Cerebrospinal fluid ubiquitin as a biomarker across neurodegenerative dementias: a systematic review and meta-analysis

Neurodegenerative dementias are a growing global health burden characterised by progressive cognitive decline and the pathological accumulation of misfolded proteins. Ubiquitin (Ub), a key mediator of proteostasis through the ubiquitin–proteasome system, has been proposed as a neurodegeneration biomarker. However, alterations in Ub across neurodegenerative dementias have not been quantitatively synthesised. A systematic review and meta-analysis were conducted per PRISMA 2020 (PROSPERO: CRD42024613738). Three databases were searched from inception to November 2024. The primary outcome was CSF ubiquitin; peripheral biomarker studies were secondary exploratory analyses only and were not pooled with CSF-based estimates. The ratio of means (RoM) with DerSimonian–Laird random-effects models was used as the primary approach. Thirteen case-control studies (n = 1,289) were included. CSF ubiquitin was elevated in Alzheimer’s disease (AD; RoM = 1.59; 95% CI 1.22–2.07; I² = 97.5%) and Creutzfeldt–Jakob disease (CJD; RoM = 6.74; 95% CI 3.20–14.20; I² = 92.1%). No significant elevation was observed in frontotemporal dementia (RoM = 1.01; p = 0.934) or vascular dementia (RoM = 1.16; p = 0.127). The mild cognitive impairment analysis (RoM = 1.19; p = 0.379) was based exclusively on peripheral biomarker studies and is not directly comparable with CSF-based analyses. Exploratory meta-regression suggested a negative association between patient age and CSF ubiquitin in AD (β = −0.0506; p < 0.001); however, this should be regarded as hypothesis-generating. Egger’s test indicated no significant publication bias (p = 0.735). Given the extreme heterogeneity observed for AD (I² = 97.5%) and the wide 95% prediction interval (0.72–3.26), the magnitude of ubiquitin elevation is likely to vary substantially across individual clinical settings, and the pooled estimate should not be over-interpreted as a precise, generalisable effect. CSF ubiquitin was elevated in AD and CJD, supporting an association between ubiquitin dysregulation and neurodegeneration. Findings for other conditions remain inconclusive. CSF ubiquitin may have potential as a complementary, non-specific biomarker of proteostatic dysfunction; however, further validation in larger, harmonised, biomarker-confirmed cohorts is required before its clinical value can be established. Because between-study heterogeneity for AD was extreme, the true magnitude of this association is likely to vary across clinical populations, and this uncertainty should be considered when interpreting the pooled estimate. PROSPERO, CRD42024613738. 1. CSF ubiquitin levels were elevated in Alzheimer’s disease and Creutzfeldt–Jakob disease relative to healthy controls in this systematic review and meta-analysis of 13 case-control studies. 2. Among the conditions examined, the largest pooled elevation in CSF ubiquitin was observed in Creutzfeldt-Jakob disease, followed by Alzheimer’s disease. Estimates for the remaining conditions were based on a small number of studies and should be interpreted with caution. 3. In Alzheimer’s disease, higher mean patient age was associated with lower CSF ubiquitin levels; this exploratory finding requires further validation. 4. CSF ubiquitin may serve as a complementary, non-specific biomarker of proteostatic dysfunction in neurodegenerative dementias; however, its disease specificity and clinical utility require further investigation in larger, methodologically harmonised cohorts.