PROGRAMME

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Alzheimer’s disease (AD) poses a formidable clinical management challenge owing to its complex pathophysiology, while digital health technologies (DHTs) offer unique value as scalable screening, diagnostic, and monitoring tools across the AD continuum. We explore the clinical translation of DHTs in integrated practice and research, with a focus on building a pragmatic AD care system in the Greater Bay Area (GBA). We developed a 3-tier hierarchical digital screening system linking primary, secondary, and tertiary care, enabling cost-effective mild cognitive impairment (MCI) identification and referral. Leveraging DHTs, we also constructed a digital-structural composite biomarker to stratify cognitive responses to the disease-modifying therapy lecanemab, laying a foundation for precision AD treatment. Beyond screening and diagnosis, we extended DHT-based care to home and community settings: wearable AmbuloSono music-walking systems deliver targeted physical therapy for AD-related deficits, and a Class II medical device cognitive training software provides personalized, multi-modal memory and attention training across mobile and desktop platforms. AI innovations, including Brain Health AI Robots and Digital TCM Doctors, further integrate health education, personalized care guidance, and traditional Chinese medicine constitution assessments for holistic AD management. Collectively, DHTs serve as robust end-to-end tools for AD screening, precise diagnosis, and personalized intervention. By bridging primary and hospital-based specialty care, DHTs advance early AD detection, optimize resource allocation, and facilitate sustainable, integrated dementia prevention and management strategies in the GBA.

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Brain age gap, defined as the difference between predicted brain age and chronological age, has emerged as a potential marker of brain health and accelerated ageing. This talk will present work examining the utility of brain age gap across local clinical populations, including validation within a Singaporean memory clinic cohort and its associations with cognitive and mental health outcomes.

Findings from longitudinal and cross-sectional studies suggest that brain age gap may provide clinically relevant insight into cognitive decline, neurodegenerative risk, and interactions with psychological factors. Together, these studies highlight the potential of brain age gap as a scalable biomarker for understanding variation in brain health across ageing populations.

Citation of Additional Authors: Elenor Morgenroth, Kymberly Goh Kai Xuan, Elaine Teo Yi Li, Jayne Tan Yi, Seyed Ehsan Saffari, Nicole Isabella Tan Yi Zhen, , Ng Kok Pin, Chiew Hui Jin, Ting Kang Seng Simon, Seyed Shahul Hameed Wahab, Jinesh Mukesh Shah, Adeline Ng Su Lyn

This talk will explore the role of blood brain barrier dysfunction in brain aging and cerebral small vessel disease, highlighting its importance as an early and potentially modifiable contributor to cognitive decline and dementia. Focusing particularly on Asian populations, the presentation will examine how advances in non-invasive neuroimaging are transforming our ability to detect and characterise vascular and neurodegenerative changes in vivo.

Drawing on multimodal MRI, including advanced structural imaging and novel techniques for assessing blood–brain barrier integrity, this talk will demonstrate how neuroimaging can be integrated with fluid biomarkers and cognitive profiling to provide a more comprehensive understanding of disease mechanisms. Particular attention will be given to the interplay between vascular dysfunction, cerebral amyloid angiopathy, and neurodegeneration, including the implications of these processes for emerging anti-amyloid therapies.

By bridging mechanistic insights with clinical application, this talk will highlight how innovative imaging approaches can improve disease phenotyping, inform patient stratification, and support the development of precision therapeutics in ageing and dementia.

MRI-derived brain age gap (BAG) quantifies how old a brain appears relative to chronological age and is increasingly used as a marker of brain health, with links to cognitive decline, neuropsychiatric disease, and mortality. In this lecture, I will outline how BAG can be used as a biologically meaningful phenotype and how genetic and transcriptomic data help explain individual differences in brain ageing.

Drawing on large population studies, I will describe an integrative framework that connects genetic variation to BAG through predicted gene expression and RNA splicing across brain and peripheral tissues. A central finding is that BAG-related molecular signals are highly reproducible and organised by tissue type, with splicing-based effects showing stronger consistency and causal support than conventional gene expression signals.

Rather than reflecting a diffuse polygenic process, the transcriptomic architecture of BAG is shaped by a small number of dominant regulatory hubs. Evidence from causal inference analyses supports isoform-level regulation as a key mechanism linking genetic variation to brain ageing, while additional neuronal, metabolic, immune, and vascular pathways likely reflect downstream or correlated biology. Focusing on the 17q21.31 locus, I will illustrate how a coordinated switch in RNA splicing can account for many local genetic–transcriptomic associations with BAG, providing insight into how genetic risk translates into brain-wide ageing patterns.

Citation of Additional Authors (if any): Qiaoyang Sun, Ling Ling Chan, Eng-King Tan

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NOTCH2NLC-related GGC repeat expansion disorders (NRED), including neuronal intranuclear inclusion disease, are progressive neurodegenerative conditions with no disease-modifying therapies. These disorders are caused by expanded GGC repeats in NOTCH2NLC, yet the mechanisms linking repeat expansion to neurodegeneration remain incompletely defined. Here, we establish and characterize a human disease-relevant model to investigate NRED pathogenesis and therapeutic targeting. We demonstrate that GGC repeat expansions drive the production of toxic polyglycine (polyG) proteins via repeat-associated non-AUG (RAN) translation, resulting in protein aggregation and cellular dysfunction. These findings provide mechanistic insight into how repeat expansions contribute to neuronal vulnerability.
To advance therapeutic development, we evaluated NOTCH2NLC mRNA-binding peptides in our in vitro models. Treatment reduced polyG aggregation and partially rescued disease-associated phenotypes, supporting the feasibility of targeting repeat-containing transcripts to mitigate downstream toxicity. Collectively, this work identifies NOTCH2NLC-polyG as a tractable therapeutic target and supports RNA-targeting strategies as a promising approach for NRED. These findings provide a translational framework bridging disease mechanism to therapeutic intervention, with potential relevance for a broader class of repeat expansion disorders.

A novel Tau11i isoform was previously found to be enriched in Alzheimer’s disease (AD) brains. Further characterization showed that the 19-amino acid peptide encoded by retained intron 11 facilitates the formation of high-molecular-weight heterodimers and phase-separated liquid droplets, as well as enhances heparin-induced beta-sheet aggregation and cellular seeding of Tau11i. Compared to full-length Tau441 isoform, expression of Tau11i in human neurons caused significant transcriptional changes that recapitulated single-cell molecular signatures of neurofibrillary tangle (NFT)-free excitatory AD neurons in the prefrontal cortex. These data suggest that Tau11i contribute to AD pathology by inducing pathological aggregation and transcriptional dysregulation that resembles the molecular signatures of NFT-free AD neurons. Importantly, Tau11i was detected in human plasma. Preliminary results indicate that Tau11i levels are elevated in blood plasma from AD patients as compared to healthy controls.

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic form of vascular dementia caused by mutations in NOTCH3, leading to progressive vascular dysfunction and cognitive decline. An Asian-specific NOTCH3 variant is carried by approximately 1% of the Singaporean Chinese population, yet its impact on blood–brain barrier (BBB) function remains poorly understood.

Here, we established patient-derived induced pluripotent stem cell (iPSC)–based BBB models to investigate CADASIL vascular pathogenesis. Patient peripheral blood mononuclear cells were reprogrammed into iPSCs, and the mutation was corrected using CRISPR–Cas9 to generate isogenic controls. Mutant and corrected iPSCs were differentiated into endothelial cells, pericytes, and astrocytes, followed by transcriptomic and functional analyses and integration into a 3D BBB-like microtissue model.

Mutant endothelial cells and astrocytes exhibited dysregulated extracellular matrix, angiogenic, and inflammatory pathways, with impaired angiogenesis and reduced barrier integrity. Correspondingly, 3D mutant BBB microtissues displayed disorganized vasculature, increased permeability, and a pro-inflammatory secretory profile. These findings highlight the multicellular consequences of this NOTCH3 variant and demonstrate the utility of precision BBB modeling for identifying therapeutic targets in CADASIL.

Age-related neurodegenerative diseases such as front-temporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) exist on a spectrum and remain largely untreatable due to an incomplete understanding of their underlying cellular and molecular mechanisms. Our laboratory focuses on elucidating the pathogenic processes driving neuronal degeneration in FTD/ALS using patient-derived human stem cell models. Over the past two decades, we have developed and refined methods to generate induced pluripotent stem cells from patients and differentiate them into disease-relevant neural cell types, including region-specific neurons and glia. These systems allow us to examine the sequence of molecular events that occur within specific cell populations during disease progression. In this presentation, I will highlight key contributions from our laboratory toward understanding the mechanisms underlying neuronal degeneration in FTD/ALS. Specifically, we investigate cell type-specific processes implicated in disease pathogenesis: aberrant intron retention, mislocalisation of the RNA-binding protein SFPQ, and the reactive transformation of astrocytes. By dissecting how these events arise, when they occur, and in which cell types they manifest, our work aims to define critical drivers of neurodegeneration. Together, these studies provide insight into the cellular and molecular origins of FTD/ALS and identify potential targets for therapeutic intervention, with the ultimate goal of developing effective treatments for patients with neurodegenerative disease.

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