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Background: Alzheimer's disease (AD) has been associated with great healthcare and non-healthcare resource consumption. The aim of this study was to estimate the burden of AD in Spain according to disease severity from a societal perspective., Methods: A self-administered questionnaire was designed by the researchers and completed by the informal caregivers of patients with AD, reporting data on themselves as caregivers and on the AD patients for whom they care. The patients' sociodemographic and clinical data, their healthcare and non-healthcare resource consumption in the previous 12 months, and the impact of the disease on labor productivity were compiled. Data collected on informal caregivers included sociodemographic data and the impact of caring for a person with AD on their quality of life and labor productivity. Costs were estimated by multiplying the number of consumed resources by their unit prices. The cost of informal care was assessed using the proxy good method, and labor productivity losses were estimated using the human capital method. Costs were estimated by disease severity and are presented per patient per year in 2021 euros (€)., Results: The study sample comprised 171 patients with AD aged 79.1 ± 7.4 years; 68.8% were female, time from diagnosis was 5.8 ± 4.1 years, diagnosis delay was 1.8 ± 2.3 years, and the mean Cumulative Illness Rating Scale-Geriatric (CIRS-G) total was score 8.2 ± 6.0. According to disease severity, 14% had mild cognitive impairment or mild AD, 43.9% moderate AD, and 42.1% severe AD. The average annual cost per patient was €42,336.4 in the most conservative scenario. The greatest proportion of this cost was attributed to direct non-healthcare costs (86%, €36,364.8), followed by direct healthcare costs (8.6%, €3647.1), social care costs (4.6%, €1957.1), and labor productivity losses (less than 1%, €367.4). Informal care was the highest cost item, representing 80% of direct non-healthcare costs and 69% of the total cost. The total direct non-healthcare cost and total cost were significantly higher in moderate to severe disease severities, compared to milder disease severity., Conclusions: AD poses a substantial burden on informal caregivers, the national healthcare system, and society at large. Early diagnosis and treatment to prevent disease progression could reduce this economic impact., (© 2023. The Author(s).)

Hypoxia inducible factor (HIF) up-regulates the transcription of a few hundred genes required for the adaptation to hypoxia. This restricted set of targets is in sharp contrast with the widespread distribution of the HIF binding motif throughout the genome. Here, we investigated the transcriptional response of GYS1 and RUVBL2 genes to hypoxia to understand the mechanisms that restrict HIF activity toward specific genes. GYS1 and RUVBL2 genes are encoded by opposite DNA strands and separated by a short intergenic region (~1 kb) that contains a functional hypoxia response element equidistant to both genes. However, hypoxia induced the expression of GYS1 gene only. Analysis of the transcriptional response of chimeric constructs derived from the intergenic region revealed an inhibitory sequence whose deletion allowed RUVBL2 induction by HIF. Enhancer blocking assays, performed in cell culture and transgenic zebrafish, confirmed the existence of an insulator element within this inhibitory region that could explain the differential regulation of GYS1 and RUVBL2 by hypoxia. Hence, in this model, the selective response to HIF is achieved with the aid of insulator elements. This is the first report suggesting a role for insulators in the regulation of differential gene expression in response to environmental signals.

The transcriptional response driven by Hypoxia-inducible factor (HIF) is central to the adaptation to oxygen restriction. Despite recent characterization of genome-wide HIF DNA binding locations and hypoxia-regulated transcripts in different cell types, the molecular bases of HIF target selection remain unresolved. Herein, we combined multi-level experimental data and computational predictions to identify sequence motifs that may contribute to HIF target selectivity. We obtained a core set of bona fide HIF binding regions by integrating multiple HIF1 DNA binding and hypoxia expression profiling datasets. This core set exhibits evolutionarily conserved binding regions and is enriched in functional responses to hypoxia. Computational prediction of enriched transcription factor binding sites identified sequence motifs corresponding to several stress-responsive transcription factors, such as activator protein 1 (AP1), cAMP response element-binding (CREB), or CCAAT-enhancer binding protein (CEBP). Experimental validations on HIF-regulated promoters suggest a functional role of the identified motifs in modulating HIF-mediated transcription. Accordingly, transcriptional targets of these factors are over-represented in a sorted list of hypoxia-regulated genes. Altogether, our results implicate cooperativity among stress-responsive transcription factors in fine-tuning the HIF transcriptional response.