Dataset Information

Association of cancer history with structural brain aging markers of Alzheimer's disease and related dementias risk.

ABSTRACT:

Introduction

Cancer survivors are less likely than comparably aged individuals without a cancer history to develop Alzheimer's disease and related dementias (ADRD).

Methods

In the UK Biobank, we investigated associations between cancer history and five structural magnetic resonance imaging (MRI) markers for ADRD risk, using linear mixed-effects models to assess differences in mean values and quantile regression to examine whether associations varied across the distribution of MRI markers.

Results

Cancer history was associated with smaller mean hippocampal volume (b = -19 mm³ , 95% CI = -36, -1) and lower mean cortical thickness in the Alzheimer's disease signature region (b = -0.004 mm, 95% CI = -0.007, -0.000). Quantile regressions indicated individuals most vulnerable to ADRD were more affected by cancer history.

Discussion

Some brain MRI markers associated with ADRD risk were elevated in adults with a history of cancer. The magnitude of the adverse associations varied across quantiles of neuroimaging markers, and the pattern suggests possible harmful associations for individuals already at high ADRD risk.

Highlights

We found no evidence of an inverse association between cancer history and ADRD-related neurodegeneration. Cancer history was associated with smaller mean hippocampal volume and lower mean cortical thickness in the Alzheimer's disease signature region. Quantile regressions indicated individuals most vulnerable to ADRD were more affected by cancer history.

SUBMITTER: Wang J

PROVIDER: S-EPMC10916958 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Publications

Association of cancer history with structural brain aging markers of Alzheimer's disease and related dementias risk.

Wang Jingxuan J Sims Kendra D KD Ackley Sarah F SF Chen Ruijia R Kobayashi Lindsay C LC Hayes-Larson Eleanor E Mayeda Elizabeth Rose ER Buto Peter P Zimmerman Scott C SC Graff Rebecca E RE Glymour M Maria MM

Alzheimer's & dementia : the journal of the Alzheimer's Association 20231009 2

<h4>Introduction</h4>Cancer survivors are less likely than comparably aged individuals without a cancer history to develop Alzheimer's disease and related dementias (ADRD).<h4>Methods</h4>In the UK Biobank, we investigated associations between cancer history and five structural magnetic resonance imaging (MRI) markers for ADRD risk, using linear mixed-effects models to assess differences in mean values and quantile regression to examine whether associations varied across the distribution of MRI ...[more]

PMID: 37811979

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Project description:Currently, more than 55 million people around the world suffer from dementia, and Alzheimer's disease-related dementia (ADRD) accounts for nearly 60-70% of all those cases. The spread of AD pathology and progressive neurodegeneration in the hippocampus and cerebral cortex is strongly correlated with cognitive decline in AD patients; however, the molecular underpinning of the ADRD causality is still unclear. Studies of postmortem AD brains and animal models of AD suggest that elevated endoplasmic reticulum (ER) stress may have a role in ADRD pathology through altered neurocellular homeostasis in brain regions associated with learning and memory. To study the ER stress-associated neurocellular response and its effects on neurocellular homeostasis and neurogenesis, we modeled an ER stress challenge using Thapsigargin (TG), a specific inhibitor of sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), in induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs) of two individuals from our Mexican American Family Study (MAFS). High-content screening and transcriptomic analysis of the control and ER stress-challenged NSCs showed that NSC’s ER stress response resulted in a significant decline in NSC self-renewal and an increase in apoptosis and cellular oxidative stress. A total of 2300 genes were significantly (moderated t statistics FDR corrected p-value ≤ 0.05 and Fold Change absolute ≥ 2.0) differentially expressed (DE). Pathway enrichment and gene network analysis of DE genes suggests that all three unfolded protein response (UPR) pathways (PERK, IRE1, and ATF6) were significantly activated and cooperatively regulated the NSC’s transcriptional response to ER stress. Our results show that IRE1/XBP1 mediated transcriptional regulation of E2F1 and its downstream targets have a dominant role in inducing G1/S-phase cell cycle arrest in the ER stress-challenged NSCs. The ER stress-challenged NSCs also showed activation of CHOP-mediated apoptosis and dysregulation of synaptic plasticity and neurotransmitter homeostasis-associated genes. Overall, our results suggest that ER stress-associated attenuation of NSC self-renewal, increased apoptosis, and dysregulated synaptic plasticity and neurotransmitter homeostasis plausibly play a role in the causation of ADRD.

Dataset Information

Association of cancer history with structural brain aging markers of Alzheimer's disease and related dementias risk.

Introduction

Methods

Results

Discussion

Highlights

Publications

Association of cancer history with structural brain aging markers of Alzheimer's disease and related dementias risk.

Similar Datasets

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