CAN-ACN 2026
Booth # 6 (tentative)
What is Touchscreen Cognition?
Featured Research Session
Advancing Translational Success By Enhancing Predictive Validity In Neurodegenerative Diseases
Thursday, July 31 | 10:00am – 11:30am | Room 718
An opportunity to learn state of the art approaches in target identification and validation and examples on how to improve the predictive value of preclinical testing for successful treatments in humans.
Chairs |
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| Marco A. M. Prado, PhD Western University, London, ON, CA |
Vania F. Prado, PhD, DDS Western University, London, ON, CA |
Presenting Authors and Subjects |
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| Stacey J. Sukof Rizzo PhD, University of Pittsburgh, Pittsburgh, PA, USA |
Predicting differential effects of sex on therapeutic benefit and limitations in Alzheimer’s disease drug development using animal models |
| Anoosha Attaran PhD, Western University, London, ON, CA |
Combining humanized mice, neurochemical, imaging, and cognitive biomarkers for drug discovery in mice |
| Neil R. Cashman MD, University of British Columbia, Vancouver, BC, and ProMIS Neurosciences, Toronto, ON, CA |
Protein misfolding-specific epitope identification for passive and active immunotherapy of neurodegenerative diseases |
| Frank M. Longo MD, PhD, Stanford Medicine, Stanford, CA, and PharmatrophiX, San Francisco, CA, USA |
p75 neurotrophin receptor: a prototype therapeutic target modulating fundamental mechanisms of degeneration and glial function in Alzheimer’s and related dementias |
Poster Information
Tuesday, May 19
Depressive-like Behaviour In A Humanized Knock-in Mouse Model Of APOE, Amyloid, And Tau Is Sex- & APOE Allele-specific
Presenter: Cadence Opoka
Poster # P1-C-125
Poster Session: P1, 3:45pm-5:15pm
| Authors: Cadence E. Opoka, Paul A.S. Sheppard, Ryan Salewski, Marco A.M. Prado, Timothy J. Bussey, Lisa M. Saksida |
| Background: Mid and late-life depression is associated with an increased risk of Alzheimer’s disease (AD) and may reflect prodromal disease processes preceding severe cognitive decline. To improve early detection of AD, combining genetic testing with depressive symptom assessment may enhance AD risk prediction. Variants of the apolipoprotein E (APOE) gene are among the strongest genetic predictors of late-onset sporadic AD. Carriers of the APOE ε4 allele (APOE4) show a substantially higher risk of developing late-onset sporadic AD than carriers of the APOE ε3 allele (APOE3), which confers neutral risk. APOE4 is also associated with increased risk of mid- and late-life depression and with greater depressive symptoms in individuals with AD. However, how APOE4 genotype and depression interact to influence AD risk remains poorly understood. |
| Methods: Two cohorts of humanized mouse models were used to assess APOE-dependent depressive-like behaviour. One cohort expressed human amyloid precursor protein (hAPP), human tau (hMAPT), and either human APOE3 or APOE4 but lacked amyloidogenic mutations, allowing assessment of APOE-dependent depressive-like behaviour in the absence of amyloid pathology. A second cohort had the same genetic background but carried two amyloidogenic mutations in the APP gene (NL-F), enabling evaluation of how amyloid pathology modifies APOE-associated depressive-like behaviour. Depressive-like behaviour was assessed at 8, 9, and 10 months of age using a touchscreen-based cognitive judgment bias (CJB) task. CJB measures the tendency to interpret ambiguous stimuli optimistically or pessimistically, capturing a core depressive symptom of pessimistic bias. |
| Results: At 8, 9, and 10 months of age, female hAPP.hMAPT.hAPOE4 mice exhibited significantly more negative CJB than female hAPP.hMAPT.hAPOE3 mice, whereas male mice showed no significant differences. In mice carrying the amyloidogenic mutations, there were no significant differences in CJB between APOE3 and APOE4 mice at any age, and no sex differences were observed. |
| Conclusions: Negative CJB in female hAPP.hMAPT.hAPOE4 mice reflects a sex-dependent depressive-like phenotype that occurs in the absence of amyloid pathology, capturing features relevant to early AD risk in humans. Screening human females with mid-life depressive symptoms for APOE4 genotype may help identify individuals at greatest risk for AD before overt cognitive decline. |
Poster Information
Monday, May 18
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Presenter: Olivia Ghosh-Swaby
Poster # 108823
| Authors: Olivia R Ghosh-Swaby, PhD, Jennifer Hanna Al-Shaikh, MSc, BA, Jane Thornton, PhD, MD, Ali R. Khan, PhD, Daniel Palmer, PhD, Paul A Sheppard, PhD, Joyla A Furiano, PhD, Teresa Liu-Ambrose, PhD, PT, Timothy J Bussey, PhD, Lisa M Saksida, PhD, and Lindsay S Nagamatsu, PhD |
| Background: Older adults at risk for type 2 diabetes (T2D) experience cognitive decline and brain health abnormalities, highlighting the need for early interventions. Resistance exercise training (RT) holds promise as a strategy to improve executive function, mitigate T2D risk factors, and support neuroplasticity, especially in aging. This study evaluated the effects of a 6-month RT intervention compared to balance-and-tone (BAT; active control) exercise on cognitive outcomes, particularly set shifting, physiological measures, and biomarkers in older adults at risk for T2D. |
| Methods: Sixty community-dwelling adults (aged 60-80 years) with risk factors for diabetes (body mass index :::25, fasting glucose 6.1-7.0 mmol/L, or CANRISK score :::21) were randomized to twice-weekly RT or BAT classes. Primary outcomes included set-shifting performance and cognitive flexibility (Trail Making Test [TMT] Part B; TMT-B minus TMT-A). Secondary outcomes encompassed working memory (Digit Span Backward), global cognitive scores (Montreal Cognitive Assessment (MoCA), Alzheimer’s Disease Assessment Scale [ADAS-Cog-11 ]) and associative learning using a novel Bussey-Saksida touchscreen cognitive task nearly identical to its rodent version. Additionally, Measures of mobility, fitness, glycemic control, and biomarkers were examined (brain derived neurotrophic factor, BDNF, insulin growth factor-1, IGF-1). An ANCOVA and repeated measures ANOVA was used to assess intervention effects on outcomes at endpoint and over time, respectively, with baseline performance and adherence as covariates (p<0.050 significant). |
| Results: RT improved working memory (Digit Span Backward; p = 0.024) compared to BAT at endpoint, with a trend toward enhanced cognitive flexibility over time (TMT-B minus TMT-A; p = 0.049). No significant differences were observed in global cognitive scores (MoCA, ADAS-Cog-11 ). Bussey-Saksida touchscreen tasks were adapted and validated for human use. Participants showed low accuracy on paired associative learning (54-64% ± 4% accuracy), irrespective of training group. RT improved lower body strength over time (p=0.036), with no changes in glycemic levels. IGF-1 levels decreased in the RT group (p = 0.037), with no changes in BDNF. |
| Conclusions: Resistance exercise training offers targeted cognitive benefits in older adults at risk for diabetes, suggesting its potential as an intervention to address both T2D risk factors and cognitive decline. Further studies should explore long-term impacts on brain structure and function. |
Tuesday, May 19
Depressive-like Behaviour In A Humanized Knock-in Mouse Model Of APOE, Amyloid, And Tau Is Sex- & APOE Allele-specific
Presenter: Cadence Opoka
Poster # P1-C-123
Poster Session: P1, 3:45pm-5:15pm
| Authors: |
| Background: Mid-life depression and apolipoprotein E (APOE) ε4 allele (APOE4) carrier status are associated with an increased risk of developing sporadic Alzheimer’s disease (AD). To improve early detection of AD, combining APOE genetic testing with depressive symptom assessment may enhance AD risk prediction. APOE4 is also associated with increased risk of mid-life depression and greater depressive symptoms in individuals with AD, particularly in women. However, the interaction between APOE genotype, sex, depression, and AD risk remains poorly understood. |
| Methods: To assess APOE genotype-dependent depressive-like behaviour, two humanized mouse models were examined longitudinally. One cohort expressed human amyloid precursor protein (hAPP), tau (hMAPT), and either APOE3 (a neutral risk allele) or APOE4. A second cohort had the same genetic background but carried two amyloidogenic mutations in the APP gene (NL-F) to model amyloid pathology. Depressive-like behaviour was assessed using a touchscreen cognitive judgment bias (CJB) task, which measures depressive-like pessimistic bias by evaluating responses to ambiguous stimuli. |
| Results: At 8, 9, and 11 months old, female hAPP.hMAPT.hAPOE4 mice exhibited more pessimistic CJB than female hAPP.hMAPT.hAPOE3 mice, whereas males showed no genotype differences. In mice carrying the NL-F mutations, CJB did not differ across genotypes or sexes. Thus, the female hAPP.hMAPT.hAPOE4 model exhibits a sex-dependent depressive-like phenotype in the absence of amyloid pathology, supporting human studies examining how depression, sex, and APOE interact to influence AD risk. |
| Conclusions: |
Wednesday, May 20
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Presenter: Alycia Crooks
Poster # 107535
| Authors: Alycia M Crooks, BSc, Kate M. Onuska, BSc, Taylor W Schmitz, PhD, Lisa M Saksida, PhD, Timothy J Bussey, PhD, Vania F Prado, PhD and Marco AM Prado, PhD |
| Background: The prevailing model of Alzheimer’s disease (AD) proposes that the accumulation of misfolded amyloid-beta (Aβ) peptides drives tau protein hyperphosphorylation and neuroinflammation, leading to neurodegeneration and cognitive decline. However, current therapeutic approaches targeting Aβ show only subtle ehects on cognitive deficits. Interestingly, the loss of cholinergic neurons of the basal forebrain precedes and predicts pathology and neurodegeneration in AD. The vesicular acetylcholine transporter (VAChT), a key regulator of cholinergic signalling, functions at the presynaptic terminal by loading acetylcholine (ACh) into vesicles for secretion. Notably, VAChT expression is significantly reduced in AD brains, with changes observed early in disease progression. Whether these early changes in cholinergic synaptic function contribute to hippocampal dysfunction remains unclear. Using the APPNL-F mouse model of AD, which expresses humanized Aβ with familial AD mutations, this study investigates the interplay between cholinergic signalling and hippocampal-dependent cognitive function. |
| Methods: ACh signalling was recorded using fibre photometry and the GRABACh sensor in the hippocampal CA1 region of freely behaving APPNL-F and control mice performing the Trial-Unique delayed Nonmatching-to-Location (TUNL) task. This task assesses spatial working memory, a cognitive domain impaired in AD. Large and small separation windows were used to challenge spatial discrimination. |
| Results: Analysis of VAChT levels have shown some dynamic regulation, but with aging VAChT levels decreased substantially. Recordings of ACh dynamics in the hippocampal CA1 region revealed behaviour-associated changes, particularly during screen approaches, touches, and predominantly reward responses. Cholinergic tone decreases substantially in response to reward, demonstrating tonic ACh signalling that can change in response to specific stimuli. Young APPNL-F mice, tested before substantial plaque accumulation, exhibit deficits in spatial working memory during challenging conditions, which associated with reduced cholinergic responses. The deficit in cholinergic tone in APPNL-F mice closely mirrors the cholinergic dysfunction observed in the forebrain VAChT knock-out mice, which showed pronounced impairments in learning, memory, and ACh signalling during the TUNL task. |
| Conclusions: These findings highlight the role of early deficits in cholinergic synaptic function associated with spatial memory impairments before overt pathology in APPNLF mice. Future experiments aim to develop strategies to rescue memory and cholinergic tone dysfunction. |
Thursday, May 21
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Presenter: Madison Longmuir
Poster # 99431
| Authors: Madison Longmuir, Aya Arrar, Kate M Onuska, R. Nathan Spreng, Daniel Palmer, Tim J. Bussey, Lisa M. Saksida, Vania F. Prado, Marco A.M. Prado, Taylor W. Schmitz, PREVENT-AD Research Group |
| Background: ApoE4 is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). Compared to ApoE4 noncarriers (ApoE4-), ApoE4 carriers (ApoE4+) exhibit earlier onset and more rapid progression of memory impairment. However, separate lines of work have suggested the opposite pattern in other cognitive domains: ApoE4+ individuals exhibit superior executive function compared to ApoE4-, but this advantage decreases with age. The antagonistic pleiotropy hypothesis proposes that ApoE4 may therefore confer advantages to brain function at earlier ages, but these advantages become detrimental later in life. To investigate this hypothesis, we took a cross-species translational approach focusing on cognitively unimpaired human adult ApoE4+ and ApoE4- within the age range 65-80 years, in combination with knock-in mouse models that express humanized wild-type App, MAPT, and ApoE3/4 genes. |
| Methods: To quantify executive function, we utilized the cross-species touchscreen-based Continuous Performance Task (CPT) to evaluate selective attention. Human participants were drawn from the PREVENT-AD program at the Douglas Research Centre, with testing conducted on MS SurfacePros. Mice performed the same task using an operant chamber platform. |
| Results: Behavioural results suggest that ApoE4 facilitates attentional processes in both older adult and mouse ApoE4 carriers, as indexed by discrimination performance on the CPT. Further strengthening this translational pattern, we found that the facilitative effect of ApoE4 on CPT was more pronounced in female ApoE4+ of both species. In mice, we examined the ApoE-dependent effects on attention longitudinally (spanning 12 months), finding that the positive effect of ApoE4 was sustained across this interval in females, though it became less robust with age. In contrast, ApoE4 was beneficial in males only during early life. Notably, these effects were observed in the absence of detectable brain pathology. |
| Conclusions: These results support the antagonistic pleiotropy hypothesis, whereby ApoE4 carriership confers greater attentional performance early in life and in the absence of classical AD pathology. This effect is detectable in both sexes but is stronger and more sustained across age in females. All these patterns are conserved across humans and mice, suggesting that this cross-species translational platform is well suited to explore the mechanistic basis of ApoE4 antagonistic pleiotropy as it relates to domain-specific cognitive function. |