Dataset Information

Combining hippocampal volume metrics to better understand Alzheimer's disease progression in at-risk individuals.

ABSTRACT: To date nearly all clinical trials of Alzheimer's disease (AD) therapies have failed. These failures are, at least in part, attributable to poor endpoint choice and to inadequate recruitment criteria. Recently, focus has shifted to targeting at-risk populations in the preclinical stages of AD thus improved predictive markers for identifying individuals likely to progress to AD are crucial to help inform the sample of individuals to be recruited into clinical trials. We focus on hippocampal volume (HV) and assess the added benefit of combining HV and rate of hippocampal atrophy over time in relation to disease progression. Following the cross-validation of previously published estimates of the predictive value of HV, we consider a series of combinations of HV metrics and show that a combination of HV and rate of hippocampal atrophy characterises disease progression better than either measure individually. Furthermore, we demonstrate that the risk of disease progression associated with HV metrics does not differ significantly between clinical states. HV and rate of hippocampal atrophy should therefore be used in tandem when describing AD progression in at-risk individuals. Analyses also suggest that the effects of HV metrics are constant across the continuum of the early stages of the disease.

SUBMITTER: McRae-McKee K

PROVIDER: S-EPMC6522521 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Combining hippocampal volume metrics to better understand Alzheimer's disease progression in at-risk individuals.

McRae-McKee K K Evans S S Hadjichrysanthou C C Wong M M MM de Wolf F F Anderson R M RM

Scientific reports 20190516 1

To date nearly all clinical trials of Alzheimer's disease (AD) therapies have failed. These failures are, at least in part, attributable to poor endpoint choice and to inadequate recruitment criteria. Recently, focus has shifted to targeting at-risk populations in the preclinical stages of AD thus improved predictive markers for identifying individuals likely to progress to AD are crucial to help inform the sample of individuals to be recruited into clinical trials. We focus on hippocampal volum ...[more]

PMID: 31097733

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Project description:The aim of this study was to explore the association between genetically predicted circulating levels of immunity and inflammation, and the risk of Alzheimer's disease (AD) and hippocampal volume, by conducting a two-sample Mendelian Randomization Study. We identified 12 markers of immune cells and derived ratios (platelet count, eosinophil count, neutrophil count, basophil count, monocyte count, lymphocyte count, platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, CD4 count, CD8 count, CD4-to-CD8 ratio, and CD56) and 5 signaling molecules (IL-6, fibrinogen, CRP, and Lp-PLA2 activity and mass) as primary exposures of interest. Other genetically available immune biomarkers with a weaker a priori link to AD were considered secondary exposures. Associations with AD were evaluated in The International Genomics of Alzheimer's Project (IGAP) GWAS dataset (21,982 cases; 41,944 controls of European ancestry). For hippocampal volume, we extracted data from a GWAS meta-analysis on 33,536 participants of European ancestry. None of the primary or secondary exposures showed statistically significant associations with AD or with hippocampal volume following P-value correction for multiple comparisons using false discovery rate < 5% (Q-value < 0.05). CD4 count showed the strongest suggestive association with AD (odds ratio 1.32, P < 0.01, Q > 0.05). There was evidence for heterogeneity in the MR inverse variance-weighted meta-analyses as measured by Cochran Q, and weighted median and weighted mode for multiple exposures. Further cluster analyses did not reveal clusters of variants that could influence the risk factor in distinct ways. This study suggests that genetically predicted circulating biomarkers of immunity and inflammation are not associated with AD risk or hippocampal volume. Future studies should assess competing risk, explore in more depth the role of adaptive immunity in AD, in particular T cells and the CD4 subtype, and confirm these findings in other ethnicities.

Dataset Information

Combining hippocampal volume metrics to better understand Alzheimer's disease progression in at-risk individuals.

Publications

Combining hippocampal volume metrics to better understand Alzheimer's disease progression in at-risk individuals.

Similar Datasets

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