Samantha A. Harker

Alzheimer's disease (AD) is characterized by the deposition of amyloid-beta (Aβ) and microtubule-associated protein tau (MAPT) neurofibrillary tangles in the brain; however, the molecular mechanisms underlying associated synaptic dysfunction remain unclear. Eratos' AI for Spatial Computing and Embedded Neurotherapeutic Discovery (ASCENDTM) engine was employed to analyze multiplexed expansion revealing (multiExR) data from the 5xFAD and wild-type mouse somatosensory cortex, enabling quantitative mapping of Aβ, RIM1, and GluA2 nanodomains. ASCENDTM identified significant and previously unreported protein associations, including nanoscale colocalization of Aβ with postsynaptic AMPA-receptor subunit GluA2 and amyloid-bridged Aβ-GluA2-RIM1 ternary assemblies. These spatial signatures indicate complex synaptic disruption, defined by distinct morphological and density profiles associated with neurobiological and neuroinflammatory pathology. Integrating high-dimensional spatial computing with cross-modal literature synthesis advances traditional microscopy analysis toward autonomous, AI-driven scientific discovery. Identifying novel, druggable interfaces within native tissue expedites the discovery of precision neurotherapeutics for AD and other complex central nervous system disorders.

Background: Recent evidence from Medicare data suggests that older autistic adults are 18 times more likely to be diagnosed with Alzheimer's disease (AD) compared to non‐autistic adults but understanding of heterogeneity in cognitive and brain aging with autism is lacking. Genetics explain substantial variance in cognitive aging outcomes and incidence of neurodegenerative disease, but there are no genetically‐informed studies of aging with autism. Polygenic risk scores (PRS) are a tool to measure an individual's genetic liability to a certain trait, which has shown to be very effective for predicting AD cases. We aim to 1) Determine whether autistic individuals carry a higher cumulative genetic risk for AD compared to non‐autistic individuals and 2) Determine if AD‐PRS differentially moderates memory performance in autistic vs. non‐autistic adults Method: Participants were 53 autistic and 48 non‐autistic adults ages 18‐70 (38.62±16.75). DNA was extracted from saliva using Oragene's DNA purification protocol and genotyped on the Illumina Global Diversity Array with an additional 180K neurodegenerative disease markers, then imputed for whole genome coverage through the TOPMed server. AD‐PRS was generated from a Genome Wide Association Study of 71,880 AD and 383,378 controls using the PRSice‐2 software. We performed an ANCOVA to test a diagnostic group difference in AD‐PRS, controlling for sex, and the interaction between group and sex. Additionally, we tested a diagnostic group difference in long‐term memory (AVLT A7), controlling for sex, age, AD‐PRS, and the interaction between group, sex, and AD‐PRS. Result: The autism group had a significantly larger AD‐PRS ( p = 0.030), and significantly worse long‐term memory scores ( p = 0.043) than non‐autistic controls. There was an interaction between autism diagnosis and AD‐PRS ( p = 0.05) that was driven by a negative slope in the autism group. Conclusion: This study was the first to investigate cumulative genetic risk for AD in autistic adults and found that autistic adults have a greater genetic risk in comparison to non‐autistic adults. Synoptically, we found that the Alzheimer's PRS has a greater negative impact on cognitive function in autistic adults compared to non‐autistic adults.

The Program for the Education and Enrichment of Relational Skills (PEERS^®) is an evidence-based intervention developed for autistic individuals to support social communication, peer interactions, independence, and interpersonal relationships. Despite a demonstrated effectiveness for young autistic individuals in the US and several other countries, PEERS has yet to be modified to support the needs of autistic adults across the lifespan. The present study describes how our team sought autistic voices to adapt PEERS for adults of any age. Specifically, we aimed to address the needs of middle-aged and older adults and adapt the curriculum to be more neurodiversity-affirming. Between two cohorts that completed the program consecutively, we evaluated the acceptability of the adapted PEERS program and made refinements based on feedback from autistic participants and their study partners. Results indicated that Cohort 2 reported higher satisfaction with the PEERS components and overall program than Cohort 1, suggesting effective refinement. We present a framework of adaptations that more specifically address the needs of middle-aged and older adults in a neurodiverse-affirming way compared to previous iterations. Our approach to implementing an adapted PEERS curriculum across the adult lifespan may serve as a model for improved clinical care and cultivate the acceptance of neurodiversity in the interpersonal domains of autistic adults’ lives.

Autism spectrum disorder (ASD) is a neurodevelopmental disability and recent evidence suggests that autistic adults are more likely to develop Alzheimer’s disease (Alz) and other dementias compared to neurotypical (NT) adults. The ε4-allele of the Apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alz and negatively impacts cognition in middle-aged and older (MA+) adults. This study aimed to determine the impact of the APOE ε4-allele on verbal learning and memory in MA+ autistic adults (ages 40–71 years) compared to matched NT adults. Using the Auditory Verbal Learning Test (AVLT), we found that ε4 carriers performed worse on short-term memory and verbal learning across diagnosis groups, but there was no interaction with diagnosis. In exploratory analyses within sex and diagnosis groups, only autistic men carrying APOE ε4 showed worse verbal learning (p = 0.02), compared to autistic men who were not carriers. Finally, the APOE ε4-allele did not significantly affect long-term memory in this sample. These findings replicate previous work indicating that the APOE ε4-allele negatively impacts short-term memory and verbal learning in MA+ adults and presents new preliminary findings that MA+ autistic men may be vulnerable to the effects of APOE ε4 on verbal learning. Future work with a larger sample is needed to determine if autistic women may also be vulnerable.