Lewy body dementia (LBD) involves Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB). LBD is one of the most devastating and rapidly rising neurodegenerative diseases worldwide. Pathologic α-synuclein (αSyn) is the hallmark of LBD. Environmental pollutants like particulate matter (PM2.5) may initiate αSyn misfolding and spread, yet large-scale epidemiological evidence differentiating LBD from Parkinson’s disease subtypes is lacking.
PM2.5 exposure has been recognized as a significant environmental risk factor for dementia in general. But its main role in accelerating or triggering LBD was not identified clearly. This research examines how chronic PM2.5 exposure may influence the pathological LBD progression compared to PD without dementia. A study published in Science aimed to systematically examine these associations to provide critical insights into the environmental pollutants of LBD. This highlights insights into targeted treatments.
The multimodal study integrated large-scale epidemiological datasets with animal models, cellular experiments, and patient-derived biospecimens. Chronic PM2.5 exposure was linked to clinical outcomes of LBD. This experiment determined the αSyn propagation and misfolding, whereas statistical analysis quantified this association and verified the inference in these databases.
Researchers analyzed the electronic health records of more than 56million Medicare beneficiaries. Results showed that a higher PM2.5 exposure was significantly linked to increased risk of first hospitalizations of α-synucleinopathies. Importantly, this association was stronger in LBD patients (PDD and DLB) compared to PD patients without dementia. This suggests a preferential vulnerability or unique pathogenic mechanism underlying LBD.
Experimental studies in wild-type mice revealed that exposure to PM2.5 induced widespread αSyn pathology in both peripheral organs (lungs and gut) and the central nervous system. These changes were accompanied by tau co-pathology, brain atrophy, and cognitive impairments. Genetic ablation of αSyn protected against these effects and establishes that αSyn is a main factor of PM2.5-induced neurotoxicity.
The molecular examination revealed that PM2.5 from different countries, such as Europe, the United States, and China, caused conformational alterations in αSyn preformed fibrils (PFFs), resulting in a unique strain known as PM-PFF. This strain showed LBD characteristics, including increased neurotoxicity, resistance to degradation, greater propagation, and enhanced aggregation compared to traditional PFFs. When introduced into humanized αSyn mice, PM-PFF specifically induced cognitive impairments rather than motor impairments. Transcriptomic analysis further confirmed that both PM-PFF generation and exposure to chronic PM2.5 revealed gene expression patterns closely resembling LBD but not observed in PD without dementia. This indicated the particular pathogenic pathway for LBD.
In conclusion, this study demonstrated that chronic PM2.5 exposure contributes to LBD by inducing neurotoxicity through strain αSyn. This research identified a novel pathogenic strain called PM-PFF, which was generated by PM2.5. This PM-PFF showed neurotoxicity, enhanced aggregation, and stability similar to αSyn strains in human LBD. In humanized mice, PM-PFF triggered cognitive defects. Overall, these findings reveal an environmental driver of LBD, emphasize αSyn’s role, and also highlight the PM-PFF as a promising therapeutic target.
References: Zhang X, Liu H, Wu X, et al. Lewy body dementia promotion by air pollutants. Science. 2025;389(6764):eadu4132. doi:10.1126/science.adu4132
