BACKGROUND: Reliable data about the natural history of lung function decline in alpha-1 antitrypsin (AAT) deficient Pi*MZ heterozygotes is largely missing. We hypothesized that, in adults with a tobacco smoking history, lung function deteriorates faster in Pi*MZ compared to Pi*MM genotype. METHODS: We identified 1856 Pi*MM and 79 Pi*MZ participants with ≥20 pack-years tobacco smoking history from the SPIROMICS cohort by DNA sequencing and followed them over a median of 4.8 years, comparing radiographic and clinical characteristics between the two groups over time using regression models. RESULTS: Adjusted for age, sex, race, smoking pack-year history and smoking status, Pi*MZ participants had a lower baseline percent-predicted FEV1 (65.4% vs. 75.1%, difference 95% CI: -15.4%, -3.9%), more radiographic emphysema (<
-950HU%: 12.9% vs. 7.8%, difference 95% CI: 2.8%, 7.5%) and non-significantly lower lung density. In the longitudinal analysis, the FEV1 annual rate of decline was similar in both groups over the course of the study (-34.5mL/year vs. -34.6mL/year for Pi*MZ and Pi*MM, difference 95%CI: -16.9,17.1mL/year). There were no significant differences between Pi*MZ and Pi*MM individuals in the annualized change in lung density, emphysema, patient-reported outcomes, exacerbations or survival. The proportion with faster FEV1 decline (annual loss ≥40mL) was similar in Pi*MZ and Pi*MM groups. In both groups, faster FEV1 decline was associated with more air trapping and small airway disease at baseline. In Pi*MZ only, faster decline was associated with higher blood eosinophil counts (310 vs. 220 cells/µL, difference 95% CI: 30, 140 cells/µL). In the subgroup analysis limited to a small number of, currently smoking participants, no significant differences in longitudinal outcomes were found. CONCLUSION: Despite a lower FEV1 and more emphysema at enrollment, the longitudinal analysis did not demonstrate significantly greater lung function decline or lung density loss in Pi*MZ compared to Pi*MM participants with tobacco smoking history. Limited sample size and duration of longitudinal follow up constrain generalizability of our findings, thus prohibiting the conclusion that longitudinal trajectories did not differ between these groups. However, our results may suggest that earlier life events could be responsible for more extensive lung disease at enrollment in Pi*MZ compared to Pi*MM tobacco-exposed individuals.