Mediating molecular mechanisms between Air pollution and Cognitive decline in midlife in the AirWave occupational cohort (MACAW)

Dementia is defined as cognitive decline sufficient to interfere with independence in everyday activities. The number of people living with dementia will increase over the coming decades, putting enormous strain on health care resources and families. Since current treatment options are limited, it is vital to understand the modifiable risk factors that contribute to cognitive decline. Risk factors present in midlife are important contributors to dementia risk and may be detected as subtle declines in cognitive function. Consistent observational and experimental evidence now links air pollution to cognitive decline and dementia risk. Air pollution is therefore an important contributor to dementia; a burden which will be greater in occupations involving considerable periods working outdoors, such as our frontline police officers. To improve the evidence in this area and inform successful public health interventions, we will examine the links between long-term air pollution exposure and cognitive decline, within the Airwave Health Monitoring Study (AIRWAVE), a large occupational cohort of employees of the police forces of Great Britain. We will apply the state-of-the-art Community Multiscale Air Quality urban model to provide high resolution estimates of long-term ambient outdoor exposure to key air pollutants (NO2, O3, PM2.5, PM10) and link these to performance across five cognitive domains (working memory, episodic memory, processing speed, attention, and fluid intelligence) assessed with standardized computer testing. In one of the largest studies to date, we will test cross-sectional associations in over 30,000 participants and longitudinal associations in over 14,000 participants with repeat cognitive assessments. We will use information on job role, time activity patterns and place of work to provide time-weighted ambient outdoor air pollution estimates for more personalized assessments. One of the key proposed mechanisms underlying this potential association between air pollution and cognition is thought to occur through the capacity of air pollution to cause inflammation in the lung, which spreads to the circulation, ultimately impacting on the brain vasculature to cause neuroinflammation. This is often referred to as the lung-to-brain axis. A full understanding of these mechanisms, particularly in human studies, is necessary to provide biological plausibility for the observed associations. We will therefore apply the latest generation of molecular profiling techniques to assess metabolic and inflammatory changes, including over 1,000 metabolites and 350 inflammatory proteins, among subsets of up to 6,000 participants. This will be one of the largest and most comprehensive studies of this type with the aim of uncovering the molecular pathways through which air pollution impacts brain health. This project aims to make an outstanding contribution to the field, building on significant previous research investments that have provided an unparalleled resource of existing data to address several remaining research gaps. We will exploit a large, nationwide cohort with sufficient contrast in exposure that will provide high quality evidence. As a working-age cohort AIRWAVE is uniquely placed to understand how air pollution impacts on the brain during midlife, the working age years, when cardiovascular risk factors for dementia begin to appear. Uniquely, the availability of state-of-the-art molecular profiling in AIRWAVE allows appraisal of the role of potential mechanistic pathways, key to inferring the causal effects necessary to guide the development of focused public and occupational health policy.