Melbourne School of Psychological Sciences - Research Publications

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Longitudinal GWAS Identifies Novel Genetic Variants and Complex Traits Associated with Resilience to Alzheimer’s Disease

Phillips, J ; Dumitrescu, L ; Archer, DB ; Smith, AN ; Mukherjee, S ; Lee, ML ; Choi, S ; Scollard, P ; Trittschuh, EH ; Mez, JB ; Mahoney, ER ; Bush, WS ; Engelman, CD ; Lu, Q ; Fardo, DW ; Widaman, KF ; Buckley, RF ; Mormino, EC ; Harrison, TM ; Sanders, E ; Clark, LR ; Gifford, KA ; Vardarajan, BN ; 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 ; Goate, A ; Neuner, S ; Renton, AE ; Marcora, E ; Fulton‐Howard, B ; Patel, T ; Bennett, DA ; Schneider, JA ; Crane, PK ; Hohman, TJ (Wiley, 2022-12)

Background We completed a large genetic analysis of resilience to cognitive decline in Alzheimer’s Disease (AD) and discovered novel variants, genes, and complex traits associated with better‐than or worse‐than‐expected cognitive performance given an individual’s age, sex, and APOE genotype. Method Leveraging 15,933 non‐Hispanic white participants across four longitudinal cohort studies of aging and AD (Figure 1), our group determined the effects of genetic variants on resilience metrics using mixed‐effects regressions. Models adjusted for age, sex, APOE ε4 allele count, presence of the APOE ε2 allele and all covariate interactions with interval (years from baseline). The outcomes of interest were residual cognitive resilience, quantified from residuals in three cognitive domains (memory, executive function, and language), and combined resilience, summarized as the covariance of educational attainment with residual cognitive resilience. Post‐GWAS analyses included gene tests using MAGMA and estimates of genetic correlation with 65 complex traits using GNOVA. Result We observed genome‐wide significant associations at multiple established AD loci, including BIN1 and CR1 (Figure 2). We observed a novel association with combined resilience on chromosome 13 (top SNP: rs11838654, MAF = 0.06, P = 4.7×10−8; Figure 3) and a novel signal on chromosome 1 approaching significance (top SNP: rs2817183, MAF = 0.41, P = 5.1×10−8). Interestingly, rs11838654 is an eQTL for four genes in hippocampus (WBP4, COG6, MRPS31, and NHLRC3I; Braineac database). We also observed an association with residual cognitive resilience on chromosome 5 that approached genome‐wide significance (top SNP: rs4482935, MAF = 0.25, P = 5.5×10−8; Figure 2). Gene‐level tests identified associations of CD2AP (P.fdr = 0.027) and ZNF146 (P.fdr = 0.049) with residual cognitive resilience and combined resilience, respectively. Additionally, we identified negative genetic correlations of combined resilience with ischemic stroke and coronary artery disease (all P.fdr<2.5×10−2; Figure 4). Conclusion Compared to models of resilience that regress out the effects of AD neuropathology on cognition, the present models benefit from larger sample size at the cost of molecular precision. Although the genetic architecture of resilience from these less precise models more closely resembles that of clinical AD, we uncovered novel genetic drivers of resilience through this approach. Such findings will require future replication but suggest a trajectory‐based definition of resilience holds substantial promise for discovery.
Sex‐specific genetic predictors of memory, executive function, and language performance

Eissman, JM ; Smith, AN ; Mukherjee, S ; Lee, ML ; Choi, S ; Scollard, P ; Trittschuh, EH ; Mez, JB ; Bush, WS ; Engelman, CD ; Lu, Q ; Fardo, DW ; Widaman, KF ; Buckley, RF ; Mormino, EC ; Kunkle, BW ; Naj, AC ; Clark, LR ; Gifford, KA ; Cuccaro, ML ; Cruchaga, C ; 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 ; Thompson, PM ; Martin, ER ; Bennett, DA ; Barnes, LL ; Schneider, JA ; Crane, PK ; Hohman, TJ ; Dumitrescu, L (Wiley, 2022-12)

Background Alzheimer’s disease (AD) is more prevalent in women than men, and robust evidence shows sex differences in the biological response to the AD neuropathological cascade. However, there is a lack of large‐scale genetic studies on sex‐specific genetic predictors of AD‐related cognitive outcomes. Thus, we sought to elucidate the sex‐specific genetic etiology of memory, executive function, and language performance. Method This study included six cohorts of cognitive aging (Nmales=7,267, Nfemales=9,518). We applied psychometric approaches to build harmonized memory, executive function, and language composite scores. Next, for all domains, we calculated slopes from the cognitive scores (two or more timepoints) with linear mixed effects models. Then we performed sex‐stratified and sex‐interaction GWAS on these phenotypes, covarying for baseline age and the first three genetic principal components. We meta‐analyzed across cohorts with a fixed‐effects model. Sensitivity analyses for all models restricted the sample to cognitively unimpaired individuals. Result In addition to well‐established associations with cognition at the APOE locus, we identified three genetic loci that showed sex‐specific effects with cognition. A chromosome 16 locus (rs114106271), a splicing‐quantitative trait locus for RP11‐152O14.4 and LINC02180 in the testis (GTEx), associated with baseline memory performance in men (β=0.13, P=2.40×10‐8; PInteraction=8.96×10‐6; Figures 1‐2) but not in women (β=‐0.01, P=0.76). A chromosome 14 locus (rs34074573), an expression‐quantitative trait locus (GTEx) for HOMEZ (a homeobox gene), and for BCL2L2 (a previously reported AD risk gene), associated with longitudinal memory performance in men (β=‐0.01, P=4.15×10‐8; PInteraction=5.83×10‐7; Figures 3‐4) but not in women (β=0.001, P=0.09). Finally, a chromosome 6 locus (rs9382966) associated with longitudinal language performance in men with near genome‐wide significance (β=‐0.004, P=6.29×10‐8; PInteraction=2.01×10‐4) but not in women (β=‐0.0003, P=0.61). Conclusion Our results highlight some key sex differences in the genetic architecture of cognitive outcomes. Findings further suggest that some sex‐specific genetic predictors have domain‐specific associations, providing an exciting opportunity to better understand the molecular basis of memory, executive function, and language through genomic analysis. Although our findings need to be replicated, our GWAS analyses highlight the contribution of sex‐specific genetic predictors beyond the APOE locus in conferring risk for late‐life cognitive decline.
Contribution of modifiable dementia risk factors to cognitive performance and subjective cognition in middle‐aged adults

Bransby, L ; Rosenich, E ; Buckley, RF ; Yassi, N ; Maruff, P ; Pase, MP ; Lim, YY (Wiley, 2022-12)

Background Characterization of the contribution of modifiable risk factors (MRF) to dementia generally consider MRFs individually, despite strong evidence that MRFs co‐occur. In a large group of middle‐aged adults, the prevalence and co‐occurrence of MRFs for dementia was determined, spanning five broad domains (mood, lifestyle behaviours (e.g., physical inactivity), cardiovascular health, cognitive/social engagement, and sleep). We then investigated relationships between MRFs, both individually and combined, to cognitive performance and subjective cognition. Method Middle‐aged adults (n = 1610), most (70%) with a family history of dementia, enrolled in the Healthy Brain Project, completed an extensive set of questionnaires about their physical and psychological health and lifestyle. Participants also completed the Cogstate Brief Battery (CBB), and the Cognitive Function Instrument (CFI), a measure of subjective cognition. Participants were classified according to the number of domains (mood, lifestyle behaviours, cardiovascular health, cognitive/social engagement, and sleep, ranging from 0‐5) in which they reported at least one MRF. Age, sex, education and ethnicity were adjusted for in analyses. Result Most participants (65%) reported at least one MRF in two or more domains (Fig 1A). Compared to participants reporting no MRFs, participants who reported at least one MRF in 3‐5 domains showed worse memory performance and reported greater subjective cognitive concerns, with magnitudes of differences moderate to large (d = 0.30‐0.93; Fig 1B). Participants who reported at least one MRF in five domains also showed worse attention than those reporting no MRFs (d = 0.58). When individual MRFs were considered simultaneously, MRFs in the mood (e.g., anxiety symptomatology) and cognitive/social engagement domains (e.g., leisure activities) were associated with worse attention and memory performance. Individual MRFs reflecting mood and sleep symptomatology were associated with greater subjective cognitive concerns. Conclusion In middle‐aged community dwelling adults, multidomain MRFs for dementia are highly prevalent and co‐occur, and are associated with poorer cognitive outcomes. This suggests that the presence of multiple MRFs as early as midlife may have negative neurological outcomes, however, this will need to be explored in future neuroimaging studies. These findings indicate that multidomain lifestyle prevention trials in middle‐aged adults may be useful to delay or prevent future cognitive impairment or dementia.
Optimizing early detection of beta‐amyloid accumulation with PET using spatial extent

Farrell, ME ; Thibault, EG ; Becker, A ; Price, JC ; Schultz, AP ; Properzi, MJ ; Buckley, RF ; Jacobs, HIL ; Hanseeuw, B ; Sperling, RA ; Johnson, KA (Wiley, 2022-12)

Background As clinical trials shift towards prevention, there has been increasing interest in improving early detection of beta‐amyloid (Aβ), below standard global PET positivity thresholds. While many studies have demonstrated that some regions appear more vulnerable to the earliest deposits, those regions have varied widely across studies. We sought to develop more flexible metrics for identifying subthreshold individuals at risk for progression to global Aβ positivity by evaluating a wide range of early regional targets and expanding our measurement beyond tracer retention (DVR/SUVR) to include spatial extent. Method 269 clinically‐normal older adults were included from the Harvard Aging Brain Study, focusing on 150 initially globally PIB‐ adults with longitudinal PET. Region‐specific positivity thresholds were computed using iterative longitudinal two‐level linear mixed effect models that identified the cutoff beyond which local accumulation significantly increases over time. Next, we identified all regions significantly predictive of future global accumulation in initially PIB‐ adults and generated 3 aggregate masks at liberal (p<.05), moderate (p<.001) and conservative a‐levels (Bonferroni p<.0007). DVR and spatial extent (number of elevated ROIs) were computed in each mask. Receiver operator characteristic (ROC) curve analysis determined sensitivity/specificity of each metric to predict future global positivity. External validation was performed using globally florbetapir‐negative (FBP‐) healthy controls from the Alzheimer’s Disease Neuroimaging Initiative (ADNI, n=211). Result Regional variations in measurement reliability were detected (Fig1) and accounted for by employing accumulation‐based regional positivity thresholds. A broad set of ROIs were identified as potential early targets based on prediction of global accumulation, encompassing bilateral cingulate, medial frontal/parietal cortices and left‐lateralized lateral frontal/parietal/temporal cortices (Fig2). ROC analyses demonstrated that spatial extent outperformed DVR in predicting progression to global PIB+ within 3 years (Fig3), with 82% sensitivity and 97% and 98.5% specificity, respectively, for the two larger aggregate masks. External validation in ADNI (Fig4) again demonstrated the superior performance of spatial extent (SE=100%, SP=91.6%) in predicting progression to global positivity within 3 years. Conclusion Our findings demonstrate that due to a high level of heterogeneity in early Aβ deposition, measures of spatial extent across a broad set of neocortical regions are more sensitive to detect early Aβ than traditional DVR/SUVR.
Sex differences in the protective effects of APOE ε2 on longitudinal cognitive decline

Wood, M ; Xiong, LY ; Buckley, RF ; Swardfager, W ; Masellis, M ; Black, SE ; Rabin, JS (Wiley, 2022-12)

Background The APOE ε2 allele confers protection against cognitive decline and Alzheimer’s disease. There is some suggestion that APOE ε2 may have sex‐specific effects on cognition. We investigated sex differences in associations between APOE ε2 and longitudinal cognitive trajectories in a large sample of older adults. Method We used data from the National Alzheimer’s Coordinating Centre (NACC) database. We included participants who were ≥ 50 years old, White, free from dementia at baseline, and completed at least one follow‐up cognitive assessment. We categorized participants as APOE ε2 carriers (combining heterozygous and homozygous ε2 carriers) or APOE ε3 homozygote carriers. APOE ε4 carriers (including ε2/ε4 carriers) were excluded. Cognition was assessed approximately annually. We computed composite scores for memory, language, attention, and executive function. We examined the interaction between APOE allele (ε2 vs ε3), sex, and time on longitudinal cognition in linear mixed models, adjusting for baseline age, baseline MMSE, education, number of follow‐up visits, NACC test version, and their interactions with time. Result We included 6,733 participants classified as cognitively normal at baseline (mean age=72.9±9.12 years, mean education=16.0±2.87 years, 62.5% female), and 1,932 participants classified as mild cognitive impairment (MCI) at baseline (mean age=75.2±8.91 years, mean education=15.6±3.28 years, 44% female). Among participants with normal cognition, we observed significant interactions between sex, genotype, and time on longitudinal memory (β=0.022, p=0.039) and language (β=0.015, p=0.038), but not attention (β=0.01, p=0.09) or executive function (β=0.006, p=0.30). In sex stratified analyses, relative to male APOE ε3 carriers, male APOE ε2 carriers showed slower rates of decline in domains of memory and language. This effect was not observed in females. No significant interactions between sex, genotype, and time were observed in participants with MCI (memory: β=‐0.04, p=0.1; language: β=‐0.02, p=0.4; attention: β=‐0.01, p=0.5; executive function: β=‐0.02, p=0.3). Conclusion Among cognitively normal adults, APOE ε2 carriage protects males but not females against longitudinal memory and language decline. The sex‐specific effect of APOE ε2 may contribute to the lower incidence of Alzheimer’s disease in males compared to females. Future research is needed to elucidate the mechanisms behind the observed sex disparities in cognitive decline.
Modifiable dementia risk factors associated with higher CSF tau and poorer cognition in middle‐aged adults

Bransby, L ; Rosenich, E ; Buckley, RF ; Maruff, P ; Yassi, N ; Lim, YY (Wiley, 2022-12)

Background Modifiable factors in domains such as mood, lifestyle behaviours, cardiovascular health, cognitive/social engagement, and sleep are associated with increased risk for dementia. These modifiable risk factors could promote Alzheimer’s disease (AD) related biological processes, such as beta‐amyloid (Aβ) or tau accumulation, but these associations remain poorly understood. This study aimed to determine associations between modifiable dementia risk factors with Aβ, tau, and cognition in cognitively unimpaired middle‐aged adults. Method Middle‐aged adults (n = 82) (age range 40‐70) enrolled in a biomarker sub‐study of the Healthy Brain Project completed self‐report questionnaires about their physical and psychological health and lifestyle. Cerebrospinal fluid (CSF) levels of Aβ42, total tau (t‐tau), and phosphorylated tau (p‐tau) (Roche Elecsys) were obtained. A comprehensive neuropsychological battery was administered to measure cognition, and composite scores were derived for memory, executive function, and the Preclinical Alzheimer’s Cognitive Composite (PACC). Participants were classified according to reporting normal modifiable risk (NMR) (risk in ≤1 domains; n = 34) or high modifiable risk (HMR) (risk in ≥2 domains; n = 48) across five domains (mood, lifestyle behaviours, cardiovascular health, cognitive and social engagement, and sleep). Result Compared to those with NMR, those with HMR had increased t‐tau (d = 0.54, p = .021) and p‐tau (d = 0.47, p = .044) levels but did not differ on Aβ42 (d = 0.23, p = .319) after adjusting for age and sex. With age, sex, and education adjusted for, HMR participants showed worse performance on PACC (d = 0.69, p = .003), executive function (d = 0.55, p = .016), and episodic memory (d = 0.40, p = 0.076) compared to NMR participants. Differences in cognitive performance remained when levels of Aβ42, t‐tau and p‐tau levels were controlled in the models [PACC (d = 0.59, p = .011), memory (d = 0.64, p = .005) and executive function (d = 0.45, p = .049)]. Conclusion Modifiable dementia risk factors across multiple domains are related to higher total and phosphorylated tau levels and with subtle cognitive deficits, but not with Aβ, in middle‐aged adults. Together with the observation that differences in cognition across modifiable risk groups remained when Aβ and tau levels were controlled statistically, this suggests that modifiable dementia risk factors may increase risk through neurodegenerative processes non‐specific to AD, such as increased cerebrovascular burden, although this needs to be confirmed in future neuroimaging studies.
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.
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.
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.
Continued white matter fibre degeneration over 3 years after ischemic stroke

Egorova, N ; Dhollander, T ; Khan, W ; Khlif, MS ; Brodtmann, A (Wiley, 2021-12)

Abstract Background We aimed to chart white matter integrity over 3 years after stroke, to examine if post‐stroke loss of white matter continues to be accelerated compared to control participants. Method We applied a longitudinal “fixel”‐based analysis, sensitive to fibre tract‐specific differences within a voxel, to assess axonal loss in stroke (N=71, 22 women) compared to control participants (N=36, 13 women) across the whole brain. We studied microstructural differences in fibre density and macrostructural (morphological) changes in fibre cross‐section. Result In stroke participants, we observed significantly lower fibre density and cross‐section from 3 months to 3 years. The changes were widespread and affected the corpus callosum, bilateral inferior fronto‐occipital fasciculus, right superior longitudinal fasciculus. Conclusion We conclude that ischemic stroke is associated with extensive and continued neurodegeneration that significantly affects white matter micro and macrostructure across the whole brain. These findings confirm that the deleterious effects of stroke on white matter continue several years following the event.

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