Abstract INTRODUCTION Magnetic resonance imaging (MRI) is crucial for dementia diagnosis and a pre‐requisite for amyloid‐lowering therapies in Alzheimer's disease. Despite guidelines, many patients never undergo MRI due to limited scanner availability. Shorter scan times would reduce costs and patient burden. We developed and tested a fast MRI protocol incorporating highly accelerated sequences. METHODS We compared blinded neuroradiologist assessments of a fast protocol with the standard‐of‐care protocol in a prospective real‐world study. We estimated agreement coefficients to evaluate reliability. RESULTS The fast protocol cut scan times by 63% and showed non‐inferior reliability measures for diagnosis, visual scale ratings, and disease‐modifying therapy eligibility assessment. Between scan‐type, intra‐rater reliability for diagnosis was greater than inter‐rater reliability on the standard‐of‐care protocol (ratio of 1.37, 95% confidence interval: 1.21–1.58). DISCUSSION This study proposed and applied a way of showing non‐inferiority of a highly accelerated dementia protocol. Ultra‐fast protocols could improve MRI access and patient equity and support the implementation of disease‐modifying therapies. Highlights The fast dementia protocol with four core sequences reduced acquisition time by 63%. The fast scan showed non‐inferior reliability for diagnosis and visual ratings. Assessment for disease‐modifying therapy eligibility was similar between scan types. Fast protocols may improve access to magnetic resonance imaging and diagnosis in dementia.
Abstract INTRODUCTION Identifying individuals with dementia in long‐term care facilities (LTCFs) at risk for delirium or dementia‐related hospitalizations can support individualized risk mitigation. METHODS Using the Registry of Senior Australians (ROSA) Historical National Cohort ( N = 207343 individuals with dementia in 2655 LTCFs), we identified predictors of delirium or dementia‐related hospitalization within 365 days of LTCF entry and developed a risk prediction model using elastic net penalized regression and Fine‐Gray model. Model discrimination using area under the receiver operating characteristics curve (AUC), calibration and clinical utility were assessed. RESULTS Within 365 days, 5.2% ( N = 10709) of individuals had a delirium or dementia‐related hospitalization. Forty predictors were identified, strongest included history of frequent emergency department presentations, physical violence history, being male, and prior delirium. Model AUC was 0.664 (95% confidence interval: 0.650–0.676) with reasonable calibration. DISCUSSION Our risk prediction model for delirium or dementia‐related hospitalizations had moderate discrimination with reasonable calibration and clinical utility. Routinely collected data can inform risk profiling in LTCFs. Highlights Using a large population‐based cohort of people living with dementia, we developed a risk prediction model for delirium or dementia‐related hospitalization within 365 days of long‐term care facility (LTCF) entry. Within 365 days after entry into LTCF, 5.2% of individuals living with dementia had a delirium or dementia‐related hospitalization. The model demonstrated moderate discriminatory performance (area under the curve [AUC] = 0.664, 95% confidence interval [CI]: 0.650–0.676) and reasonable calibration in predicting delirium or dementia‐related hospitalization risk. Our model showed net benefits within 2%–22% risk threshold ranges assessed via decision curve analysis . Risk stratification at LTCF entry may support clinicians and aged care providers in identifying high risk individuals and implementing targeted interventions to reduce delirium or dementia‐related hospitalizations .
Abstract BACKGROUND Tau‐derived cerebrospinal fluid (CSF) biomarkers correlate with amyloid‐beta (Aβ) plaques or tau tangles in Alzheimer's disease (AD). This study assessed the effects of long‐term anti‐Aβ antibodies on amyloid plaques, tau tangles, and CSF tau species to determine the relationships between them. METHODS A post‐hoc analysis of the DIAN‐TU‐001 trial (NCT01760005) examined 142 participants at risk for dominantly inherited AD randomized to solanezumab ( n = 50), gantenerumab ( n = 52), or placebo ( n = 40). High‐resolution mass spectrometry quantified CSF tau species over four years. RESULTS Phosphorylated tau (p‐tau) species (153, 181, 217, 231) increased early in preclinical AD but were reduced with gantenerumab‐mediated Aβ plaque reduction. Nearly a decade later, MTBR‐tau243 and p‐tau205 increased, showing no association with Aβ reduction, aligning with tau tangle pathology progression. DISCUSSION Initially changing soluble p‐tau species track Aβ plaque reduction, while ptau205 and MTBR‐243 reflect tau tangle pathology, informing different pathways of therapeutic strategies. Highlights p‐tau217 and p‐tau231 correlate with Aβ‐PET and respond to Aβ‐plaque lowering therapies. Aβ immunotherapy trials support a direct link between p‐tau changes and Aβ plaques Gantenerumab reduces Aβ plaques but does not affect tau NFT‐related biomarkers. Blood‐based p‐tau217 assays may provide a non‐invasive tool to monitor Aβ therapies. MTBR‐tau243 strongly correlates with tau PET and tracks NFT pathology progression. Further studies are needed to validate tau biomarkers for tracking NFT‐targeting therapies.
Abstract INTRODUCTION Developing effective therapeutics for Alzheimer's disease (AD) requires a better understanding of the molecular drivers of the disease. Our previous work nominated DLGAP2 as a modifier of age‐related cognitive decline and risk for AD. We tested the hypothesis that overexpression of DLGAP2 in the hippocampus would protect against cognitive and synaptic deficits in a susceptible F1 5XFAD model. METHODS DLGAP2 was overexpressed in the hippocampus of F1 hybrid 5XFAD and non‐transgenic littermates using a viral approach. Cognitive function, electrophysiological properties, and dendritic spine morphology were assessed at 6 and 14 months of age. RESULTS DLGAP2 overexpression impaired synaptic plasticity and exacerbated AD‐related memory deficits but had minimal effect on spine structure or intrinsic neuronal properties. DISCUSSION We highlight the complex role of DLGAP2 in AD pathology. Targeted interventions involving postsynaptic proteins must consider potential adverse effects on synaptic integrity and cognitive performance, particularly in the context of AD. HighlightsDLGAP2 overexpression accelerates AD‐related impairment of contextual fear acquisition and memory. DLGAP2 overexpression impairs synaptic plasticity prior to AD‐related memory impairment, but not intrinsic excitability. Effect of DLGAP2 overexpression on thin spine density was blunted in AD mice from in vivo dendritic spine results that were replicated in cultured rodent neurons.
Abstract Dementia rates are rising globally, with the burden increasing most rapidly in low‐ to middle‐income countries. Despite this, research into Alzheimer's disease and related dementias (ADRD) among African populations remains limited, with existing models based on Western cohorts that overlook sex‐, gender‐, and ancestry‐specific factors. The Female Brain Health and Endocrine Research in Africa (FemBER‐Africa) project, hosted at the Brain and Mind Institute, Aga Khan University, Kenya, will establish a deeply phenotyped cohort of 250 African individuals across the ADRD spectrum. It will assess sex‐specific risk factors linked to ethnicity, lifestyle, and endocrinological variables using fluid‐based biomarkers (blood and saliva), neuroimaging (magnetic resonance imaging and positron emission tomography), and culturally adapted cognitive tests. By comparing data with Western and diasporic cohorts, the study aims to identify ancestry‐specific and shared mechanisms driving ADRD risk and progression. The findings will support targeted, culturally relevant prevention and intervention strategies, addressing the underrepresentation of African populations in global dementia research. Highlights By 2030, > 78 million individuals are expected to have dementia, with the highest burden among women in low‐ to middle‐income countries. Despite this, African populations remain underrepresented in Alzheimer's disease and related dementias (ADRD) research. Existing ADRD risk models fail to account for the unique influence of sex, gender, and ancestry on dementia risk. Female‐specific reproductive and hormonal factors, including menopause transition and hormone therapy use, are poorly integrated into current models. The Female Brain Health and Endocrine Research in Africa (FemBER‐Africa) project is the first large‐scale study to examine sex‐ or gender‐specific and endocrine contributors to ADRD in an African population, using advanced diagnostic, biomarker, and culturally adapted cognitive assessments. The study will assess how biological (hormonal, metabolic), lifestyle (physical activity, diet), and socio‐cultural (education, health‐care access) factors interact to influence ADRD risk in African women. Insights from FemBER‐Africa will inform the development of sex‐ and gender‐specific, culturally adapted ADRD prevention strategies, enhancing the precision and equity of dementia mitigation efforts globally.
Abstract INTRODUCTION This study aimed to identify distinct dementia risk profiles in middle‐aged adults with two or more potential dementia risk factors, to inform targeted prevention strategies. METHODS Cross‐sectional analysis of baseline sociodemographic, clinical, and dementia‐risk data from the HAPPI MIND trial. Dementia risk was assessed using the Australian National University Alzheimer's Disease Risk Index. Risk profiles were identified using latent class analysis (LCA). RESULTS Among 403 participants (mean age 56.4 ± 5.7 years, 62.5% female), the median number of dementia risk factors was 5.0; hyperlipidaemia (92.5%), low cognitive activity (72.5%), obesity (57.6%), and hypertension (52.7%) were the most prevalent. Several risk factors showed significant positive correlations. LCA identified three distinct classes: 1−High Cardiometabolic Burden; 2−High Behavioural and Psychosocial Risk ; and 3−Low Risk with Healthy Behaviours . DISCUSSION The identified latent classes highlight heterogeneity of dementia risk profile in midlife. Tailored, multidomain interventions addressing each group's specific needs may improve dementia risk profiles and support broader health outcomes. Highlights Middle‐aged Australians who participated in the HAPPI MIND dementia risk reduction trial had a median of five modifiable risk factors. Significant positive correlations were observed between behavioral and clinical risk factors, such as depression, along with poor diet, social isolation, and smoking. Latent class analysis revealed three distinct profiles: High Cardiometabolic Burden; High Behavioral and Psychosocial Risk; and Low Risk with Healthy Behaviors . The findings suggest there is a need for personalized, multidomain prevention strategies tailored to individual risk profiles in primary care.
Abstract INTRODUCTION Sleep disturbances are common in older people with cognitive impairment, potentially contributing to negative outcomes. A core outcome set (COS) is required to reduce heterogeneity in clinical trials and promote the development of high‐quality evidence to support clinical management. METHODS A multi‐stage mixed methods study was conducted in accordance with The Core Outcome Set Standards for Development. RESULTS A systematic review identified 287 sleep outcomes from previous clinical trials. Qualitative interviews ensured the COS was informed by what matters most to people with cognitive impairment and their caregivers. A modified Delphi process identified nine outcomes for the COS: total sleep time, sleep onset latency, wakefulness after sleep onset, number of night‐time awakenings, sleep efficiency, and measures of sleep quality, daytime sleepiness, cognition, and mood. DISCUSSION This COS will support researchers to produce more reliable and coherent trial data to guide the management of sleep disturbances in people with neurodegenerative cognitive impairment. Highlights Evidence is lacking regarding the treatment of sleep disturbances in people with cognitive impairment. Heterogeneity of reported outcomes in clinical trials limits data synthesis. A qualitative analysis established what matters most to people with cognitive impairment and their caregivers when determining treatment effectiveness. A Delphi panel of experts agreed upon a core outcome set. This core outcome set will improve the reliability and comparability of data from future trials.
Abstract INTRODUCTION Our previous work established the AD‐BXD mouse panel as an innovative model for studying the genetic complexity and heterogeneity underlying Alzheimer's disease (AD). In this study, we leveraged this model and proteomics approach to identify protein signatures linked to cognitive resilience in AD. METHODS We assessed cognitive performance in 6‐month‐old AD‐BXD mice using contextual fear conditioning and calculated a quantitative resilience score. Frontal cortex proteomes were analyzed using data‐independent acquisition mass spectrometry. Protein quantitative trait loci (pQTL) mapping and transcription factor motif analysis were performed. RESULTS Cognitive resilience was highly heritable. Of nine pQTL proteins associated with resilience, eight mapped to a shared locus on chromosome 1, forming a genetically regulated module. This module mediates the link between specific SNPs and cognitive outcomes in AD. DISCUSSION These findings reveal a protein network underlying resilience to early AD pathology, with Nr1d1 emerging as a key transcriptional regulator. Highlights Quantitative proteomics analysis using the genetically diverse AD‐BXD mouse panel identified nine proteins whose abundances are under genetic control and associated with differences in cognitive response to early‐onset AD mutations. Genetic mapping revealed that the abundances of eight of these nine proteins are regulated by the same genomic region on chromosome 1, forming a module that mediates the relationship between specific SNPs and cognitive outcomes in response to AD mutations. Integrating proteomic and genomic data suggests that SNP rs46128598, located in the transcription factor binding site of nuclear receptor subfamily 1 group D member 1 (Nr1d1), is a novel effector of metabolic pathways involved in cognitive performance differences in AD mutant carriers. This study indicates that targeting the molecular drivers of genetic resilience to AD mutations, including Nr1d1‐mediated proteins (Ak1a1, Gars1, Nudt3, Ogdh, Ptpn11, Iars2, Uba1, Ppt1, and Tmem223), could lead to new therapeutic approaches to delay the onset and/or progression of AD.