Alzheimer disease (AD) is characterized by progressive cognitive decline in older individuals accompanied by the presence of two pathological protein aggregates — amyloid-β and phosphorylated tau — in the brain. The disease results in brain atrophy caused by neuronal loss and synapse degeneration. Synaptic loss strongly correlates with cognitive decline in both humans and animal models of AD. Indeed, evidence suggests that soluble forms of amyloid-β and tau can cause synaptotoxicity and spread through neural circuits. These pathological changes are accompanied by an altered phenotype in the glial cells of the brain — one hypothesis is that glia excessively ingest synapses and modulate the trans-synaptic spread of pathology. To date, effective therapies for the treatment or prevention of AD are lacking, but understanding how synaptic degeneration occurs will be essential for the development of new interventions. Here, we highlight the mechanisms through which synapses degenerate in the AD brain, and discuss key questions that still need to be answered. We also cover the ways in which our understanding of the mechanisms of synaptic degeneration is leading to new therapeutic approaches for AD.
Synaptic degeneration is a prominent feature of Alzheimer disease (AD) both in humans and in preclinical models of the disease.
Evidence indicates that synaptic degeneration is the best neuropathological correlate of cognitive decline in AD; however, effective treatments to slow down or stop synaptic loss are lacking.
Amyloid-β (Aβ) and tau are the most well-studied contributors to synaptic degeneration in AD and, although most anti-Aβ therapies have so far failed in clinical trials, targeting these proteins earlier in the disease process might ameliorate neurodegeneration.
Microglia and astrocytes can drive synaptic degeneration in animal models of ageing and AD via ingestion of tagged synapses, contributing to cognitive decline.
Many clinical trials are now focusing on the interactions between immune responses and neurons in AD, as opposed to focusing only on the reduction of Aβ and tau levels.
New synaptic biomarkers are being developed with the aim of aiding the earlier diagnosis of AD and distinguishing between people who will stay cognitively healthy as they age and people who will develop AD.
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T.L.S.-J. is on the Scientific Advisory Board of Cognition Therapeutics and receives collaborative grant funding from two industry partners. None of these had any influence over the current paper. The other authors declare no competing interests.
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Nature Reviews Neurology thanks Monica di Luca, Erik Roberson and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
- APP/PS1 transgenic mice
Mice that express the human amyloid precursor protein (APP) gene with the Swedish mutation and presenilin gene with exon 9 deletion; both are genetic causes of early-onset AD.
- BV2 microglia
A mouse immortalized cell line developed to model microglia in vitro.
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Tzioras, M., McGeachan, R.I., Durrant, C.S. et al. Synaptic degeneration in Alzheimer disease. Nat Rev Neurol 19, 19–38 (2023). https://doi.org/10.1038/s41582-022-00749-z
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