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. 2025 Jun;21(6):e70321.
doi: 10.1002/alz.70321.

Examining the association between synaptic density and neurofibrillary tau among cognitively impaired and unimpaired older adults with and without Alzheimer's disease pathology

Alexandra H DiFilippo  1 , Erin M Jonaitis  2 , Gilda E Ennis  2 , Andrew K McVea  1 , Max McLachlan  1 , Brecca Bettcher  1 , Nicholas Schulz  2 , Mary-Elizabeth Pasquesi  2 , Nancy J Davenport-Sis  2 , Yer Thor  2 , Ethan Grover  2 , Nathaniel Chin  2 , Todd E Barnhart  2 , Sanjay Asthana  2 , Tobey J Betthauser  2 , Jonathan W Engle  2 , Sterling C Johnson  2 , Barbara B Bendlin  2 , Bradley T Christian  1   2
Affiliations

Examining the association between synaptic density and neurofibrillary tau among cognitively impaired and unimpaired older adults with and without Alzheimer's disease pathology

Alexandra H DiFilippo et al. Alzheimers Dement. 2025 Jun.

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 ([11C]UCB-J distribution volume ratio [DVR]), Aβ plaque burden ([11C]PiB DVR), and NFT burden ([18F]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.

Keywords: Alzheimer's disease; SV2A; [11C]UCB‐J PET; neurofibrillary tau tangle; synaptic density.

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Conflict of interest statement

Bradley T. Christian, Sterling C. Johnson, and Barbara B. Bendlin report grants from the National Institutes of Health for the conduct of the study. Sterling C. Johnson receives research funding from Cerveau Technologies. Barbara Bendlin received precursor and compounds from Avid Radiopharmaceuticals. Bradley T. Christian receives precursor and compounds from Avid and equipment from Cerveau Technologies and Lantheus. No other disclosures are reported. Author disclosures are available in the Supporting Information.

Figures

FIGURE 1
FIGURE 1
Association between hippocampus (Hp) synaptic density:Hp neurofibrillary tau tangle (NFT) (A), entorhinal cortex (ERC) synaptic density:ERC NFT burden (B), and ERC NFT burden:Hp synaptic density (C). Black dashed line indicates line of best fit across all participants. Note that the Hp NFT burden range is smaller than that for the ERC.
FIGURE 2
FIGURE 2
Regional association between synaptic density ([11C]UCB‐J) and neurofibrillary tau tangle (NFT) ([18F]MK‐6240) in regions of NFT accumulation in Alzheimer's disease (NFTIII [A], NFTIV [B], NFTV [C], NFTVI [D], NFTVII [E]). Black dashed line indicates line of best fit across all participants. Correlations between synaptic density and NFT burden across all participants calculated using Pearson's r.
FIGURE 3
FIGURE 3
Comparison of hippocampus (Hp) (A) and entorhinal cortex (ERC) (B) synaptic density between participants grouped by cognitive and Aβ status. Significance of group differences in synaptic density and neurofibrillary tau tangle were evaluated using one‐way ANOVAs with post hoc pairwise testing using Tukey's Honestly Significant Difference (significant relationships indicated by horizontal lines between groups). Significance: ***p < 0.001; **p < 0.01, *p < 0.05. †Significance lost after partial volume correction.
See this image and copyright information in PMC

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