Maitée Rosende-Roca

Introduction: Ageing is accompanied by gradual biological and cognitive changes that increase vulnerability to chronic diseases and neurodegenerative conditions. As populations age, dementia prevalence continues to rise, highlighting the need for earlier detection and personalised prevention strategies. Against this background, the COMFORTage project, funded by Horizon Europe, brings together a multidisciplinary consortium across 12 countries to advance innovative, scalable solutions for dementia care. By integrating digital platforms, biomarker research, and precision medicine, COMFORTage seeks to develop artificial intelligence (AI)-driven tools that support more precise and adaptive interventions. Central to this effort are the Virtualized AI-Based Healthcare Platform and Patient Digital Twins, which enable personalised monitoring and decision support. Within this framework, Pilot 3 at Ace Alzheimer Center Barcelona focuses on individuals with mild cognitive impairment and mild Alzheimer's disease dementia, evaluating the effects of cognitive and functional stimulation and contributing multimodal data to optimise the AI platform. Methods: Pilot 3 is a randomised, open-label study involving retrospective and prospective datasets. Participants undergo clinical, genetic, neuropsychological, cerebrospinal fluid (CSF) and plasma biomarker assessments, magnetic resonance imaging (MRI), and spontaneous speech analysis. The primary outcomes assess cognitive decline using composite scores from the Neuropsychological Battery used in Ace (NBACE), targeting attention, memory, visuospatial/perceptual functions, executive functions, and language, over a two-year follow-up. Three digital platforms provided by the consortium will be used as cognitive and functional stimulation tools for participants. The intervention's effects on cognitive decline will be evaluated through changes in NBACE composite scores. Secondary objectives include assessing impacts on physical, psychological, social, and functional well-being; examining associations between biological variables and cognitive changes; and analyzing spontaneous speech as a remote, scalable proxy for cognitive status. Discussion: Findings from Pilot 3 will contribute to COMFORTage's broader mission, offering critical insights into the scalability and real-world implementation of AI-powered dementia care solutions. This integrated approach highlights the potential of precision medicine and advanced digital tools to elevate global standards in dementia management. Clinical Trial Registration: identifier NCT07031167.

The cerebrospinal fluid (CSF) proteome offers a direct readout of central nervous system (CNS) biology but its genetic architecture remains incompletely defined. We conducted the largest single-site CSF genome-wide association study (GWAS) to date, analysing 7,092 SomaScan proteins in 1,259 individuals. Using a covariate-adjusted model including proteomic PCs and disease status, we identified 1,971 genome-wide significant pQTLs (954 cis, 971 trans), 1,409 of which replicated in an independent CSF dataset. We discovered 264 previously unreported loci, replicated 511 associations, refined 80 known loci, and 265 proxy-based associations. Using a previously published reproducibility framework, we show that robust discovery concentrates in reliable measurements, underscoring the importance of rigorous quality control. Enrichment analyses revealed immune/complement and extracellular matrix biology. Mendelian randomization prioritised causal proteins: PILRA, TREM2, IL34, CR2, SHARPIN and ERBB1 (Alzheimer's disease); BST1 and GPNMB (Parkinson's disease); STX6 (Creutzfeldt Jacobs disease); and ATXN3 and B4GALNT1 (Amyotrophic lateral sclerosis), providing a scalable framework for orthogonal target validation in neurodegeneration.

Background:The apolipoprotein E (APOE) ε4 allele remains the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), yet the marked variability in its pathogenicity suggests underlying genetic complexity. Historically, efforts to resolve the intragenic architecture of APOE have been hampered by the limitations of conventional genotyping and short-read sequencing, as well as the presence of homoplasy in common intragenic markers—misleading similarities arising from convergent variants.Objective:We leveraged Oxford Nanopore Technology (ONT) to phase intragenic APOE variants, resolve homoplasy, and examine the impact of phased haplotypes on cerebrospinal fluid (CSF) APOE protein levels and AD progression.Methods:Using long-read sequencing in a Spanish memory clinic cohort (n = 1,267), we reconstructed full-length 4 kb APOE haplotypes, identifying 59 unique configurations grouped into five major haplogroups. Common intragenic variants defined ancestral ε4 (4A, 4B) and ε3 (3A, 3B) haplogroups. These were analyzed for associations with CSF APOE levels (Olink platform) and progression from mild cognitive impairment (MCI) to dementia using adjusted Cox regression models.Results:ONT sequencing successfully resolved homoplasy between the APOE promoter region—particularly at rs405509—and the canonical protein isoforms, uncovering common but functionally distinct ε3A/B and ε4A/B intragenic sub-haplotypes with independent biological effects. Carriers of the ε4A haplotype exhibited significantly lower CSF APOE protein levels (p = 0.004), whereas the ε3B haplotype was associated with elevated CSF APOE protein levels (p = 0.025). Notably, both haplotypes were linked to a slower progression from MCI to AD, independent of APOE genotype, age, sex and core CSF biomarkers.Conclusion:This study redefines the human APOE ε3 and ε4 alleles as genetically heterogeneous entities. Using ONT long-read sequencing, we achieved high-resolution mapping of intragenic haplotypic structure and regulatory variation previously obscured by conventional approaches. This enabled the identification of ancestral haplotypes with distinct functional profiles and potential relevance to Alzheimer’s disease pathogenesis. These findings highlight the importance of incorporating haplotype-level resolution into Alzheimer’s risk assessment, therapeutic targeting, and precision medicine strategies.