GMv and EF, mainly driven by processing speed, but not EM. DWI parameters in these lesions were compatible with incipient demyelination and axonal loss. These findings lead to the reflection on the relevance of the control of cardiovascular risk factors in middle‐aged individuals as a valuable preventive strategy to reduce or delay cognitive decline.

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Section: Methodsmentioning

confidence: 99%

White matter hyperintensities mediate gray matter volume and processing speed relationship in cognitively unimpaired participants

Brugulat‐Serrat

Salvadó

Operto

et al. 2019

Human Brain Mapping

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“…We also performed a logistic regression to calculate the odds of having insomnia as a function of the APOE status while adjusting by age and sex. Potential confounders for those analyses evaluating the effect of insomnia in different outcomes were selected a priori based on well-known risk factors for sleep disturbances and/or cognitive impairment, as well as other variables associated to brain function and/or structure, such as cardiovascular risk factors [34][35][36], APOE ε4 allele carriership [37][38][39][40], body mass index (BMI) [41][42][43], and the level of anxiety and depression [36,44,45], among others. Associations between the presence of insomnia and cognitive performance were first evaluated with a multivariable linear regression model with a p value threshold for statistical significance of p < 0.005 using a Bonferroni-type correction (≈ 0.05 divided by nine cognitive outcomes).…”

Section: Statistical Analysesmentioning

confidence: 99%

“…All statistical analyses were adjusted by age, sex, education, number of APOE-ε4 alleles, GADS, and BMI. VBM analyses were also adjusted by squared age (to account for non-linear effects) [38] and total intracranial volume. We did not adjust TBSS analyses for age squared, as we did not found evidence of a non-linear association between age and TBSS metrics in a previous work based on the same dataset [39].…”

Section: Statistical Analysesmentioning

confidence: 99%

Association between insomnia and cognitive performance, gray matter volume, and white matter microstructure in cognitively unimpaired adults

et al. 2020

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Background: Mounting evidence links poor sleep quality with a higher risk of late-life dementia. However, the structural and cognitive correlates of insomnia are still not well understood. The study aims were to characterize the cognitive performance and brain structural pattern of cognitively unimpaired adults at increased risk for Alzheimer's disease (AD) with insomnia. Methods: This cross-sectional study included 1683 cognitively unimpaired middle/late-middle-aged adults from the ALFA (ALzheimer and FAmilies) study who underwent neuropsychological assessment, T1-weighted structural imaging (n = 366), and diffusion-weighted imaging (n = 334). The World Health Organization's World Mental Health Survey Initiative version of the Composite International Diagnostic Interview was used to define the presence or absence of insomnia. Multivariable regression models were used to evaluate differences in cognitive performance between individuals with and without insomnia, as well as potential interactions between insomnia and the APOE genotype. Voxel-based morphometry and tractbased spatial statistics were used to assess between-group differences and potential interactions between insomnia and the APOE genotype in gray matter volume and white matter diffusion metrics. Results: Insomnia was reported by 615 out of 1683 participants (36.5%), including 137 out of 366 (37.4%) with T1-weighted structural imaging available and 119 out of 334 (35.6%) with diffusion-weighted imaging. Individuals with insomnia (n = 615) performed worse in executive function tests than non-insomniacs and displayed lower gray matter volume in left orbitofrontal and right middle temporal cortex, bilateral precuneus, posterior cingulate cortex and thalamus, higher gray matter volume in the left caudate nucleus, and widespread reduction of mean and axial diffusivity in right hemisphere white matter tracts. Insomnia interacted with the APOE genotype, with APOE-ε4 carriers displaying lower gray matter volumes when insomnia was present, but higher volumes when insomnia was not present, in several gray matter regions, including the left angular gyrus, the bilateral superior frontal gyri, the thalami, and the right hippocampus.

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“…Brain damage associated to AD starts decades before the symptomatic onset and clinical diagnose, which has led to consider AD as a continuum (Dubois et al, 2016;Jack et al, 2018). In this line, studies performed on AD risk population such as carriers of apolipoprotein E (APOE)-ε4 or rs405509 alleles have detected brain differences between these subjects and control subjects in elderly Reiter et al, 2017;Shu et al, 2015) and middle-age healthy population (Cacciaglia et al, 2018;Habib et al, 2017;Mak et al, 2017;ten Kate et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Brain connectivity during Alzheimer’s disease progression and its cognitive impact in a transgenic rat model

Muñoz‐Moreno

Tudela

López-Gil

et al. 2019

Preprint

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The research of Alzheimer's disease (AD) in their early stages and its progression till symptomatic onset 12 is essential to understand the pathology and investigate new treatments. Animal models provide a helpful 13 approach to this research, since they allow for controlled follow-up during the disease evolution. In this 14 work, transgenic TgF344-AD rats were longitudinally evaluated starting at 6 months of age. Every 3 15 months, cognitive abilities were assessed by a memory-related task and magnetic resonance imaging 16 (MRI) was acquired. Structural and functional brain networks were estimated and characterized by graph 17 metrics to identify differences between the groups in connectivity, its evolution with age, and its influence 18 on cognition. Structural networks of transgenic animals were altered since the earliest stage. Likewise, 19 aging significantly affected network metrics in TgF344-AD, but not in the control group. In addition, 20 while the structural brain network influenced cognitive outcome in transgenic animals, functional 21 network impacted how control subjects performed. TgF344-AD brain network alterations were present 22 from very early stages, difficult to identify in clinical research. Likewise, the characterization of aging in 23 these animals, involving structural network reorganization and its effects on cognition, opens a window to 24 evaluate new treatments for the disease. 25 1 AUTHOR SUMMARYWe have applied magnetic resonance image based connectomics to characterize TgF344-AD rats, a 26 transgenic model of Alzheimer's disease (AD). This represents a highly translational approach, what is 27 essential to investigate potential treatments. TgF344-AD animals were evaluated from early to advanced 28 ages to describe alterations in brain connectivity and how brain networks are affected by age. Results 29showed that aging had a bigger impact in the structural connectivity of the TgF344-AD than in control 30 animals, and that changes in the structural network, already observed at early ages, significantly 31 influenced cognitive outcome of transgenic animals. Alterations in connectivity were similar to the 32 described in AD human studies, and complement them providing insights into earlier stages and a plot of 33

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Effects of APOE‐ε4 allele load on brain morphology in a cohort of middle‐aged healthy individuals with enriched genetic risk for Alzheimer's disease

Cited by 105 publications

References 55 publications

White matter hyperintensities mediate gray matter volume and processing speed relationship in cognitively unimpaired participants

White matter hyperintensities mediate gray matter volume and processing speed relationship in cognitively unimpaired participants

Association between insomnia and cognitive performance, gray matter volume, and white matter microstructure in cognitively unimpaired adults

Brain connectivity during Alzheimer’s disease progression and its cognitive impact in a transgenic rat model

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