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The synapse plays a key role in this process, both by facilitating the spread of tau between neurons and by serving as a direct target of tau-induced neurotoxicity. However, few studies in humans have explored synaptic density, both as a facilitating factor and as a target of tau pathology.<\/jats:p>\n                  <jats:p>In this dual PET tracer study, we used 18F-SynVesT-1 synaptic vesicle glycoprotein 2A (SV2A) PET to assess synaptic density and 18F-MK6240 tau-PET to assess fibrillar tau in 59 amyloid-PET-positive patients and 25 amyloid-PET-negative cognitively normal individuals from the Chinese Preclinical Alzheimer\u2019s Disease Study (CPAS). Spatial correlation analyses revealed that brain regions with higher SV2A tracer uptake in cognitively normal individuals exhibited higher 18F-MK6240 uptake in Alzheimer\u2019s disease. These findings were replicated independently in the Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI), where normal SV2A-PET maps from CPAS were correlated with tau-PET data from 372 amyloid-\u03b2-positive participants, including longitudinal follow-up in 204 cases. In both cohorts, regions with higher normal synaptic density showed greater tau burden, and in ADNI, higher synaptic density in normal brain also predicted faster tau accumulation over time. Gene-set enrichment analyses of transcriptomic data mapped onto regional tau-PET uptake further showed that areas of high 18F-MK6240 uptake were enriched in genes encoding synapse-related proteins.<\/jats:p>\n                  <jats:p>Together, these findings suggest that synapse-rich regions are especially prone to tau accumulation. We also investigated the downstream impact of tau on synaptic integrity. Notably, regions with higher 18F-MK6240 uptake showed reduced SV2A tracer uptake, indicating synaptic loss, not only in the same regions but also in areas connected to those with high tau. Stronger loss of SV2A tracer uptake was observed in the regions with stronger resting-state functional connectivity to epicentres of high 18F-MK6240 uptake in the Alzheimer\u2019s disease group. The connectivity-dependent synaptic loss could not be explained fully by tau levels in the connected target regions but was found to be mediated, in part, by them. These findings suggest that tau pathology contributes to synaptic loss both locally and in distant, connected brain regions.<\/jats:p>\n                  <jats:p>Overall, our results highlight the central importance of the synapse in Alzheimer\u2019s disease: synapses appear both to facilitate fibrillar tau accumulation and to become impaired through its toxic effects. Understanding the role of the synapse in tau pathology might open new avenues for therapeutic interventions aimed at slowing down tau progression and neurodegeneration.<\/jats:p>","DOI":"10.1093\/brain\/awaf425","type":"journal-article","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T13:04:44Z","timestamp":1762952684000},"page":"1958-1972","source":"Crossref","is-referenced-by-count":2,"title":["Synaptic density and tau pathology in Alzheimer\u2019s disease: a dual role in susceptibility and degeneration"],"prefix":"10.1093","volume":"149","author":[{"given":"Ying","family":"Luan","sequence":"first","affiliation":[{"name":"Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University , Shanghai 200040 ,","place":["China"]},{"name":"Cultivation and Construction Site of the State Key Laboratory of Intelligent Imaging and Interventional Medicine, Department of Radiology, Zhongda Hospital, Medical School of Southeast University , Nanjing 210009 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