A proposed cholinergic phenotype of Parkinson’s disease: candidate clinical, biofluid, and imaging markers

Objective Various non-motor symptom (NMS)-dominant clinical subtypes are recognised in Parkinson’s disease (PD), and a cognitive dysfunction-dominant “cholinergic subtype” has also been proposed. Cognitive impairment of varying degrees occurs in the prodromal phase of PD and is partly related to dysfunction of central cholinergic pathways, which can contribute to varying clinical phenotypes. In a subset of patients with PD, a cognitive dysfunction-dominant phenotype identified using clinical tests can be recognised and has been termed the “cholinergic” subtype. In this narrative review of the proposed cholinergic subtype, we provide details of clinical, biofluid, and imaging markers that may help further define and refine this non-motor subtype of PD, although the majority of biomarkers remain exploratory. Methods We reviewed the available English-language literature published between 2000 and 2025 that was identified through Embase, PubMed, and Web of Science. Results Based on the cross-sectional and longitudinal data from the Cambridgeshire Parkinson’s Incidence from GP to Neurologist (CamPaIGN) study, we identified two clinical tests—copying an intersecting pentagon and assessing semantic fluency—as the clinical anchors and constructed a clinical phenotype of late-onset PD characterised by hyposmia, constipation, low body weight, high frailty, gait dysfunction, and other cognitive and neuropsychiatric deficits as associated features. Potential biomarkers, such as plasma phosphorylated tau 217 (p-tau217) and imaging of the nucleus basalis of Meynert (NBM), remain exploratory and need to be studied in well-enriched and well-characterised cholinergic PD cohorts. Conclusion This narrative review describes a proposed clinical phenotype of the cholinergic subtype of PD, which needs to be validated, and highlights that the majority of biomarkers remain exploratory.