Yen Y. Lim

Journal of Alzheimer's disease : JAD • December 17, 2024

Yen Lim, Andrea Mills, Maya Norfolk, Emily Rosenich, Paul Maruff

Background: In older adults with preclinical Alzheimer's disease (AD), learning curves derived from validated psychological learning paradigms are reduced to an extent greater than impairment, or decline, on neuropsychological memory tests. Objective: This study aimed to examine how age, sex, education, mood, and general dementia risk, which also increases risk for preclinical AD, could influence learning curves. Methods: 1050 adults enrolled in the BetterBrains trial completed 10 blocks of ORCA-LLT learning trials over 5 days. Learning curves were derived from improvement in accuracy over trials. Participants also completed questionnaires of demography and mood, and the CAIDE risk score was computed for each participant. Results: Most participants (67%) completed ≥6 blocks of ORCA-LLT. Older age (d = 0.75), lower education (d = 0.50), and higher dementia risk (d = 0.36) were associated significantly with slower learning rates. Conclusions: In older adults, learning curves are influenced subtly by age, education, and dementia risk but not by sex or mood.

Alzheimer's & Dementia (Amsterdam, Netherlands)

Ying Xia, Pierrick Bourgeat, Vincent Doré, Jurgen Fripp, Yen Lim, Simon Laws, Christopher Fowler, Christopher Rowe, Colin Masters, Elizabeth Coulson, Paul Maruff

Background: Emergent Alzheimer's disease (AD) represents a transitional stage where cognitively unimpaired (CU) individuals exhibit subthreshold but increasing amyloid-β (Aβ) levels. The impact of Aβ accumulation on brain volume loss and cognition during this early stage remains unclear. Methods: This retrospective cohort study analyzed data from 408 CU participants who were initially Aβ- (< 15 Centiloids) and followed for up to 15 years. Changes in basal forebrain and hippocampal volume, along with domain-specific cognitive performance, were compared between those who progressed to Aβ+ (≥20 Centiloids) and those who remained Aβ-. Results: Sixty-five CU participants progressed to Aβ+, indicating emergent AD, and showed faster Aβ accumulation and subtle memory decline. However, no significant differences in rate of BF and hippocampal atrophy were observed between groups. Conclusions: The results suggest that during this emergent phase of AD, Aβ accumulation is associated with episodic memory loss, in the absence of detectable accelerated brain atrophy. Identified cognitively unimpaired individuals in the emergent stage of Alzheimer's disease (AD).Emergent AD exhibits a greater rate of amyloid-β (Aβ) accumulation.No accelerated volume loss detected in the basal forebrain or hippocampus.Emergent AD is also associated with a subtle decline in memory.Early Aβ accumulation may impair cognitive function before structural atrophy.

International Journal For Equity In Health • December 13, 2024

Hannah Gulline, Sarah Carmody, Mark Yates, Amelia Bevins, Amy Brodtmann, Samantha Loi, Yen Lim, Heather Macklin, Karen Glennen, Michael Woodward, Scott Ayton, Darshini Ayton

Background: The limited allocation of resources to rural and regional communities is a major contributor to healthcare inequities in Australia. Distribution of health service resources between metropolitan and rural communities commonly sees highly populated areas prioritised over more sparsely populated and geographically vast areas. As such, challenges impacting dementia diagnosis, management, and care in metropolitan areas are experienced more acutely in rural areas. This study aimed to examine equity of access to dementia diagnosis, management, and care services amongst people who experienced the process of dementia diagnosis as a patient or significant other (partner/spouse, adult children, siblings, and friends) throughout rural and metropolitan Australia. Methods: This exploratory qualitative study consisted of thirty-three online semi-structured interviews with thirty-seven people with experience of the dementia diagnosis process as a patient and/or significant other. Interviews explored symptoms of dementia, health professionals consulted, tests conducted, and challenges faced throughout the diagnosis and post-diagnosis process. Rurality was defined by the Australian Statistical Geography Standard Remoteness Areas (ASGS-RA) and the Modified Monash Model (MMM). Thematic analysis was conducted, with Russell's (2013) Dimensions of Access framework (geography, affordability, availability, acceptability, accommodation, awareness, and timeliness) guiding data analysis. Results: Participants were distributed across various regions of Australia: seven interviews from inner regional Australia, five interviews from outer regional Australia, and twenty-one interviews from metropolitan areas. Disparities in access between metropolitan and rural areas emerged in five key dimensions: 1) geography impeding ability to access services; 2) affordability of travel expenses; 3) availability of healthcare and support services; 4) acceptability of available health professionals and services; and 5) awareness of local services and resources. The dimensions of accommodation and timeliness of care were experienced as challenges irrespective of location, with lengthy appointment wait times and difficulty navigating complex systems. However, rurality often compounded the challenges in dementia diagnosis, management, and care. Conclusions: Significant health inequities persist between rural and metropolitan communities that must be prioritised in endeavours to promote equitable dementia diagnosis, management, and care. Targeted action to address disparities is vital to mitigate the impact of rurality, particularly as clinical practice evolves with research advancements.

Alzheimer's Research & Therapy • November 19, 2024

Emily Rosenich, Yen Lim

Background: Beta-amyloid (Aβ) plaques and tau tangles are pathological hallmarks of Alzheimer's disease (AD); however, autopsy studies reveal that most older adults also present with cerebrovascular disease (CVD) markers. It remains unclear how Aβ and tau relate to cognition in the context of concurrent CVD. In initially cognitively unimpaired older adults with CVD, this study aimed to determine ante-mortem cognitive trajectories associated with elevated Aβ and/or tau at autopsy. Methods: Participants aged 65-95 classified as cognitively unimpaired at baseline from the National Alzheimer's Coordinating Center database, with ≥ 1 follow-up between 2005 and 2015, and available autopsy/APOE data were included in this cohort study (N = 863). All participants had at least one of six CVD markers at autopsy. Participants were classified into four groups (A - T-, A + T-, A - T+, A + T+) based on semiquantitative Consortium to Establish a Registry for Alzheimer's Disease neuritic plaque staging and Braak staging. Linear mixed models assessed rate of change in Preclinical Alzheimer's Cognitive Composite scores, episodic memory, and executive function. Results: A + T + adults demonstrated significantly faster cognitive decline on all outcomes in the ~ 10 years preceding death compared to A - T- adults (d = 0.34-0.46). Similarly, when compared to A + T - adults, A + T + adults showed significantly faster decline on all outcomes (d = 0.19-0.37). At the last visit prior to death, a greater proportion of A + T + adults (36%) received a dementia diagnosis compared to A - T+ (15%; OR = 6.00), A + T- (14%; OR = 8.00) and A - T- adults (12%; OR = 6.86), p <.001. When analyses were restricted to exclude dementia diagnoses, significantly faster decline on all outcomes (p's < 0.001, d = 0.29-0.37) was similarly observed in A + T + adults compared to A - T- adults. Conclusions: In older adults with concurrent CVD, A + T + at autopsy was associated with greater cognitive decline over 10 years preceding death compared to A - T- older adults. Faster cognitive decline in A + T + in the context of low final visit dementia diagnoses may suggest that post-mortem A + T + is associated with a steep trajectory of cognitive decline ante-mortem, but that dementia progression is not inevitable.

JAMA Neurology • November 04, 2024

Scott Ayton, David Barton, Bruce Brew, Amy Brodtmann, Roger Clarnette, Patricia Desmond, David Devos, Kathryn Ellis, Amir Fazlollahi, Caroline Fradette, Anita M Goh, Pawel Kalinowski, Christopher Kyndt, Rosalyn Lai, Yen Lim, Paul Maruff, Terence O'brien, Christopher Rowe, Olivier Salvado, Peter Schofield, Michael Spino, Fernando Tricta, Aaron Wagen, Robert Williams, Michael Woodward, Ashley Bush

Interventions that substantially slow neurodegeneration are needed to address the growing burden of Alzheimer disease (AD) to societies worldwide. Elevated brain iron observed in AD has been associated with accelerated cognitive decline and may be a tractable drug target. To investigate whether the brain-permeable iron chelator deferiprone slows cognitive decline in people with AD. This phase 2, double-masked, placebo-controlled randomized clinical trial of 12-month duration was conducted at 9 sites in Australia between August 2, 2018, and April 1, 2023. Patients older than 54 years with amyloid-confirmed mild cognitive impairment or early AD (a Mini-Mental State Examination score of 20 or higher) were screened. Randomization was 2:1 and masked to participants and all study staff. Deferiprone 15 mg/kg twice a day or placebo administered orally for 12 months. The primary outcome was a composite cognitive measure assessed at baseline, 6 months, and 12 months using a neuropsychological test battery (NTB) of memory, executive function, and attention tasks. Secondary outcomes included change in brain iron burden measured by quantitative susceptibility mapping (QSM) magnetic resonance imaging (target engagement), brain volume changes (secondary efficacy measure), and adverse events (safety analysis). Of 167 patients screened for eligibility, 81 were included, with 53 randomly assigned to the deferiprone group (mean [SD] age, 73.0 [8.0] years; 29 male [54.7%]) and 28 to the placebo group (mean [SD] age, 71.6 [7.2] years; 17 male [60.7%]); 54 participants completed the study (7 [25.0%] withdrew from the placebo group and 20 [37.7%] from the deferiprone group). In an intention-to-treat analysis, participants in the deferiprone group showed accelerated cognitive decline on the NTB primary outcome (β for interaction = -0.50; 95% CI, -0.80 to -0.20) compared with placebo (change in NTB composite z score for deferiprone, -0.80 [95% CI, -0.98 to -0.62]; for placebo, -0.30 [95% CI, -0.54 to -0.06]). Secondary analysis revealed that this result was driven by worsening performance on executive function tests. The QSM confirmed that deferiprone decreased iron in the hippocampus compared with placebo (change in hippocampal QSM for deferiprone, -0.36 ppb [95% CI, -0.76 to 0.04 ppb]; for placebo, 0.32 ppb [95% CI, -0.12 to 0.75 ppb]; β for interaction = -0.68 [95% CI, -1.27 to -0.09]). Longitudinal hippocampal volume loss was not affected by deferiprone, but exploratory analysis of other brain regions revealed increased volume loss with deferiprone in frontal areas. The frequency of the adverse effect of neutropenia (4 participants [7.5%] in the deferiprone group) was higher than in similar studies (1.6%-4.4%). These trial findings show that deferiprone 15 mg/kg twice a day decreased hippocampal QSM and accelerated cognitive decline in patients with amyloid-confirmed early AD, suggesting that lowering iron with deferiprone is detrimental to patients with AD. ClinicalTrials.gov Identifier: NCT03234686.