SV2A <EM >IN VIVO</EM>-POSTMORTEM CORRELATION: UTILISING HIGH-RESOLUTION ARRAY TOMOGRAPHY TO VALIDATE SV2A PET AS A BIOMARKER FOR SYNAPSE DENSITY IN ALZHEIMER'S DISEASE

Positron emission tomography (PET) using radioligands targeting synaptic vesicle glycoprotein 2A (SV2A) has demonstrated reduced SV2A binding in individuals with Alzheimer’s disease (AD) dementia compared with healthy controls. It remains unclear whether the SV2A PET signal accurately reflects region-specific synapse loss. This study investigates the biological basis of the SV2A PET signal through within-case correlations between in vivo PET measures and post-mortem regional SV2A density using high-resolution synaptic imaging. A cohort of people with dementia (n=12), mild cognitive impairment (n=17) and cognitively unimpaired ageing (n=37) underwent cognitive testing and SV2A PET imaging with [¹⁸F]SynVesT-1 and consented to brain donation. To date, post‑mortem brain tissue has been obtained from one participant with Alzheimer’s disease, permitting a pilot comparison of SV2A PET measures with histologically assessed synapse density. Brain samples from ten regions were prepared for high-resolution array tomography. Post-mortem SV2A puncta density was compared with corresponding in vivo PET measures using linear mixed-effects models and Spearman’s correlations. Preliminary findings show concordance between post-mortem synapse density and SV2A PET. Both methods indicate minimal to absent synapses in the centrum semiovale, with regional variation between cerebellar cortex and entorhinal cortex. Ongoing analyses extend comparisons to additional cortical and subcortical regions. These results will clarify the regional specificity and sensitivity of SV2A PET for detecting synaptic loss, informing its validity as a biomarker in AD. This work is part of the FNIH SV2A project, which aims to further elucidate the biological underpinnings of the SV2A PET signal.