Abstract
INTRODUCTION: Synapse loss is a key driver of cognitive decline in Alzheimer's disease (AD), yet its direct relationship with neurofibrillary tau tangle (NFT) burden remains unclear. This study leveraged positron emission tomography (PET) imaging to investigate the link between NFT accumulation and synaptic density in older adults with and without AD pathology. METHODS: Older adults (N = 94) underwent PET imaging to quantify synaptic density ([(11)C]UCB-J distribution volume ratio [DVR]), Aβ plaque burden ([(11)C]PiB DVR), and NFT burden ([(18)F]MK-6240 standardized uptake value ratio). Analyses focused on NFT-synaptic density correlations in the hippocampus (Hp) and entorhinal cortex (ERC), with additional subgroup analyses based on cognitive and Aβ status. RESULTS: Hp NFT burden strongly correlated with synaptic density, while the ERC showed weaker effects. Subgroup analyses found robust Hp associations in unimpaired AD participants. CONCLUSION: Hippocampal synaptic density is highly vulnerable to early NFT accumulation. SV2A PET imaging enables early detection of synaptic loss and may also identify resilience to AD pathology. HIGHLIGHTS: Hippocampal synaptic density is similar in controls and unimpaired biologic AD. Hp synaptic density particularly vulnerable to Hp, ERC NFT burden. NFT-synaptic density relationship may vary between unimpaired and impaired biologic AD.