Peter R. Schofield

Background: Older adults facing social or structural marginalization for reasons such as lower literacy, digital exclusion, financial constraints, restricted living environments, or complex health histories, face persistent barriers to much-needed health screening. Digital health tools, particularly those using audio computer-assisted self-interview (ACASI) technology, offer potential to overcome these barriers (audio-delivered and self-administrable), but their application to marginalized populations remains underexplored. Moreover, guidance is limited for developing such tools which require collaboration within cross-disciplinary teams. This paper presents development insights and user testing findings from the ASCAPE (Audio App-Delivered Screening for Cognition and Age-Related Health in Prisoners) project, which aimed to develop equitable digital frailty and cognition screening for older people in Australian prisons. Objective: This study aims to describe the collaborative development of the “ASCAPE-HS” prototype, a tablet-based ACASI-delivered Frailty Index and aging screener, and to synthesize key lessons from the project that can inform equitable digital health tool development in hard-to-reach older adults. Also, to present findings on the usability and acceptability of ASCAPE-HS in a diverse community sample. Methods: The ASCAPE-HS prototype was developed through an iterative process involving researchers, clinicians, software developers, and end users under a digital health equity framework. The prototype included a self-administered, audio-delivered Frailty Index, alongside other items relevant to aging. The design process prioritized accessibility, sociocultural relevance, and technical feasibility, with regular multidisciplinary consultation and iterative refinement. Exploratory user testing with 20 older adults (aged 47‐93 years, including n=5 who had not finished secondary schooling, n=3 people with previous imprisonment history, and n=9 with mild or moderate cognitive impairment) provided feedback on usability and acceptability. Results: A 50-item Frailty Index was developed, alongside an additional selection of holistic questions that could meaningfully capture age-related health, and transferred to an iOS app (Apple, Inc), with ACASI features. Key elements included lay wording, consistent interface, simple “tapping” response options with repeatable audio feedback, a tutorial, and artificial intelligence–generated audio guidance. Key development considerations were synthesized into a checklist for teams undertaking similar projects. Successful strategies for the collaborative design process included diverse teams abreast of emerging literature and policy with varying expectations for engagement during development, and dedicating time to flexible, iterative development processes. Acceptability (median scores ≥4 out of 5 across 6 constructs) and usability (mean System Usability Scale score 79.0, SD 8.8) were high. Conclusions: A collaborative approach can produce ACASI-based health screening tools that are well-received by older adults. We highlight the feasibility of integrating frailty and aging assessment into a usable and acceptable digital tool, and offer actionable principles for collaborative, evidence-based development of equitable health screening tools in diverse, hard-to-reach populations.

Cognitive reserve has been shown to modulate the onset and progression of Alzheimer disease (AD) symptoms. Although its role in sporadic AD is well-studied, how cognitive reserve influences the timing and progression of symptoms in dominantly inherited AD (DIAD) remains unclear. This study aimed to quantify cognitive reserve in DIAD carriers and test whether higher cognitive reserve is associated with later symptom onset and slower functional decline. We analyzed data from the Dominantly Inherited Alzheimer's Network study. Cognitive reserve was modeled using a residual-based latent variable approach, decomposing cognitive performance into demographic (CogD), biomarker (CogB), and reserve or residual (CogR) components. Primary outcomes were age at clinical symptom onset (CDR >0) and longitudinal change in the Clinical Dementia Rating-Sum of Boxes (CDR-SBs). Data were analyzed using Cox proportional hazards models and linear mixed-effects models, adjusting for estimated years from onset (EYO). A total of 710 Dominantly Inherited Alzheimer Network (DIAN) participants were included in the analysis, comprising 271 non-DIAD carriers (nMC), 284 asymptomatic DIAD carriers (aMC), and 155 symptomatic DIAD carriers. In asymptomatic carriers, using a zero-inflation model adjusted for EYO showed that a 1 SD increase in the reserve component (CogR) was associated with a 4.06-fold increase in the odds of being clinically unimpaired (CDR-SB = 0; 95% CI 1.84-8.95). Similarly, a 1 SD increase in the demographic (CogD) and biomarker (CogB) components increased the odds of being CDR-SB = 0 by 2.60 (95% CI 1.10-6.16) and 5.16 (95% CI 2.00-13.33), respectively. Among symptomatic carriers, only the reserve and the biomarker components were significant. A 1 SD increase in CogR was associated with a 0.81-fold reduction in baseline CDR-SB score (95% CI 0.72-0.92), and a 1 SD increase in CogB was associated with a 0.60-fold reduction in CDR-SB (95% CI 0.50-0.71). Our findings indicate that higher cognitive reserve values are associated with delayed conversion to mild cognitive impairment and slower progression on clinical dementia rating scales. These findings suggest that cognitive reserve plays a protective role in modifying the clinical trajectory of genetically determined AD.

Alternative-splicing events (ASE) increase transcriptomic variability and play key roles in biological functions. The contribution of ASE to bipolar disorder (BD) remains largely unexplored. We performed a Transcriptome-Wide Alternative-Splicing Analysis (TWASA) to identify ASEs and genes potentially involved in BD. The study comprised 635 individuals: a discovery sample (DS) of 31 individuals from eight multiplex BD families (16 BD cases; 15 unaffected relatives), and a replication sample (RS) of 604 subjects (372 BD cases; 232 controls). Sequencing was conducted on RNA from lymphoblastoid cell lines (DS) and whole blood (RS). TWASA was performed using VAST-TOOLS (VT), rMATS (RM), and MAJIQ/MOCCASIN (MCC). Gene-set association analyses of genes containing ASEs were performed across six psychiatric disorders. Novel ASE (nASE) were investigated in the DS using FRASER. Limited gene overlap was observed across TWASA tools. MCC identified 2,031 complex ASEs involving 1,508 genes, showing the strongest genetic association with BD across psychiatric phenotypes. Prioritization of MCC-identified ASE genes yielded 441 candidates, including DOCK2 as top candidate from the DS. Replication was obtained for 98 genes, five with an identical ASE, and four ( RBM26 , QKI , ANKRD36 , and TATDN2 ) showing a concordant percentage-spliced-in direction with the DS. Finally, 578 nASE were identified in the DS, with no evidence of familial segregation or differences in ASE types. This first TWASA in BD reveals tool-specific variability, complex ASE for genes specifically associated with BD, and novel candidate genes for BD. Alternative transcript isoform abundance may represent a mechanism contributing to BD pathophysiology.

Psychiatric conditions share common genes, but mechanisms that differentiate diagnoses remain unclear. We present a multidimensional framework for functional analysis of rare copy number variants (CNVs) across 6 diagnostic categories, including schizophrenia (SCZ), autism (ASD), bipolar disorder (BD), depression (MDD), PTSD, and ADHD (N = 574,965). Using gene-set burden analysis (GSBA), we tested duplication (DUP) and deletion (DEL) burden across 2,645 functional gene sets defined by the intersections of pathways, cell types, and cortical regions. While diagnoses converge on shared pathways, mixed-effects modeling revealed divergence of pathway effects by cell type, brain region, and gene dosage. Factor analysis identified latent dimensions aligned with clinical axes. A primary factor (F1) captured reciprocal dose-dependent effects of DUP and DEL in SCZ reflecting positive and negative effects in excitatory versus inhibitory neurons and association versus sensory cortex. SCZ and ASD were both strongly aligned with F1 but with opposing directionalities. Orthogonal factors highlighted neuronal versus non-neuronal effects in mood disorders (F2) and differential spatial distributions of DEL effects in ADHD and MDD (F3). High-impact CNVs at 16p11.2 and 22q11.2 were enriched for combinations of cell-type-specific genes involved in pathways consistent with our broader findings. These results reveal molecular and cellular mechanisms that are broadly shared across psychiatric traits but differ between diagnostic categories in context and directionality.

Bipolar disorder is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 bipolar disorder risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci and prioritized 17 likely causal SNPs for bipolar disorder. We mapped these SNPs to genes and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci and results from rare variant exome sequencing in bipolar disorder. Convergent lines of evidence supported the roles of genes involved in neurotransmission and neurodevelopment, including SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, FKBP2, RASGRP1, FURIN, FES, MED24 and THRA among others in bipolar disorder. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance of bipolar disorder polygenic risk scores across diverse populations and present a high-throughput fine-mapping pipeline.

Background: Game-based cognitive assessments (GBCAs) have the potential to transform the field of cognitive testing by enabling more effective screening of age-related cognitive decline. However, we lack a strong understanding of the usability and overall user experience of these games. This is a risk because the primary target users for GBCAs, older people, are seldom involved in game design research and development. Objective: This study aims to address this gap by investigating the usability, acceptability, and enjoyability of GBCAs for older people. Methods: This study followed established practices for undertaking evidence-based systematic reviews. Results: The initial database search returned 15,232 records. After a thorough screening process, 8 studies remained for extraction and analysis. A synthesis of the included papers identified 2 overlapping yet distinct areas of focus: system usability and subjective user experience. Usability scores were mostly positive across the studies included. However, in several of the game studies, older adults and those with cognitive impairment tended to find GBCAs less usable. This trend was observed even when the games were explicitly designed for these populations, and the tasks were simplistic and representative of basic daily activities. In our second focus area, user experience, we identified the importance of perceived challenge in mediating gameplay experience across groups. That is, generating the appropriate level of difficulty for each user is important for positive user experiences, specifically enjoyment. Conclusions: On the basis of these findings, we identified key learnings for researchers interested in designing and developing GBCAs. These include (1) recognizing that validity is essential but not sufficient on its own; (2) clearly defining the intended user; (3) designing games that align with the unique preferences and needs of older people; and (4), whenever possible, providing each user with their optimal level of challenge. Trial Registration: PROSPERO CRD42023433298; https://www.crd.york.ac.uk/PROSPERO/view/CRD42023433298