Melbourne School of Psychological Sciences - Research Publications

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    Scientific challenges underlying adaptation of existing cognitive tests or development of new tests to address cultural and linguistic diversity
    Bowden, SC (Wiley, 2022-12)
    Background High quality cognitive assessments may be a requisite part of care for people with any disease associated with cognitive changes. While extensive research has been devoted to development of reliable and valid cognitive assessment in some cultures, the development of cognitive assessments that address cultural and linguistic diversity has been relatively neglected. Method This talk will provide a conceptual overview of the principal scientific issues involved in developing culturally‐sensitive and scientifically robust assessments of cognition. The issues will be illustrated with examples of successful application of these principles, together with limitations. Recent research highlighting the risks of over‐interpretation of normative comparisons across cultural or ethnic diversity will be highlighted. Result Two broad scientific precepts underpin development of any new cognitive test. The first of these involves establishing construct validity, that is, the scientifically defensible measurement of target cognitive functions. Secondly, a normative basis for individual assessment is desirable. Regarding the first of these requirements, establishing construct validity can most efficiently triangulate from established cognitive measures, for example, informed by the best available model of cognitive abilities, namely the Cattell‐Horn‐Carroll model. Using the empirical methods of convergent and discriminant, any new test can be evaluated for convergence on construct estimation, within the limits of measurement error, with an established test of the target construct developed in another culture. The best available methods for this purpose involve multi‐group confirmatory factor analysis, which allows evaluation of measurement invariance (MI). If established, MI permits generalization of construct validity research across cultures. Regarding the second broad requirement, representative normative samples are ideal for individual assessment, but are expensive. An alternative is to use an individual baseline approach where repeat assessment within any one patient provides the control standard against which to monitor change, for example, in response to progressive disease. Methods for evaluating the reliability or precision of repeat assessments will be briefly delineated. Conclusion Providing rigorous cross‐cultural assessment of dementia and other cognitive disorders entails addressing significant scientific challenges. However, all of challenges fall within established methods that are readily available to researchers.
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    The effect of sad mood on subjective appraisal of memory performance in older people with and without subjective memory complaints: An experimental study
    Farmer, HF ; Bahar‐Fuchs, A ; Bryant, C (Wiley, 2021-12)
    Background Subjective memory complaints (SMC) have been identified as a possible precursor to cognitive decline and may indicate a need for an early intervention for at‐risk older adults. However, it is well‐established that low mood is associated with SMC, leading to claims that memory concerns in older people may often reflect primarily psychological symptoms. This study aimed to determine the effect of low mood on subjective memory appraisal in older adults. Method We used a film‐based mood induction procedure (MIP) to test the effect of sad vs. neutral mood on subjective appraisal of memory performance in an experimental 2X2 between‐subjects design. Participants were 98 cognitively unimpaired older people (n=45 with SMC), randomised to the sad MIP (n=56) or the neutral MIP (n=42). All participants completed measures of trait SMC and ruminative self‐focused attention (RSFA) as well as perceived performance and metacognitive experience (ME) following the MIP and completion of a face‐name and a maze‐learning task. Result Participants in the sad MIP condition (M=42.75, SD=30.97) reported significantly greater sadness than those in the neutral condition following the manipulation (M=11.57, SD=18.44). The association between objective and subjective memory performance was stronger for cued recall on the face‐name task (r=.61, p=.001) and was weaker free recall on the face‐name task (r=.26, p=0.016) as well on the maze‐learning task (r=‐.16, p=.200). Contrary to expectation, there was no significant effect of mood condition on perceived performance on Face‐Name learning task (MD=‐2.43, p=498), but sad mood was associated with better perceived performance on the maze‐learning task (MD=13.34, p=.015). Results also indicated that RSFA and ME were implicated as mechanisms in subjective memory performance appraisal. Conclusion Findings indicate that SMC is a complex multifaceted phenomenon which may be underpinned by maladaptive self‐regulation and attentional systems, suggesting that psychological interventions may be appropriate for many older adults with SMC.
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    Music interventions for dementia and depression in elderly care (MIDDEL): The Australian part of an international cluster randomised controlled trial
    Baker, F ; Lee, YEC ; Sousa, T ; Stretton-Smith, P ; Clark, I ; Sveinsdottir, V ; Geretsegger, M ; Gold, C (Wiley, 2021-12-01)
    BACKGROUND: Dementia and depression are highly prevalent, comorbid conditions in older adults residing in care homes and are associated with individual distress and associated challenges for care staff. Music-based interventions are widely used and potentially effective nonpharmacological interventions, due to the relative preservation of the ability of people with dementia to respond to music even with disease progression. However, there is a lack of large-scale studies evaluating the effectiveness of music-based interventions in dementia care. Music Interventions for Dementia and Depression in the Elderly (MIDDEL) is the first large-scale international cluster-randomised controlled trial to investigate the effectiveness of small group music therapy (GMT), recreational choir singing (RCS) and their combination on levels of depression in residents with dementia. The trial is currently being conducted across six countries, and this presentation will outline the study outcomes from the Australian arm of the trial. METHOD: Between June 2018 and November 2019, 20 care home units were randomised to music interventions (GMT, RCS, GMT and RCS) or standard care delivered over 6 months. The primary outcome was level of depression as measured by the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes included neuropsychiatric symptoms, quality of life, care staff burden and adverse events collected at baseline, 3-months, 6-months and 12-months post-randomisation. Outcomes were analysed as intention-to-treat, per-protocol, and with exploratory predictor analyses. RESULTS: 318 participants (215 female; 103 male) aged 65 years or more with diagnoses of dementia and at least mild depressive symptoms (as defined by score of 8 or above on MADRS) residing in care homes were recruited. In addition, 131 care staff (108 female; 23 male) answered questions regarding perceived care burden to search for potential ripple effects of the music interventions. We will present the main findings of the study including the predictive effects of clinical characteristics on efficacy. CONCLUSION: The presentation will include discussion of contextual factors and conditions that support efficacy, and clinical implications for safety and quality of life for people with dementia living in care homes.
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    Sex differences in the genetic architecture underlying resilience in AD
    Eissman, JM ; Dumitrescu, L ; Mahoney, ER ; Mukherjee, S ; Lee, ML ; Bush, WS ; Engelman, CD ; Lu, Q ; Fardo, DW ; Trittschuh, EH ; Mez, J ; Kaczorowski, CC ; Saucedo, HH ; Widaman, KF ; Buckley, RF ; Properzi, MJ ; Mormino, EC ; Yang, H ; Harrison, TM ; Hedden, T ; Nho, K ; Andrews, SJ ; Tommet, D ; Hadad, N ; Sanders, RE ; Ruderfer, DM ; Gifford, KA ; Zhong, X ; Raghavan, NS ; Vardarajan, BN ; Initiative, ADN ; Consortium, ADG ; Team, AS ; Pericak‐Vance, MA ; Farrer, LA ; Wang, L ; Cruchaga, C ; Schellenberg, GD ; Cox, NJ ; Haines, JL ; Keene, CD ; Saykin, AJ ; Larson, EB ; Sperling, RA ; Mayeux, R ; Cuccaro, ML ; Bennett, DA ; Schneider, JA ; Crane, PK ; Jefferson, AL ; Hohman, TJ (Wiley, 2021-12-01)
    Background Approximately 30% of older adults are cognitively normal at death despite presence of Alzheimer’s disease (AD) neuropathology at autopsy. Studying these “resilient” individuals may lead to the discovery of novel therapeutic targets. In addition, growing evidence suggests sex differences in downstream neurodegenerative consequences of AD neuropathology, with recent studies highlighting notable sex-specific genetic drivers of AD pathogenesis. We sought to extend this work by elucidating sex-specific genetic factors underlying resilience to AD. Method We used our published genetic resilience pipeline to assess sex-specific genetic predictors (Dumitrescu et al., 2020). Briefly, we used modern psychometric approaches to harmonize cognitive measures across four cohorts of cognitive aging (N=5054), in-vivo amyloid PET across two studies, and leveraged autopsy measures of amyloidosis (CERAD staging) across two studies. A continuous measure of resilience was quantified using a latent variable framework whereby higher scores reflected better-than-predicted cognitive performance given amyloidosis level and lower scores reflected worse-than-predicted performance. We then performed sex-stratified GWASs and sex-interaction GWASs, covarying for age and the first three principal components and meta-analyzed across cohorts. Finally, we performed sex-stratified genetic correlation analyses (GNOVA) between our meta-analysis results and summary statistics from 63 complex traits. Result Among individuals with normal cognition, we identified a female-specific locus on chromosome 10 (rs827389, [p(females)=7.4E-09, p(males)=0.64, p(interaction)=8.3E-05, MAF=0.46]). This variant is a modest eQTL for KIN (p=0.003), a gene encoding a DNA/RNA binding protein (http://www.braineac.org). In our genetic correlation analyses, we observed male-specific correlations between resilience and two heart rate-related traits, whereby higher resilience was associated with lower genetic risk for poor heart health. We also observed opposing genetic correlations between resilience and multiple sclerosis such that females with higher resilience scores had lower susceptibility for multiple sclerosis (p.FDR=0.009), whereas males with higher resilience had higher susceptibility (p.FDR=0.001). Conclusion Our results highlight sex-specific genes and pathways that may drive resilience in a biological sex-dependent manner, although independent replication is needed. The best target to enhance resilience to AD neuropathology may depend on sex and genetic context of an individual. Future work should continue to evaluate sex differences in the genetic architecture of the AD neuropathological cascade.
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    Sex‐specific genetic predictors of memory performance
    Smith, AN ; Dumitrescu, L ; Mukherjee, S ; Lee, ML ; Choi, S ; Trittschuh, EH ; Mez, J ; Mahoney, ER ; Bush, WS ; Engelman, CD ; Lu, Q ; Fardo, DW ; Widaman, KF ; Buckley, RF ; Mormino, EC ; Harrison, TM ; Sanders, RE ; Clark, LR ; Gifford, KA ; Vardarajan, BN ; Initiative, ADN ; Consortium, ADG ; Team, AS ; Project, TADS ; Cuccaro, ML ; Pericak‐Vance, MA ; Farrer, LA ; Wang, L ; Schellenberg, GD ; Haines, JL ; Jefferson, AL ; Johnson, SC ; Kukull, WA ; Albert, MS ; Keene, CD ; Saykin, AJ ; Larson, EB ; Sperling, RA ; Mayeux, R ; Bennett, DA ; Schneider, JA ; Crane, PK ; Hohman, TJ (Wiley, 2021-12-01)
    Background There are notable sex differences in the clinical manifestation of Alzheimer’s disease (AD), including differences in baseline and longitudinal changes in memory performance. However, sex-stratified models have not been routinely incorporated into genetic studies of cognitive performance or decline. We sought to identify sex-specific genetic predictors of memory performance in aging adults. Method We obtained harmonized memory scores from 11,601 females and 8,885 males from 7 cohorts of cognitive aging. We calculated scores using latent variable modeling techniques anchored on overlapping neuropsychological test items across datasets to perform both sex-stratified and sex-interaction genome-wide association studies in each cohort using mixed-effects regression models to assess genetic associations with baseline memory score and rate of memory decline. Covariates included age at baseline and population principal components. We then combined results in a fixed-effect meta-analysis. Results As expected, we observed robust associations at the APOE locus in males and females in both baseline and longitudinal models. Additionally, we identified a sex-specific locus for longitudinal memory performance (interaction-p=2.54e-6) on chromosome 7 within LINC-PINT that was genome-wide significant in males (index SNP= rs66754621; p=1.62e-8; MAF=0.20), but not females (p=0.65). This variant is in an enhancer region within several brain regions, as well as within a promoter-anchored chromatin interaction loop and a methylation eQTL in the prefrontal cortex. No female-specific loci were identified. Interestingly, we did observe nominal associations in baseline memory at some known AD loci, including male-specific effects at MS4A6A, FERMT2, and KAT8 (interaction ps=0.0026, 0.027, and 0.0058, respectively) and opposing effects between males and females at INPP5D (interaction p=0.0021). Conclusion These results highlight a novel male-specific locus of memory performance on chromosome 7 near the LINC-PINT gene. LINC-PINT is upregulated in the substantia nigra in Parkinson’s disease and is downregulated in multiple brain regions over the course of normal aging, making it a fascinating male-specific candidate gene. Replicate and functional analyses of the region are ongoing to verify our finding and elucidate the biological mechanism. Our results add to the growing body of literature suggesting that there are sex-specific genetic contributors to cognitive decline.
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    Association between APOE‐ε4 allele and CSF amyloid in memory performance differ by sex
    Brugulat‐Serrat, A ; Tsoy, E ; Milà‐Alomà, M ; Sánchez‐Benavides, G ; Buckley, RF ; Gispert, JD ; Molinuevo, J ; Possin, KL ; Kramer, JH (Wiley, 2021-12)
    Background There is growing evidence of sex differences in the association between Alzheimer’s disease (AD) biomarkers and cognition. However, few studies have examined the effect of sex on the associations between established AD risk factors and cognitive performance in clinically normal older adults. This study aimed to elucidate potential sex differences in the relationship between APOE‐ε4 status, AD biomarkers, and cognitive performance in a large multinational cohort of clinically normal older adults. Method Participants were 952 cognitively unimpaired older adults from the multicenter European Prevention of Alzheimer’s Disease (EPAD) study (age range 50‐88 years, mean age 65.0(7.0), mean education 14.6(3.6) years, 58% females). All participants underwent a lumbar puncture and CSF Aβ42, p‐tau and t‐tau biomarkers (Roche Elecsys®) were measured, APOE genotyping, and a battery of digital cognitive tests (UCSF TabCAT; Favorites (associative memory), Dot Counting (executive function), and Flanker (processing speed)). APOE genotype was dichotomized (ε4 carrier vs. ε4 non‐carrier). We performed multiple linear regression models to examine the effect of sex, CSF biomarkers, APOE‐ε4, and their interactions on cognitive performance covarying for age, education, and testing language. Result There were no differences in age (p=.07), frequency of APOE‐ε4 carriers (33.1%, p=.55) or CSF biomarkers (all p>0.1) between males and females. Females had lower educational attainment (p=.01). Females outperformed males on an associative memory task (p=.002), whereas males performed better on tasks of working memory (p=.01) and inhibitory control (p=.01). A sex*Aβ*APOE‐ε4 status interaction (p=.01) revealed APOE‐ε4 carriership and abnormal levels of CSF Aβ were associated with poorer associative memory performance only in males (Fig 1). Conclusion Sex seems to moderate the association between CSF Aβ and APOE‐ε4 allele and memory performance in cognitively unimpaired older adults. Our results suggest a cross‐sectional association of APOE‐ε4 and CSF Aβ with cognitive performance in males that complement previous literature on the relationship between APOE‐ε4 and longitudinal cognitive decline in females. Taken together, these findings highlight the importance of understanding the complexity of sex differences in individuals at higher risk of AD.
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    Menopause moderates sex differences in tau PET signal: Findings from the Framingham Study
    Buckley, RF ; O’Donnell, A ; McGrath, ER ; Jacobs, HIL ; Satizabal, CL ; Ghosh, S ; Rubinstein, ZB ; Murabito, JM ; Sperling, RA ; Beiser, AS ; Seshadri, S (Wiley, 2021-12)
    Background Cognitively‐normal (CN) older women exhibit elevated tau‐PET signal in medial temporal and neocortical regions compared with men. The effect of menopause on tau deposition remains unclear. We explored menopausal status as a moderator of sex differences in tau deposition in middle‐aged adults. Method 273 CN (Age=55yrs(±8), Female(n)=134, Post‐menopausal(n)=70) from the Framingham Study 3rd generation cohort underwent 18F‐Flortaucipir (FTP)‐PET and/or 11C‐Pittsburgh Compound‐B (PiB)‐PET scans. We examined FTP‐PET signal in four a priori regions that demonstrate large sex differences in CN older adults (entorhinal, rostral middle frontal, inferior parietal and lateral occipital). FTP‐PET and global PiB‐PET signal were referenced to cerebellar grey. Linear regression examined sex differences in each ROI, adjusting for age and PET camera. Separate models examined menopausal status (post‐menopause/pre‐menopause females), menopausal age (≤|>50 years), and interactions with APOEε4. Sensitivity analyses included age‐matched males (‘pseudo‐premenopausal’/‘pseudo‐menopausal’) against the menopause groups to account for confounds with chronological age. Result Middle‐aged females exhibited higher FTP‐PET signal in the inferior parietal, rostral middle frontal and lateral occipital regions than males by ∼0.04SUVr (p<0.009; Fig. 1). No sex or menopause differences were evident in PiB‐PET. Post‐menopausal females exhibited higher FTP‐PET signal in the lateral occipital lobe than pre‐menopausal (p=0.05; Fig. 2). Menopause age≤50 years corresponded with higher lateral occipital and rostral middle frontal FTP‐PET signal than >50years (p<0.05; Fig. 2). Post‐menopausal females maintained higher signal in lateral occipital, inferior parietal and rostral middle frontal regions compared with even age‐matched ‘pseudo‐menopausal’ males (Table 1). Finally, a significant menopause*APOEε4 interaction suggested that the menopause effect was only evident in APOEε4 non‐carriers, localized to the parietal lobe (p∼0.03; Fig. 3). Conclusion Sex differences in tauopathy are apparent in CN individuals approximately 20 years earlier than previously demonstrated. Our findings suggest that sex differences are exacerbated by menopause, particularly when the age‐at‐menopause is below 50 years. Chronological age did not appear to confound the results, as age‐matched males exhibited significantly lower tau signal. Finally, the effect of APOEε4 carriership may ameliorate menopause effects; only pre‐menopausal APOEε4 non‐carriers appeared to exhibit protective effects of circulating estradiol relative to post‐menopausal non‐carriers. Future work will need to identify direct hormonal contributions, the impact of surgery and hormone‐therapy.
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    Extraneous neuroimaging factors do not contribute to sex differences in flortaucipir signal: Analysis of skull binding and partial volume effects
    Scott, MR ; Edwards, NC ; Properzi, MJ ; Jacobs, HIL ; Price, JC ; Manning, LK ; Mayblyum, DV ; Rubinstein, ZB ; Rentz, DM ; Johnson, KA ; Sperling, RA ; Schultz, AP ; Buckley, RF (Wiley, 2021-12)
    Background Clinically normal females exhibit greater [18]F‐flortaucipir (FTP) PET signal than males in both temporal and neocortices. It remains unclear whether sex differences in neocortical regions are primarily explained by technical variability issues. We aimed to investigate the contribution of signal spillover/off‐target skull binding to sex differences in FTP‐PET. Next, we explored partial volume effects (PVE) by simulating sex differences in smoothed FTP‐PET signal. Discerning sex differences in tau signal versus noise is pivotal to understanding sex differences in the pathology of Alzheimer’s disease and associated tauopathies. Method 343 clinically normal (female=58%; mean[SD]=73.8[8.5] years) (female=38%; mean[SD]=76.9[7.3] years) participants from the Harvard Aging Brain Study and the Alzheimer’s Disease Neuroimaging Initiative underwent cross‐sectional FTP‐PET (standardized uptake value ratios [SUVrs]). For skull analyses, we created skull ROIs based on signal 12mm from the outer perimeter of voxels in FreeSurfer‐defined tau ROIs. Linear regression models estimated the main effects of sex across cortical tau ROIs while correcting for local skull binding. We simulated PVE by convolving group‐level SUVr means in each ROI with 6mm Gaussian kernels, and then compared the sexes with linear regression models post‐smoothing. Result Widespread sex differences in skull binding were observed (Table 1). Covarying for skull binding ameliorated weaker sex differences in cortical FTP signal but did not impact the largest effects. Sex differences in PVE were observed in both female and male directions; no clear sex‐related biases in PVE were found to impact cortical tau sex differences except for the rostral middle frontal region (Figure 1). Conclusion Our findings suggest that sex differences in FTP‐PET are not solely attributed to skull ‘clouding’ or PVE, but rather support hypotheses of female‐related tau vulnerability. Nevertheless, as only two potential confounds were investigated, and gross morphology/volumetric issues remain a key concern, further investigation is needed to fully elucidate this phenomenon. Investigations of sex differences in longitudinal tau accumulation (a few preliminary reports already suggest faster rates in females) will add further support to the argument that noise properties inherent in FTP‐PET do not significantly contribute to sex differences in cortical tau signal.
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    The QuickSort: A brief cognitive screen to detect cognitive impairment in older adults
    Foran, AM ; Mathias, JL ; Bowden, SC (Wiley, 2021-12)
    Abstract Background Sorting tests are amongst the most sensitive cognitive tests for detecting brain injury, but are rarely used to screen older adults for cognitive impairment. A recent meta‐analysis (Foran, Mathias & Bowden) found that sorting ability deteriorates in older adults who have been diagnosed with one of a number of common neurodegenerative disorders, suggesting that sorting tests may provide an alternative to cognitive screens. The QuickSort is a new test that improves on existing sorting tasks, with the manual and test stimuli freely accessible to users (Foran, Mathias & Bowden, 2020). It is quicker to administer and score, and better suited for use with older adults whose cognitive ability may be compromised. Method A consecutive cohort of older (≥60 years) community‐dwelling adults (n=187) and hospital inpatients who were referred for a neuropsychological assessment (n=73) were administered the Mini‐Mental Status Examination (MMSE), Frontal Assessment Battery (FAB) and QuickSort (9‐stimuli, which must be sorted by color, shape & number; Total score range = 0‐18; higher scores indicate better cognition). A Cognitively‐Healthy normative subsample (n=115), screened for cognitive and psychological disorders, was formed from the community sample. Results The Cognitively‐Healthy subsample completed the QuickSort within 2‐minutes, 50% had errorless performance, and 95% scored 10 or more. The likelihood of community‐dwelling older adults and inpatients (n=260) being impaired on either the MMSE or FAB, or both, increased by a factor of 3.52 for QuickSort Total scores <10 and reduced by a factor of 0.23 for scores ≥10. Conclusion Most healthy older adults complete the QuickSort quickly and easily. The QuickSort performance of a patient can be compared to their cognitively‐healthy peers in order to estimate the likelihood that they will be impaired on either the MMSE or FAB, or both. The QuickSort can also be customized for use in specific settings. The QuickSort may provide an alternative to lengthier cognitive screens (MMSE and FAB) in settings that have very limited clinical resources.
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    Monthly computerized at‐home assessments to detect cognitive change in preclinical Alzheimer’s disease
    Jutten, RJ ; Amariglio, RE ; Properzi, MJ ; Buckley, RF ; Maruff, PT ; Stark, CE ; Yassa, MA ; Johnson, KA ; Sperling, RA ; Rentz, DM ; Papp, KV (Wiley, 2021-12)
    Abstract Background Alongside the increased focus on detecting Alzheimer’s disease (AD) pathology in the preclinical stage, there is a need to more rapidly track AD‐related cognitive changes that may emerge during this stage. Computerized cognitive testing has the potential to achieve this by enabling more frequent, remote, unsupervised assessments. Here, we aimed to investigate whether monthly at‐home assessments of a modified version of the Behavioural Pattern Separation Task‐Object Version (BPSO) could detect cognitive change in cognitively unimpaired (CU) individuals with and without abnormal AD biomarkers. Method N=110 CU participants (age=77.1±4.9, 61% female, MMSE 29±1.3) from the Harvard Aging Brain Study completed the BPSO monthly at‐home on an iPad as part of the Cogstate C3 battery for up to one year (6.3±3.9 months follow‐up). All participants underwent PIB‐PET imaging (1.25±1.05 years before at‐home baseline) and a subset (n=82) underwent Flortaucipir PET (0.56±0.4 years before at‐home baseline). Primary outcome of the BPSO is a metric reflecting the ability to correctly discriminate between stimuli that are similar but not identical to previously learned targets (score range 0‐1, higher scores reflecting better performance). Linear mixed models were used to characterize BPSO performance over months (including both linear and quadratic time terms to investigate nonlinear change), and to examine associations with amyloid (dichotomous) and medial‐temporal tau deposition (continuous) while adjusting for age, sex, education and their interactions with time. Result Overall, individuals’ BPSO performance improved over months, as shown by a significant quadratic effect of time (β=‐.002,p<.001) with a plateauing learning curve (Figure 1). On average, amyloid‐positive individuals (n=29) showed slightly worse BPSO performance (β=‐.06,p=.03) than amyloid‐negative individuals, but similar trajectories over time. However, the baseline amyloid effect was attenuated when limiting the sample to those with both amyloid and tau imaging. Less improvement over the year was associated with greater tau burden in the entorhinal cortex (Time*tau β=‐0.02,p=.019) (Figure 2). Conclusion We show that subtle alterations in pattern separation performance over repeated exposure in CU individuals are associated with tau deposition in the medial‐temporal lobe. This implies that unsupervised computerized testing using monthly learning paradigms may be an efficient way to early detect cognitive change associated with preclinical AD.