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  • Review Article
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Synapse vulnerability and resilience across the clinical spectrum of dementias

Nature Reviews Neurology volume 21, pages 353–369 (2025)Cite this article

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Abstract

Preservation of synapses is crucial for healthy cognitive ageing, and synapse loss is one of the closest anatomical correlates of cognitive decline in Alzheimer disease, dementia with Lewy bodies and frontotemporal dementia. In these conditions, some synapses seem particularly vulnerable to degeneration whereas others are resilient and remain preserved. Evidence has highlighted that vulnerability and resilience are intrinsically distinct phenomena linked to specific brain structural and/or functional signatures, yet the key features of vulnerable and resilient synapses in the dementias remain incompletely understood. Defining the characteristics of vulnerable and resilient synapses in each form of dementia could offer novel insight into the mechanisms of synapse preservation and of synapse loss that underlies cognitive decline, thereby facilitating the discovery of targeted biomarkers and disease-modifying therapies. In this Review, we consider the concepts of synapse vulnerability and resilience, and provide an overview of our current understanding of the associations between synaptic protein changes, neuropathology and cognitive decline. We also consider how understanding of the underlying mechanisms could identify novel strategies to mitigate the cognitive dysfunction associated with dementias.

Key points

  • Synaptic pathology is a robust hallmark of dementia, and selective synapse degeneration could be the anatomical basis of varying clinical presentations and disease severities of dementia disorders.

  • Vulnerable synapses are preferentially affected in dementia, whereas resilient synapses are comparatively spared; understanding the mechanisms of selective synapse degeneration could provide clinically more relevant outcomes than current neuropathology-centred approaches.

  • Studies of temporal synapse changes are now possible with biofluid analysis and brain imaging; disease- and stage-specific synaptic signatures could reveal novel biomarkers for dementia, and their study in brain tissue may propose tailored synapse-protective targets for timely interventions.

  • Neuroinflammation, which involves central (glial cells) and peripheral (innate immunity, adaptive immunity) elements, has a key role in synapse pathology across dementias, and its modulation with central and/or peripheral treatment approaches holds promise for mitigating dementia symptoms.

  • Convergence of multiple oligomeric proteins and neuroinflammatory elements at synapses is a shared feature of dementias; dissecting their intricate crosstalk and combined cognitive effects could unravel critical therapeutic targets to block potentially deleterious interactions at synapses.

  • Synapse pathology in rapidly progressive dementias remains under-studied but could reveal novel mechanisms of fulminant synapse degeneration and/or synapse recovery that could be exploited therapeutically in all dementias.

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Fig. 1: Cognitive, synaptic and neuropathological vulnerability in dementia.
Fig. 2: Mechanisms and processes associated with synaptic vulnerability and resilience in dementia.

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Authors and Affiliations

  1. Neurology Department, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Raquel N. Taddei

  2. UK Dementia Research Institute at UCL, Institute of Neurology, University College London, London, UK

    Raquel N. Taddei & Karen E. Duff

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R.N.T. researched data for the article and wrote the article. Both authors made substantial contributions to discussion of the content and reviewed and edited the manuscript before submission.

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Review criteria

We searched PubMed and the Cochrane Library for studies published in English up to August 2024, using the search terms “Alzheimer disease”, “AD”, “dementia with Lewy bodies”, ”DLB”, ”frontotemporal dementia”, “FTD”, “cognitive decline”, “mild cognitive impairment”, “dementia severity”, “autoimmune encephalitis”, “prion disease”, “NMDA-R”, “CJD”, “synapse dysfunction”, “synapse loss”, “synapse biomarkers”, “plasma biomarkers”, “proteomic studies”, “resilience”, “resistance”, “vulnerability” and “locoregional”. Meta-analyses, systematic reviews and observational studies were selected from the results. In addition, we manually searched the references of selected meta-analyses, systematic reviews, observational studies, internet articles from international institutions and hospitals, and practice guidelines. Emphasis was given to meta-analyses and observational studies published in the past 5 years. The studies included focused on human-derived data obtained from biofluids and/or brain tissue samples unless otherwise indicated. The articles selected were agreed upon by the authors.

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Taddei, R.N., Duff, K.E. Synapse vulnerability and resilience across the clinical spectrum of dementias. Nat Rev Neurol 21, 353–369 (2025). https://doi.org/10.1038/s41582-025-01094-7

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