Abstract
Parkinson's disease (PD) is a common neurodegenerative disorder caused by progressive loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies. While PD is most recognized by its motor symptoms (resting tremor, rigidity, bradykinesia, and postural instability), cognitive decline (CD) may become apparent as PD progresses, leading to Parkinson's disease dementia (PDD). Type 2 diabetes mellitus (T2DM) and insulin resistance (IR) are risk factors for dementia, especially Alzheimer's disease; however, their influence on dementia in PD is underexplored. Therefore, we sought to determine the effect of T2DM and IR on dementia in PD. A systematic search of articles from 2005 to March 2025 was undertaken using Embase, PubMed, Scopus, Web of Science, and citation searching. Case-control, cross-sectional, longitudinal, and non-human population studies assessing cognitive outcomes in individuals with PD, with and without T2DM and IR, were included (PROSPERO registration number CRD420251013367). In total, 27 studies met the inclusion criteria, with clinical sample sizes ranging from 23 to 544,162 participants. Among the 23 clinical studies, 15 identified T2DM as a contributor to cognitive decline (CD) in PD, and 4 specifically examined insulin resistance (IR). Elevated HbA1c was consistently associated with poorer cognitive performance and increased risk of Parkinson's disease dementia (PDD); HbA1c ≥ 7% independently predicted cognitive impairment (OR = 4.25, 95% CI: 1.59-11.34). Vascular and inflammatory markers, including elevated LDL-C, fibrinogen, and hs-CRP, further exacerbated CD. MoCA and MMSE scores were the most common cognitive measures, consistently showing worse outcomes in PD patients with T2DM. Preclinical studies supported these associations, showing that high-fat-diet-induced T2DM and IR aggravated dopaminergic neuronal loss by 38-45%, increased α-synuclein by 35%, and heightened microglial activation, providing mechanistic evidence for the observed clinical associations. This systematic review, the first to examine the impact of T2DM and IRs on the occurrence and advancement of CD in PD patients, demonstrates a possible association between the two. However, these results demonstrate the need for larger sample sizes and the inclusion of additional clinical variables, such as HbA1c levels and pharmacological interventions, providing further information about the link between metabolic dysfunction and CD in PD. To further strengthen this link, longitudinal studies with systematic follow-ups are essential to establish causal links and avoid misdiagnosis in clinical practice.