Causal evidence linking ambient air pollution and pulmonary dysfunction to Alzheimer’s disease pathology along the lung-brain axis

Air pollution is a well-known risk factor for both pulmonary disorders and neurodegenerative diseases, including Alzheimer’s disease (AD) and related dementia, yet the causal pathways along the lung-brain axis linking airborne exposures, pulmonary disorders, and AD pathology remain poorly understood, hampering the development of effective preventions and interventions for typical sporadic AD. Mendelian randomization (MR) analyses - including univariable, bidirectional, and multivariable MR (MVMR) with formal two-step mediation analysis - leveraging summary statistics from 28 GWAS were used to assess the causal networks along the lung-brain axis. These MR-based analyses captured reciprocal molecular associations, tested via bidirectional MR, among air pollutants (PM2.5, PM10, NO2, NOx), pulmonary disorders, inflammatory and blood-brain barrier (BBB) injury markers (IL-6, IL-17A, MMP-9, VEGF, GFAP), and lowered soluble LRP1 that mediates clearance of pathological amyloid-β (Aβ). MR-based analyses evaluate how air pollution causally increased the risk of inflammation and pulmonary diseases (asthma, emphysema/COPD, pulmonary fibrosis, and lung cancer), lung function impairment (FEV1, FVC, FEV1/FVC), and elevated AD risk. In turn, pulmonary disorders can lower expression of soluble LRP1. Bidirectional MR-based causal analyses indicate that air pollution-driven pulmonary diseases (e.g. emphysema/COPD ) causally lowered expression of soluble LRP1, and reduced LRP1 was reciprocally associated with elevated inflammatory markers (IL-6→LRP1, p = 1.13 × 10 − 15 ) and vascular/BBB injury markers (MMP-9→LRP1, p = 9.96 × 10 − 14 ), forming an interconnected network along the lung-brain axis. Formal two-step mediation analysis further indicated that MMP-9 significantly mediates part of the causal pathway from emphysema to reduced soluble LRP1. Reciprocally, reduced LRP1 aggravated inflammation (IL-6, p = 6.73 × 10 − 6 ) and BBB injury (MMP-9, p = 7.51 × 10 − 8 ), which in turn, caused/aggravated emphysema/COPD (or pulmonary fibrosis) and further reduced LRP1 levels thereby forming an air pollution-triggered/reinforced vicious cycle of pulmonary diseases and BBB disruption and reduced LRP1, a central molecular node in Aβ-induced AD pathology. Additionally, air pollutants were associated with reduced FEV1 and elevated AD risk. Moreover, FEV1 reduction, MMP-9 elevation, and LRP1 reduction formed an interconnected network of associations along the lung-brain axis, consistent with a potential pathway linking pulmonary dysfunction, systemic inflammation, and BBB-related receptor dysregulation to AD risk. MR-based causal analysis of the lung-brain axis indicated chronic air pollution is associated with pulmonary disorders, neuroinflammation, vascular injury/BBB leakage, and dysregulation of LRP1. Moreover, causal analysis indicated dysregulated soluble LRP1 and chronic air pollution can disrupt MMP-9 and BBB integrity, and aggravate neuroinflammation via dysregulation of IL-6/IL-17A, and in turn, can cause pulmonary disorders thereby forming a vicious cycle along the lung-brain axis further reinforced by chronic exposure to air pollutants. The newly evaluated causal network provides opportunities for developing novel prevention and intervention measures for AD which currently has neither a cure nor treatments to effectively halt disease progression broadly.