Dementia Risk Factors Modify Hubs but Leave Other Connectivity Measures Unchanged in Asymptomatic Individuals: A Graph Theoretical Analysis

Clarke, Hannah Jayne; Messaritaki, E.; Dimitriadis, Stavros I.; Metzler‐Baddeley, Claudia

doi:10.1089/brain.2020.0935

Cited by 10 publications

(7 citation statements)

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“…Our study is the first to examine changes in rT1w/T2w ratio maps associated with a parental history of AD. Similarly to the group showing the co-occurrence of APOE4 and FH, the FH group exhibited higher rT1w/T2w ratio levels in fronto-temporal regions and lower rT1w/T2w ratios in the right paracentral lobule, a cortical hub able to distinguish between individuals at low and high risk of developing AD [ 45 ]. Multiple lines of evidence have shown that early Aβ pathology could manifest either as focal myelin loss in AD patients and transgenic mouse models of AD [ 46 , 47 ] or as an increase in oligodendrogenesis paralleled by thicker myelin sheaths in hippocampal axons of transgenic mouse models of AD [ 48 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

“…Our findings suggest that co-occurrence of APOE4 and FH of AD has synergistic effects on tissue integrity in normal-appearing cortical GM, which further lead to aberrant patterns of rs-FC. The precentral gyrus showed abnormal FC with the precuneus and paracentral gyrus of the right hemisphere, which are early myelinating regions involved in AD [ 53 ] and affected by non-modifiable AD risk factors [ 45 ]. In addition, the precentral gyrus, one of the cortical areas containing the highest density of myelinated axons in the human neocortex [ 17 ], exhibited lower relative T1w/T2w ratios bilaterally in individuals with APOE4+FH.…”

Section: Discussionmentioning

confidence: 99%

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Effects of non-modifiable risk factors of Alzheimer’s disease on intracortical myelin content

2022

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Background Non-modifiable risk factors of Alzheimer’s disease (AD) have lifelong effects on cortical integrity that could be mitigated if identified at early stages. However, it remains unknown whether cortical microstructure is affected in older individuals with non-modifiable AD risk factors and whether altered cortical tissue integrity produces abnormalities in brain functional networks in this AD-risk population. Methods Using relative T1w/T2w (rT1w/T2w) ratio maps, we have compared tissue integrity of normal-appearing cortical GM between controls and cognitively normal older adults with either APOE4 (N = 50), with a first-degree family history (FH) of AD (N = 52), or with the co-occurrence of both AD risk factors (APOE4+FH) (N = 35). Additionally, individuals with only one risk factor (APOE4 or FH) were combined into one group (N = 102) and compared with controls. The same number of controls matched in age, sex, and years of education was employed for each of these comparisons. Group differences in resting state functional connectivity (rs-FC) patterns were also investigated, using as FC seeds those cortical regions showing significant changes in rT1w/T2w ratios. Results Overall, individuals with non-modifiable AD risk factors exhibited significant variations in rT1w/T2w ratios compared to controls, being APOE4 and APOE4+FH at opposite ends of a continuum. The co-occurrence of APOE4 and FH was further accompanied by altered patterns of rs-FC. Conclusions These findings may have practical implications for early detection of cortical abnormalities in older populations with APOE4 and/or FH of AD and open new avenues to monitor changes in cortical tissue integrity associated with non-modifiable AD risk factors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of non-modifiable risk factors of Alzheimer’s disease on intracortical myelin content

2022

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“…Besides regions involved in executive function and memory, the APOE3 versus APOE4 comparison emphasized the role of sensory and motor areas including vision (V1), taste, and pain (insula, periaqueductal gray). Sensory and motor associated regions have also been found to differ in asymptomatic APOE4 carriers relative to APOE3 carriers (Clarke, Messaritaki et al 2022). We noted connectivity differences for the cerebellum, which has a well-known role in movement control but also in language processing, learning and memory (Koziol, Budding et al 2014).…”

Section: Discussionmentioning

confidence: 99%

APOE, Immune Factors, Sex, and Diet Interact to Shape Brain Networks in Mouse Models of Aging

Winter,

Mahzarnia,

Anderson

et al. 2023

Preprint

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The exact mechanisms through which the APOE gene influences Alzheimers disease risk (AD) are under intense investigation. Yet, much remains unknown about how APOE alleles interact with age, sex, and diet to confer vulnerability to select brain networks. To address this question, we used mouse models that carry the three major human APOE alleles, and have a mouse like, or humanized innate immune system. This was realized through the replacement of the mouse with the human inducible nitric oxide synthase (iNOS) gene, leading to a lower immune response. Our study combines advanced, accelerated diffusion imaging methods with novel statistical analyses to reveal global and local brain graph differences, associated with each of the following risk factors for abnormal aging and AD: age, APOE genotype, sex, diet, innate immune response. We used a sparse logistic regression model (GraphClass) with complimentary pairs stability selection to identify small and robust subnetworks predictive of individual risk factors. The comparison of APOE3 versus APOE4 carriage identified 773 edges, with no more than 40 false selections; age resulted in 300 high selection probability edges with <5 false selections, sex resulted in 540 high selection probability edges with <7 false selections; diet in 1626 high selection probability edges with <31 false selections; and humanizing NOS in 411 edges with <9 false selections. Our results revealed widespread network differences due to age and diet, including the temporal association cortex, and also regions involved in response to threatening stimuli, such as the amygdala and periaqueductal gray. Sex associated differences affected regions such as the thalamus, insula and hypothalamus, but also fimbria and septum, involved in memory processes. APOE genotype was associated with differences in the connectivity of memory related areas, and also in sensory and motor areas; while diet and innate immunity (HN) were associated with differences in insula and hypothalamus connectivity. We pooled these models to identify common networks across multiple traits, giving insight into shared vulnerability amongst the risk factors. We identified 63 edges out of the total 54,946 edges (0.11% of the connectome) as common to all risk factors tested. Our results revealed common subnetworks vulnerable to several risk factors for AD, in an approach that can provide new biomarkers, and targets for therapies.

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“…Specifically, Ma et al (2017) observed that the values for the APOE4 carriers were higher than those of the non-carriers in a normal-cognition group, while the opposite pattern was observed in a group of participants suffering from Mild Cognitive Impairment (MCI). Middle-aged adults with genetic, family and lifestyle risks of developing AD have a hub in their structural connectome that is not present in the structural connectome of people with no such risks of developing AD ( Clarke et al, 2020 ). Significant functional connectivity differences in the brain networks implicated in cognition were seen in middle-aged individuals with a genetic risk for AD ( Goveas et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

The impact of genetic risk for Alzheimer’s disease on the structural brain networks of young adults

et al. 2022

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IntroductionWe investigated the structural brain networks of 562 young adults in relation to polygenic risk for Alzheimer’s disease, using magnetic resonance imaging (MRI) and genotype data from the Avon Longitudinal Study of Parents and Children.MethodsDiffusion MRI data were used to perform whole-brain tractography and generate structural brain networks for the whole-brain connectome, and for the default mode, limbic and visual subnetworks. The mean clustering coefficient, mean betweenness centrality, characteristic path length, global efficiency and mean nodal strength were calculated for these networks, for each participant. The connectivity of the rich-club, feeder and local connections was also calculated. Polygenic risk scores (PRS), estimating each participant’s genetic risk, were calculated at genome-wide level and for nine specific disease pathways. Correlations were calculated between the PRS and (a) the graph theoretical metrics of the structural networks and (b) the rich-club, feeder and local connectivity of the whole-brain networks.ResultsIn the visual subnetwork, the mean nodal strength was negatively correlated with the genome-wide PRS (r = –0.19, p = 1.4 × 10–3), the mean betweenness centrality was positively correlated with the plasma lipoprotein particle assembly PRS (r = 0.16, p = 5.5 × 10–3), and the mean clustering coefficient was negatively correlated with the tau-protein binding PRS (r = –0.16, p = 0.016). In the default mode network, the mean nodal strength was negatively correlated with the genome-wide PRS (r = –0.14, p = 0.044). The rich-club and feeder connectivities were negatively correlated with the genome-wide PRS (r = –0.16, p = 0.035; r = –0.15, p = 0.036).DiscussionWe identified small reductions in brain connectivity in young adults at risk of developing Alzheimer’s disease in later life.

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Dementia Risk Factors Modify Hubs but Leave Other Connectivity Measures Unchanged in Asymptomatic Individuals: A Graph Theoretical Analysis

Abstract: Dementia risk factors modify hubs but leave other connectivity measures unchanged in asymptomatic individuals: a graph theoretical analysis.

Cited by 10 publications

References 55 publications

Effects of non-modifiable risk factors of Alzheimer’s disease on intracortical myelin content

Effects of non-modifiable risk factors of Alzheimer’s disease on intracortical myelin content

APOE, Immune Factors, Sex, and Diet Interact to Shape Brain Networks in Mouse Models of Aging

The impact of genetic risk for Alzheimer’s disease on the structural brain networks of young adults

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