Baseline Cognition Is the Best Predictor of 4-year Cognitive Change in Cognitively Intact Older Adults

Schaeverbeke, Jolien; Gabel, Silvy; Luckett, Emma S.; Meersmans, Karen; Meyer, Simon De; Adamczuk, Katarzyna; Nelissen, Natalie; Goovaerts, Valerie; Radwan, Ahmed; Sunaert, Stefan; Dupont, Patrick; Laere, Koen Van; Vandenberghe, Rik

doi:10.21203/rs.3.rs-125104/v1

Cited by 2 publications

(1 citation statement)

References 35 publications

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“…Correlation coefficient values between 0.3 and 0.7 were considered as moderate [52] and, thus relevant correlations. Variables that showed significant correlation with neuronal density in CA1 and/or layer III of the temporal cortex were further used for hierarchical regression analysis using R statistical software [59]. Repeated k-fold cross-validated models were computed using the R package caret (http://topepo.github.io/caret/index.html).…”

Section: Statistical Analysesmentioning

confidence: 99%

Pyroptosis in Alzheimer’s disease: cell type-specific activation in microglia, astrocytes and neurons

et al. 2022

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Human post-mortem brain tissue was collected in accordance with the applicable laws in Belgium (UZ Leuven) and Germany (Ulm). The recruitment protocols for the collection of human brains were approved by the ethical committees of the UZ Leuven (Belgium; S-59292, S-52791) and the University of Ulm (Germany; 54/08). This study was approved by the UZ Leuven ethical committee (Leuven, Belgium; S-64378).

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Section: Statistical Analysesmentioning

confidence: 99%

Pyroptosis in Alzheimer’s disease: cell type-specific activation in microglia, astrocytes and neurons

et al. 2022

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Longitudinal APOE4- and amyloid-dependent changes in the blood transcriptome in cognitively intact older adults

Luckett,

Zielonka,

Kordjani

et al. 2023

Alz Res Therapy

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Background Gene expression is dysregulated in Alzheimer’s disease (AD) patients, both in peripheral blood and post mortem brain. We investigated peripheral whole-blood gene (co)expression to determine molecular changes prior to symptom onset. Methods RNA was extracted and sequenced for 65 cognitively healthy F-PACK participants (65 (56–80) years, 34 APOE4 non-carriers, 31 APOE4 carriers), at baseline and follow-up (interval: 5.0 (3.4–8.6) years). Participants received amyloid PET at both time points and amyloid rate of change derived. Accumulators were defined with rate of change ≥ 2.19 Centiloids. We performed differential gene expression and weighted gene co-expression network analysis to identify differentially expressed genes and networks of co-expressed genes, respectively, with respect to traits of interest (APOE4 status, amyloid accumulation (binary/continuous)), and amyloid positivity status, followed by Gene Ontology annotation. Results There were 166 significant differentially expressed genes at follow-up compared to baseline in APOE4 carriers only, whereas 12 significant differentially expressed genes were found only in APOE4 non-carriers, over time. Among the significant genes in APOE4 carriers, several had strong evidence for a pathogenic role in AD based on direct association scores generated from the DISQOVER platform: NGRN, IGF2, GMPR, CLDN5, SMIM24. Top enrichment terms showed upregulated mitochondrial and metabolic pathways, and an exacerbated upregulation of ribosomal pathways in APOE4 carriers compared to non-carriers. Similarly, there were 33 unique significant differentially expressed genes at follow-up compared to baseline in individuals classified as amyloid negative at baseline and positive at follow-up or amyloid positive at both time points and 32 unique significant differentially expressed genes over time in individuals amyloid negative at both time points. Among the significant genes in the first group, the top five with the highest direct association scores were as follows: RPL17-C18orf32, HSP90AA1, MBP, SIRPB1, and GRINA. Top enrichment terms included upregulated metabolism and focal adhesion pathways. Baseline and follow-up gene co-expression networks were separately built. Seventeen baseline co-expression modules were derived, with one significantly negatively associated with amyloid accumulator status (r2 = − 0.25, p = 0.046). This was enriched for proteasomal protein catabolic process and myeloid cell development. Thirty-two follow-up modules were derived, with two significantly associated with APOE4 status: one downregulated (r2 = − 0.27, p = 0.035) and one upregulated (r2 = 0.26, p = 0.039) module. Top enrichment processes for the downregulated module included proteasomal protein catabolic process and myeloid cell homeostasis. Top enrichment processes for the upregulated module included cytoplasmic translation and rRNA processing. Conclusions We show that there are longitudinal gene expression changes that implicate a disrupted immune system, protein removal, and metabolism in cognitively intact individuals who carry APOE4 or who accumulate in cortical amyloid. This provides insight into the pathophysiology of AD, whilst providing novel targets for drug and therapeutic development.

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Baseline Cognition Is the Best Predictor of 4-year Cognitive Change in Cognitively Intact Older Adults

Cited by 2 publications

References 35 publications

Pyroptosis in Alzheimer’s disease: cell type-specific activation in microglia, astrocytes and neurons

Pyroptosis in Alzheimer’s disease: cell type-specific activation in microglia, astrocytes and neurons

Longitudinal APOE4- and amyloid-dependent changes in the blood transcriptome in cognitively intact older adults

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