Abstract Details Title Early-onset Alzheimer’s Disease with Combined SETD2 Deletion and APOE4 Homozygosity: Evidence for a Dual-pathology Mechanism Topic Aging, Dementia, and Behavioral Neurology Presentation(s) P10 - Poster Session 10 (8:00 AM-9:00 AM) Poster/Presentation Number 12-011 Objective To describe the first reported case of autopsy-confirmed early-onset Alzheimer’s disease (EOAD) associated with a pathogenic SETD2 deletion and APOE4 homozygosity, suggesting a dual-pathology mechanism linking neurodevelopmental and neurodegenerative processes. Background SETD2 encodes a histone methyltransferase essential for chromatin regulation and neurodevelopment. Germline SETD2 mutations cause macrocephaly–intellectual disability syndromes but have not previously been linked to progressive dementia. APOE4 homozygosity confers the highest genetic risk for sporadic Alzheimer’s disease, typically resulting in earlier onset and aggressive clinical course. Design/Methods A 60-year-old man with lifelong intellectual disability and dysmorphic features developed progressive cognitive decline in his late 50s. Genetic testing included chromosomal microarray, Fragile X, and whole-exome sequencing. Neuropathological examination was performed postmortem. Results Whole-exome sequencing revealed a large pathogenic deletion in SETD2 and APOE4/E4 genotype. The patient’s decline spanned eight years, progressing from mild forgetfulness to total dependency with behavioral changes. Imaging showed diffuse frontal atrophy. Autopsy demonstrated severe Alzheimer’s pathology (Braak VI, Thal 4, CERAD frequent) with numerous cotton wool plaques, moderate cerebral amyloid angiopathy, and limbic-predominant TDP-43 pathology. These findings are consistent with a highly aggressive EOAD phenotype. The overlap of SETD2 loss and APOE4 homozygosity may converge on lipid metabolism, cell-cycle dysregulation, and microtubule instability to amplify neurodegeneration. Conclusions This case expands the phenotype of SETD2 mutations to include progressive dementia and supports a synergistic interaction between SETD2 deficiency and APOE4-driven amyloid pathology. It underscores the importance of considering dual genetic mechanisms in atypical EOAD and advocates for integrated genetic and neuropathological evaluation in early or rapidly progressive dementias. Authors/Disclosures Waad Alshammari, MBBS (KFSHRC) PRESENTER Dr. Alshammari has nothing to disclose.