When bad turns good: a systematic review on cholesterol and LDL in longitudinal patient cohorts with Parkinson’s disease

BACKGROUND: While the aetiology of Parkinson's disease (PD) involves genetic and environmental factors, emerging evidence has suggested a surprising link between lipid metabolism - particularly serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) - and the pathogenesis of PD. Cholesterol plays a vital role in neuronal membrane integrity, myelination, and synaptic function. However, its peripheral concentration and regulatory mechanisms in the central nervous system (CNS), remain incompletely understood in the context of PD. OBJECTIVE: This review aims to systematically examine the current literature on the relationship between TC and LDL-C with the risk and progression of PD in longitudinal patient cohorts. METHODS: A systematic literature search was conducted using PubMed with the keywords "Parkinson's disease" AND "cholesterol" and "Parkinson's disease" AND "LDL." Inclusion criteria encompassed English-language longitudinal human studies published before October 2024, with data on cholesterol levels in relation to PD incidence or progression. Fourteen studies met the eligibility criteria. RESULTS: Twelve of the 14 included studies reported an inverse association between lower serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels and increased risk for PD onset as well as faster disease progression. Notably, this pattern was not uniform across all subgroups: age, sex, BMI, and statin use modulated the strength and direction of associations. CONCLUSION: Despite some heterogeneity across studies, there is growing evidence that lower TC and LDL-C may be associated with a higher risk and more rapid progression of PD. Future research should focus on mechanistic studies and stratified analyses to clarify whether and how cholesterol modulation could contribute to neuroprotective strategies in PD.