Promising Genetic Biomarkers of Preclinical Alzheimer's Disease: The Influence of APOE and TOMM40 on Brain Integrity

Finding biomarkers constitutes a crucial step for early detection of Alzheimer's disease (AD). Brain imaging techniques have revealed structural alterations in the brain that may be phenotypic in preclinical AD. The most prominent polymorphism that has been associated with AD and related neural changes is the Apolipoprotein E (APOE) ε4. The translocase of outer mitochondrial membrane 40 (TOMM40), which is in linkage disequilibrium with APOE, has received increasing attention as a promising gene in AD. TOMM40 also impacts brain areas vulnerable in AD, by downstream apoptotic processes that forego extracellular amyloid beta aggregation. The present paper aims to extend on the mitochondrial influence in AD pathogenesis and we propose a TOMM40-induced disconnection of the medial temporal lobe. Finally, we discuss the possibility of mitochondrial dysfunction being the earliest pathophysiological event in AD, which indeed is supported by recent findings

Social health and cognitive change in old age: the role of brain reserve

OBJECTIVE: Individual aspects of social health (SH; e.g. network, engagement, support) have been linked to cognitive health. However, their combined effect, and the role of the structural properties of the brain (brain reserve, BR) remain unclear. We investigated the interplay of SH and BR on cognitive change in older adults. METHODS: Within the Swedish National study on Aging and Care-Kungsholmen, 368 dementia-free adults aged ≥60 years with baseline brain magnetic resonance imaging were followed over 12 years to assess cognitive change. A measure of global cognition was computed at each of the five waves of assessment by averaging domain-specific Z-scores for episodic memory, perceptual speed, semantic memory, letter and category fluency. An SH composite score was computed at baseline by combining leisure activities and social network. BR was proxied by total brain tissue volume (TBTV). Linear mixed models (adjusted for sociodemographic, vascular, and genetic factors) were used to estimate cognitive trajectories in relation to SH, TBTV. Interaction analysis and stratification were used to examine the interplay between SH and TBTV. RESULTS: Moderate-good SH (n=245; vs. poor; β-slope=0.01 [95% CI 0.002, 0.02]; p=0.018) and moderate-to-large TBTV (n=245; vs. small; β-slope=0.03 [95% CI 0.02, 0.04]; p<0.001) were separately associated with slower cognitive decline. In stratified analysis, moderate-good SH was associated with higher cognitive levels (but not change) only in participants with moderate-to-large TBTV (β-intercept=0.21 [95%CI 0.06; 0.37], p<0.01; interaction SH*TBTV p<0.05). INTERPRETATION: Our findings highlight the interplay between social health and brain reserve that likely unfolds throughout the entire life course to shape old-age cognitive outcomes. This article is protected by copyright. All rights reserved

Modifications de la mémoire épisodique au cours du vieillissement normal (étude cognitive et par imagerie cérébrale structurale et fonctionnelle)

CAEN-BU Droit Lettres (141182101) / SudocSudocFranceF

Study design.

<p>Study design.</p

Brain activity differences when encoding future intentions.

<p>P<0.001 uncorrected, k≥10 voxels, and adjusted for sex.</p><p>Abbreviations: BA = Brodmann Area; L = left; MNI = Montreal Neurological Institute; R = right.</p

Individual encoding-related brain activity within the low vs. high memory self-efficacy comparison.

<p>These graphs show the detail of the group effects in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0073850#pone-0073850-g003" target="_blank">Figure 3</a> at the individual level.</p

Behavioral data and comparisons between the low and high memory self-efficacy believers.

<p>Mean (Standard Deviation).</p>*<p>Analyses of covariance, controlling for sex. Performance in inhibition and attention is expressed in ms (Inhibition = incongruent trials – congruent trials; Attention = invalid trials – valid trials).</p><p>Abbreviations: F = female; M = male; PRMQ = Prospective and Retrospective Memory Questionnaire; VS = visuospatial; WM = working memory.</p

Differences in brain activity during encoding between the low and high memory self-efficacy believers.

<p>Group differences in brain activity is overlaid on a standard MNI brain: Red clusters represent regions where more activity was found in the low-memory beliefs group in comparison with the high-memory beliefs group; the yellow cluster denotes the region more activated by the high-memory beliefs group in comparison with the other group. For the sake of comparison with the most engaged regions during encoding in the whole group, the same sagittal and coronal slices are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0073850#pone-0073850-g002" target="_blank">Figure 2</a>. The graphs display the mean difference in activity between the encoding and control conditions in each group (red: low-memory believers; yellow: high-memory believers) for the highlighted regions. Values on y-axes represent beta values from the comparison analyses. Dorsal ant cingulate = dorsal part of the anterior cingulate gyrus; HC = hippocampus; L = left; ParaHC = parahippocampal cortex; R = right; Temporal inf = inferior temporal cortex.</p

Influence of the DRD2/ANKK1 Taq1A polymorphism on caudate volume in older adults without dementia

Dopaminergic neuromodulation is critically important for brain and cognitive integrity. The DRD2/ANKK1 Taq1A polymorphism is associated with striatal dopamine (DA) D2 receptor availability. Some previous studies have found that the A allele of the Taq1A polymorphism influences brain structure, but the results are inconsistent, likely due to population heterogeneity and small sample sizes. We investigated the genetic effect on caudate volume in a large sample of older adults without dementia. Results show that A-allele carriers have smaller caudate volume compared to non-carriers in relatively older adults (n = 167; Mage = 77.8 years), whereas the genotype did not influence caudate volume in a younger age group (n = 220; Mage = 62.8 years). Cognitive performance was not significantly affected by the DRD2 gene. Our findings extend previous observations by showing magnified genetic effects on brain volume in old age, and provide evidence for a link between a DA-related genetic polymorphism and grey matter volume in a brain region within the nigrostriatal dopaminergic pathway.Funding Agencies:Ministry of Health and Social Affairs, SwedenAlexander von Humboldt Foundation</p

Neurocognitive systems related to real-world prospective memory

Taken together, these findings show how brain systems complementary interact during real-world PM, and support a more complete model of PM that can be applied to naturalistic PM tasks and that we named PROspective MEmory DYnamic (PROMEDY) model because of its dynamics on both multi-phase iteration and the interactions of distinct neurocognitive networks