Authors: Liu, Shu | Maruff, Paul | Fedyashov, Victor | Masters, Colin L. | Goudey, Benjamin
Article Type: Research Article
Abstract: Background: Integrating scores from multiple cognitive tests into a single cognitive composite has been shown to improve sensitivity to detect AD-related cognitive impairment. However, existing composites have little sensitivity to amyloid-β status (Aβ +/–) in preclinical AD. Objective: Evaluate whether a data-driven approach for deriving cognitive composites can improve the sensitivity to detect Aβ status among cognitively unimpaired (CU) individuals compared to existing cognitive composites. Methods: Based on the data from the Anti-Amyloid Treatment in the Asymptomatic Alzheimer’s Disease (A4) study, a novel composite, the Data-driven Preclinical Alzheimer’s Cognitive Composite (D-PACC), was developed based on test scores and response durations …selected using a machine learning algorithm from the Cogstate Brief Battery (CBB). The D-PACC was then compared with conventional composites in the follow-up A4 visits and in individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Result: The D-PACC showed a comparable or significantly higher ability to discriminate Aβ status [median Cohen’s d = 0.172] than existing composites at the A4 baseline visit, with similar results at the second visit. The D-PACC demonstrated the most consistent sensitivity to Aβ status in both A4 and ADNI datasets. Conclusions: The D-PACC showed similar or improved sensitivity when screening for Aβ+ in CU populations compared to existing composites but with higher consistency across studies. Show more
Keywords: Alzheimer’s disease, amyloid-β peptides, machine learning, neuropsychological tests
DOI: 10.3233/JAD-231319
Citation: Journal of Alzheimer's Disease, vol. 101, no. 3, pp. 889-899, 2024
Authors: van Havre, Zoe | Maruff, Paul | Villemagne, Victor L. | Mengersen, Kerrie | Rousseau, Judith | White, Nicole | Doecke, James D.
Article Type: Research Article
Abstract: Alzheimer’s disease (AD) has a long pathological process, with an approximate lead-time of 20 years. During the early stages of the disease process, little evidence of the building pathology is identifiable without cerebrospinal fluid and/or imaging analyses. Clinical manifestations of AD do not present until irreversible pathological changes have occurred. Given an opportunity to provide treatment prior to irreversible pathological change, this study aims to identify a subgroup of cognitively normal (CN) participants from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL), where subtle changes in cognition are indicative of early AD-related pathology. Using a Bayesian method …for unsupervised clustering via mixture models, we define an aggregate measure of posterior probabilities (AMPP score) establishing the likelihood of pre-clinical AD. From Baseline through to 54 months, visuo-spatial function had the greatest contribution to the AMPP score, followed by attention and processing speed and visual memory. Participants with the highest AMPP scores had both increasing neo-cortical amyloid burden and decreasing hippocampus volume over 54 months, compared to those in the lowest category with stable amyloid burden and hippocampus volume. The identification of a possible pre-clinical stage in CN participants via this method, without the aid of disease specific biomarkers, represents an important step in utilizing the strength of cognitive composite scores for the early detection of AD pathology. Show more
Keywords: Alzheimer’s disease, Bayesian, mixture models, model averaging, neuropsychological composite score, overfitting, posterior probability, unsupervised clustering
DOI: 10.3233/JAD-191095
Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 683-693, 2020
Authors: Sarant, Julia Z. | Harris, David C. | Busby, Peter A. | Fowler, Christopher | Fripp, Jurgen | Masters, Colin L. | Maruff, Paul
Article Type: Research Article
Abstract: Background: Hearing loss is independently associated with a faster rate of cognitive decline in older adults and has been identified as a modifiable risk factor for dementia. The mechanism for this association is unknown, and there has been limited exploration of potential casual pathology. Objective: Our objective was to investigate whether there was an association between degree of audiometrically measured hearing loss (HL) and brain amyloid-β (Aβ) in a pre-clinical sample. Methods: Participants of the Australian Imaging and Biomarker Longitudinal Study (AIBL; n = 143) underwent positron emission tomography (PET) imaging and objective measurement of hearing thresholds within 5 years of …imaging, as well as cognitive assessment within 2 years of imaging in this observational cohort study. Results: With one exception, study participants who had cognitive assessments within 2 years of their PET imaging (n = 113) were classified as having normal cognition. There was no association between cognitive scores and degree of hearing loss, or between cognitive scores and Aβ load. No association between HL and Aβ load was found once age was controlled for. As previously reported, positive Apolipoprotein E4 (APOE4 ) carrier status increased the risk of being Aβ positive (p = 0.002). Conclusion: Degree of HL was not associated with positive Aβ status. Show more
Keywords: Amyloid, cognition, dementia, hearing loss, neuroimaging
DOI: 10.3233/JAD-215121
Citation: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 359-367, 2022
Authors: Yassi, Nawaf | Pase, Matthew P. | Buckley, Rachel F. | Rosenich, Emily | Watson, Rosie | Maruff, Paul | Lim, Yen Ying
Article Type: Research Article
Abstract: Background: Midlife cardiovascular risk factors (CVRF) are associated with reduced cognition and an increased risk of dementia. Objective: To further investigate this association using remote unsupervised online assessment of cognition and cardiovascular risk in middle-aged adults; and to explore the extent to which the association is altered by carriage of the APOE ɛ4 allele. Methods: The Healthy Brain Project is an online cohort of middle-aged cognitively unimpaired adults (40–70 years) who have undergone cognitive assessment and provided self-reports of demographic and health history. Cardiovascular risk was determined by ascertaining history of hypertension, hypercholesterolemia, diabetes mellitus, overweight (body mass index≥25), and …current cigarette smoking. Participants (n = 2,480) were then grouped based on the number of reported CVRF into no CVRF, 1, 2, and≥3 CVRF. Associations between the number of CVRF as a continuous variable, CVRF group, and each individual CVRF with composite measures of attention, memory and subjective cognitive function were investigated. Results: Higher number of CVRF was associated with poorer attention (β= –0.042, p = 0.039) and memory (β= –0.080, p < 0.001), but not with subjective cognitive function. When considered individually, current smoking (β= –0.400, p = 0.015), diabetes (β= –0.251, p = 0.023), and hypercholesterolemia (β= –0.109, p = 0.044) were independently associated with poorer memory performance. APOE ɛ4 carriers with≥1 CVRF performed worse on memory than ɛ4 carriers with no CVRFs (β(SE) = 0.259(0.077), p = 0.004). This was not observed in ɛ4 non-carriers. Conclusion: In cognitively normal middle-aged adults, CVRF were associated with poorer cognition, particularly in the memory domain. These results support feasibility of online assessment of cardiovascular risk for cognitive impairment. Show more
Keywords: Alzheimer’s disease, cardiovascular risk factors, diabetes mellitus, dyslipidemias, smoking
DOI: 10.3233/JAD-215375
Citation: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1081-1091, 2022
Authors: Darby, David G. | Brodtmann, Amy | Pietrzak, Robert H. | Fredrickson, Julia | Woodward, Michael | Villemagne, Victor L. | Fredrickson, Amy | Maruff, Paul | Rowe, Christopher
Article Type: Research Article
Abstract: Intra-individual decline in memory and cognition is characteristic of prodromal Alzheimer's disease (AD) and may allow detection of very early AD pathology. Episodic memory task scores on a brief computerized cognitive battery (CogState) were prospectively evaluated at baseline, and 3-, 6-, 9-, 12-, and 24-months post-baseline. Linear mixed models were conducted to compute age-adjusted slopes. Subjects with slopes declining ≥90th percentile (“memory decliners”) and age- and gender-matched subjects without such decline (“non-decliners”) were studied with clinical, neuropsychological, and neuroimaging evaluations. Of 195 who completed 24-month evaluation (age 51 to 80 years), 15 memory decliners (mean age 62.7 years, SD 7.6) …were identified, and matched with 33 non-decliners (mean age 63.3 years, SD 8.2). Amyloid-PET imaging was qualitatively abnormal with excess cortical amyloid accumulation in 7 memory decliners (46.7%) and 4 (12.1%) non-decliners (odds ratio 6.34), and quantitatively abnormal with standardized uptake value ratios >1.4 in 5 memory decliners (33.3%) and 2 (6.1%) non-decliners (odds ratio 8.3). One of the memory decliners and none of the non-decliners fulfilled criteria for mild cognitive impairment, but the groups did not differ with respect to subjective memory impairment, neuropsychological evidence of episodic memory impairment, or MRI imaging abnormalities. Intra-individual decline in episodic memory can be detected using a brief computerized cognitive performance test optimized to detect change in community-dwelling non-demented older persons and appears predictive of the presence of cerebral amyloid in about half of these persons. This approach may help detect early prodromal AD pathology in wider-scale community screening programs. Show more
Keywords: Alzheimer's disease, cognition, cognitive decline, memory, pre-clinical diagnosis
DOI: 10.3233/JAD-2011-110818
Citation: Journal of Alzheimer's Disease, vol. 27, no. 3, pp. 627-637, 2011
Authors: Ayton, Darshini | Pirotta, Stephanie | Morello, Renata | Rosenich, Emily | Barton, Chris | Lavale, Alexandra | Pase, Matthew P. | Maruff, Paul | Yassi, Nawaf | Brodtmann, Amy | Lim, Yen Ying | Barker, Anna
Article Type: Research Article
Abstract: Background: The BetterBrains Randomized Controlled Trial (RCT) will evaluate the effectiveness of an online, person-centered, risk factor management, coaching intervention in community-dwelling, healthy adults at risk of cognitive decline. Multi-component interventions are challenging to evaluate due to program complexity and personalization to individual needs and contexts. This paper describes a multi-level process evaluation conducted alongside the BetterBrains RCT. Objective: To understand how and why the BetterBrains intervention was effective or ineffective at reducing cognitive decline in healthy adults whilst considering the context in which it was implemented. Methods: 1,510 non cognitively-deteriorated community-dwelling adults aged 40–70 years old at risk of …cognitive decline will be recruited and randomly assigned to the intervention or control group. All BetterBrains intervention participants, coaches, and the research team will be included in the evaluation. A mixed-methods design will be used, guided by The Framework for Implementation Fidelity and the program logic model. Data will be sourced from interviews, focus groups, surveys, BetterBrains coach notes, participant weekly check-in surveys, and audio recordings of intervention coaching sessions. Quantitative data will be analyzed via descriptive and inferential statistics and qualitative data will be analyzed using content and thematic analysis. Results: The process evaluation will provide information about contextual and influencing factors related to the implementation of BetterBrains and the RCT outcomes. Conclusion: Understanding how BetterBrains was implemented and its associated impacts will inform the translation of the program into community and clinical settings, providing easy access to online, personalized dementia prevention services. Show more
Keywords: Chronic disease prevention, cognitive decline, implementation, process evaluation
DOI: 10.3233/JAD-220341
Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1689-1703, 2022
Authors: Lim, Yen Ying | Pase, Matthew P. | Buckley, Rachel F. | Yassi, Nawaf | Bransby, Lisa | Fowler, Christopher | Laws, Simon M. | Masters, Colin L. | Maruff, Paul
Article Type: Research Article
Abstract: Background: The apolipoprotein E (APOE ) ɛ 4 allele is associated with dose-response effects on cognitive dysfunction and dementia risk in older adults. However, its effects on cognition in middle-aged adults remains unclear. Objective: We examined effects of ɛ 4 heterozygosity and homozygosity on objective and subjective cognition in middle-aged adults enrolled in the Healthy Brain Project (HBP) and in older adults from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Methods: HBP participants (1,000 non-carriers; 450 ɛ 4 heterozygotes; 50 ɛ 4 homozygotes) completed unsupervised assessments of the Cogstate Brief Battery (CBB), ratings of subjective cognitive function and provided …a saliva sample. AIBL cognitively normal participants (650 non-carriers; 204 ɛ 4 heterozygotes; 31 ɛ 4 homozygotes) completed in-person assessments of the CBB, ratings of subjective cognitive function and provided a blood sample. Results: Greater memory impairment was observed in middle-aged ɛ 4 homozygotes compared with ɛ 4 heterozygotes and non-carriers. When data from middle-aged (HBP) and older (AIBL) adults were pooled, the effect of ɛ 4 homozygosity and memory impairment increased with age. In both middle-aged and older adults, ɛ 4 heterozygotes did not differ from non-carriers on any measure of objective or subjective cognition. Conclusion: Memory impairment in ɛ 4 homozygotes is evident in adults aged 50-60 years, and this can be detected through unsupervised cognitive assessments. The effect of ɛ 4 homozygosity increases with older age. APOE ɛ 4 homozygosity has a negative impact on memory as early as midlife, but due to the subtle magnitude of effect, our findings support the necessity of online platforms in large cohorts to assess these complex relationships. Show more
Keywords: Alzheimer’s disease, apolipoprotein E, early detection, memory
DOI: 10.3233/JAD-201281
Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1563-1573, 2021
Authors: Santos, Cláudia Yang | Lim, Yen Ying | Wu, Wen-Chih | Machan, Jason Timothy | Polynice, Shahena | Schindler, Rachel | Maruff, Paul | Snyder, Peter Jeffrey
Article Type: Research Article
Abstract: We sought to determine whether there is any association between a cardiac workload marker, rate pressure product (RPP), working memory, and cortical amyloid-β (Aβ) burden in 63 cognitively normal midlife adults (Mage = 62.8 years; range = 55 to 75 years) at risk for Alzheimer’s disease (AD). The results show a small-to-moderate relationship between increasing cardiac workload (at rest) and neocortical amyloidosis in individuals at the preclinical stage of AD. Moreover, increasing RPP was linearly related to increasing relative impairments on a spatial working memory task (R2 = 0.30), but only for those individuals with neuroimaging evidence suggestive of preclinical AD. These results support …a relationship between the aggregation of Aβ protein plaques in the neocortex, increased cognitive impairment, and more inefficient myocardial oxygen use in the absence of significant metabolic demands. Show more
Keywords: Alzheimer’s disease, amyloid beta-peptides, blood pressure, cardiovascular diseases, cerebrovascular disorders, comorbidity, memory, mild cognitive impairment, risk factors, short-term, workload
DOI: 10.3233/JAD-150576
Citation: Journal of Alzheimer's Disease, vol. 50, no. 1, pp. 127-131, 2016
Authors: Edgar, Chris J. | Siemers, Eric | Maruff, Paul | Petersen, Ronald C. | Aisen, Paul S. | Weiner, Michael W. | Albala, Bruce | for the Alzheimer’s Disease Neuroimaging Initiative
Article Type: Research Article
Abstract: Background: There is a need for feasible, scalable assessments to detect cognitive impairment and decline. The Cogstate Brief Battery (CBB) is validated for Alzheimer’s disease (AD) and in unsupervised and bring your own device contexts. The CBB has shown usability for self-completion in the home but has not been employed in this way in a multisite clinical trial in AD. Objective: The objective of the pilot was to evaluate feasibility of at-home, self-completion of the CBB in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) over 24 months. Methods: The CBB was included as a pilot for cognitively normal (CN) and mild …cognitive impairment (MCI) participants in ADNI-2, invited to take the assessment in-clinic, then at at-home over a period of 24 months follow-up. Data were analyzed to explore acceptability/usability, concordance of in-clinic and at-home assessment, and validity. Results: Data were collected for 104 participants (46 CN, 51 MCI, and 7 AD) who consented to provide CBB data. Subsequent analyses were performed for the CN and MCI groups only. Test completion rates were 100%for both the first in-clinic supervised and first at-home unsupervised assessments, with few repeat performances required. However, available follow-up data declined sharply over time. Good concordance was seen between in-clinic and at-home assessments, with non-significant and small effect size differences (Cohen’s d between -0.04 and 0.28) and generally moderate correlations (r = 0.42 to 0.73). Known groups validity was also supported (11/16 comparisons with Cohen’s d ≥0.3). Conclusion: These data demonstrate the feasibility of use for the CBB for unsupervised at-home, testing, including MCI groups. Optimal approaches to the application of assessments to support compliance over time remain to be determined. Show more
Keywords: Alzheimer’s disease, clinical trials as a topic, cognition, digital technology, healthcare research
DOI: 10.3233/JAD-210201
Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 915-925, 2021
Authors: White, Joshua P. | Schembri, Adrian | Prenn-Gologranc, Carmen | Ondrus, Matej | Katina, Stanislav | Novak, Petr | Lim, Yen Ying | Edgar, Chris | Maruff, Paul
Article Type: Research Article
Abstract: Background: The Cogstate Brief Battery (CBB) is a computerized cognitive test battery used commonly to identify cognitive deficits related to Alzheimer’s disease (AD). However, AD and normative samples used to understand the sensitivity of the CBB to AD in the clinic have been limited, as have the outcome measures studied. Objective: This study investigated the sensitivity of CBB outcomes, including potential composite scores, to cognitive impairment in mild cognitive impairment (MCI) and dementia due to AD, in carefully selected samples. Methods: Samples consisted of 4,871 cognitively unimpaired adults and 184 adults who met clinical criteria for MCI (Clinical Dementia Rating …(CDR) = 0.5) or dementia (CDR > 0.5) due to AD and CBB naive. Speed and accuracy measures from each test were examined, and theoretically- and statistically-derived composites were created. Sensitivity and specificity of classification of cognitive impairment were compared between outcomes. Results: Individual CBB measures of learning and working memory showed high discriminability for AD-related cognitive impairment for CDR 0.5 (AUCs ∼ 0.79–0.88), and CDR > 0.5 (AUCs ∼ 0.89–0.96) groups. Discrimination ability for theoretically derived CBB composite measures was high, particularly for the Learning and Working Memory (LWM) composite (CDR 0.5 AUC = 0.90, CDR > 0.5 AUC = 0.97). As expected, statistically optimized linear composite measures showed strong discrimination abilities albeit similar to the LWM composite. Conclusions: In older adults, the CBB is effective for discriminating cognitive impairment due to MCI or AD-dementia from unimpaired cognition with the LWM composite providing the strongest sensitivity. Show more
Keywords: Alzheimer’s disease, cogstate brief battery, composites, dementia, discriminability, mild cognitive impairment
DOI: 10.3233/JAD-230352
Citation: Journal of Alzheimer's Disease, vol. 96, no. 4, pp. 1781-1799, 2023
