Loneliness Independently Associated With Incident Parkinson Disease


Loneliness was associated with a higher risk of subsequent PD after accounting for basic demographic variables and other risk, protective, prodromal, or confounding factors.

Antonio Terracciano, PhD

Using a large population-based sample of nearly 500,000 individuals from the UK Biobank, findings showed that loneliness was associated with risk of incident Parkinson disease (PD) across demographic groups and was independent of depression and other prominent risk factors and genetic risk.1

Published in JAMA Neurology, the prospective cohort study included 491,603 participants aged 38 to 73 years with loneliness data and without a diagnosis of PD at baseline, first assessed from 2006 to 2010. During the 15-year follow-up, 2822 patients developed PD, with increased risk observed in those who reported being lonely (HR, 1.37; 95% CI, 1.25-1.51). To the study authors knowledge, this was the first trial to examine the association between loneliness and risk of subsequent PD.

Led by Antonio Terracciano, PhD, professor in the department of geriatrics at Florida State University, the association between loneliness and PD was attenuated by 13.1% with certain health variables such as body mass index, diabetes, hypertension, MI, and stroke (HR, 1.32; 95% CI, 1.20-1.46). The association continued to be diminished 24.1% with the mental health variables (depression, ever seen a psychiatrist; HR, 1.28; 95% CI, 1.16-1.42) and by 33.8% in the fully adjusted model (HR, 1.25; 95% CI, 1.12-1.39). Even after full adjustment, the association between loneliness and PD remained.

Terracciano et al provided notes on the plausible and non-mutually exclusive interpretations of the observed association between loneliness and PD. They hypothesized that the association could be due to unaccounted for confounding factors or residual confounding due to imprecisely measured covariates. Another possible interpretation was that PD neuropathology may be associated with a rise of loneliness in the preclinical or prodromal stages of the disease, implicating potential reverse causality.


"The most probable (and parsimonious) interpretation is that loneliness is a risk factor for PD through various pathways," the study authors wrote.
"This study tested a broad range of covariates that could be potential mediators. Individuals who experience loneliness tend to engage in detrimental behaviors, such as physical inactivity, but this pathway seems unlikely to play a major role given that the association between loneliness and PD was unchanged with the inclusion of 2 prominent health behaviors. Loneliness seems more likely to be associated with increased risk of PD through metabolic, inflammatory, and neuroendocrine pathways, as the association was attenuated by 13.1% after accounting for chronic conditions, such as diabetes.”

Top Takeaways

  1. Loneliness is a significant independent risk factor for developing Parkinson's disease (PD). This association persists even after accounting for various potential confounding factors such as social isolation, genetic risk, smoking, physical activity, and mental health conditions.
  2. The link between loneliness and PD is not specific to certain demographics or genetic predispositions; it applies across age groups, genders, and genetic risk scores. This suggests that loneliness can influence PD risk in a broad population.
  3. While the exact mechanisms behind the association between loneliness and PD are not fully understood, it is likely related to multiple pathways, including metabolic, inflammatory, and neuroendocrine factors. Addressing loneliness through psychosocial interventions may not only reduce the risk of PD but also improve the overall quality of life, particularly in individuals with PD.

In follow-up analyses, there was no significant interaction between loneliness and sex (overall: HR, 0.98 [95% CI, 0.81-1.18]; female: HR, 1.39 [95% CI, 1.21-1.59]; male: HR, 1.36 [95% CI, 1.20-1.55]) loneliness and age (HR, 0.99; 95% CI, 0.98-1.01) or loneliness and PD polygenic risk score (HR, 0.93; 95% CI, 0.85-1.02). In analyses stratified by follow-up time, loneliness was not associated with incident PD during the first 5 years after baseline (388 of 8780 [4.4%] had PD; HR, 1.15; 95% CI, 0.91-1.45) but it was the during the subsequent 5 to 15 years of follow-up (2341 of 481,499 [0.5%] had PD; HR, 1.32; 95% CI, 1.19-1.46).

The study authors wrote that there may be other pathways that contribute to the risk of PD associated with loneliness, such as microglia-mediated neuroinflammation. "It would be fruitful to examine whether loneliness is associated with markers of neuropathology, such as α-synuclein and neurofilament light chain," they added.1 "Of note, loneliness could be directly associated with the risk of neuropathology but could also be associated with increased risk of PD by eroding resilience against neurodegenerative processes that contribute to the development of PD."

When comparing those with and without PD, those who were diagnosed were older; more likely to be male; to be former smokers; to have higher BMI; to have a higher PD polygenic risk score; to have a diagnosis of diabetes, hypertension MI, or stroke; and to have seen a psychiatrist for anxiety or depression compared with individuals who were not diagnosed with PD by the censoring date (n = 488, 781). Additionally, this group was less likely to have a college degree or to be current smokers.

1. Terracciano A, Luchetti M, Karakose S, et al. Loneliness and risk of Parkinson disease. JAMA Netw Open. Published online October 2, 2023. doi:10.1001/jamaneurol.2023.3382
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