In vivo tau pathology is associated with synaptic loss and altered synaptic function

Area of Science:

• Neuroscience
• Medical Imaging
• Neurology

Background:

• Synaptic loss in Alzheimer's disease (AD) is not well understood and may involve tau pathology.
• Investigating the relationship between tau, synaptic density, and synaptic function is crucial for understanding AD pathogenesis.

Purpose of the Study:

• To explore the spatial associations between regional tau pathology, synaptic density, and synaptic function in Alzheimer's disease.
• To utilize combined Positron Emission Tomography (PET) and Magnetoencephalography (MEG) for a comprehensive assessment.

Main Methods:

• Seven amyloid-positive AD subjects underwent dynamic [18F]flortaucipir PET, [11C]UCB-J PET with arterial sampling, and resting-state MEG.
• Quantified regional tau pathology ( [18F]flortaucipir binding potential, BPND) and synaptic density ( [11C]UCB-J BPND).
• Assessed synaptic function using MEG spectral measures and analyzed associations with tau and synaptic density via Spearman correlations and GEE models.

Main Results:

• Higher regional tau deposition ([18F]flortaucipir uptake) was linked to lower synaptic density ([11C]UCB-J uptake).
• The association between synaptic density and tau varied with neocortical tau load, showing negative correlations at high tau burden.
• Increased tau and decreased synaptic density correlated with altered synaptic function, including slowed oscillatory activity, particularly in the occipital lobe.

Conclusions:

• Tau pathology in Alzheimer's disease is strongly associated with reduced synaptic density.
• The findings highlight a direct link between tau accumulation, synaptic dysfunction, and impaired neuronal activity in AD.