BACKGROUND: Ambient air pollution is a pervasive and ubiquitous hazard, which has been linked to premature morbidity and a growing number of morbidity endpoints. Air pollution may be linked to neurodegeneration, and via this or other pathways, to neurodegenerative diseases. Emerging evidence suggests that air pollution may contribute to neurodegenerative diseases such as dementia, Parkinson's Disease (PD), Multiple Sclerosis (MS) and Motor Neuron Diseases (MND), although this evidence remains inconsistent and very limited for MS and MND. In addition, this evidence base is rapidly emerging and would benefit from a wide and critical synthesis, including a better understanding of heterogeneity.

OBJECTIVES: In this paper, we present a protocol for a systematic review and meta-analysis and specify our methods a priori. The main aim of the planned systematic review is to answer the question of whether long-term exposure (>1 year) to ambient (outdoor) air pollution (exposure, compared to lower exposure) increases the risk of adult (population) incidence of neurodegenerative diseases (outcomes) in epidemiological observational studies (study design). Another aim is to meta-analyze the associations between long-term exposure to ambient air pollutants and the risk of the selected outcomes and assess the shape of exposure-response functions. To set the stage for the proposed work, we also overview the existing epidemiological evidence in this protocol, but do not critically evaluate it, as these results will be fully presented in the planned systematic review.

SEARCH AND STUDY ELIGIBILITY: We will search the electronic databases Medline (via Ovid), Embase (via Ovid), Cochrane Library, Cinahl (via Ebscohost), Global Health (via Ebscohost), PsycINFO (via Ebscohost), Scopus, Web of Science (Core Collection), from inception to October 2022. Eligible studies must contain primary research investigating the link between 1-year + exposure to any outdoor air pollutant, from any source, and dementia, PD, MS, and MND, or dementia subtypes: Alzheimer's Disease, vascular dementia, and mixed dementia. The search strategy and eligibility criteria are pre-determined and described in full in this protocol.

STUDY APPRAISAL AND SYNTHESIS METHODS: Articles will be stored and screened using Rayyan QCRI. Title and abstract screening, full text review, data extraction, risk of bias assessment and data preparation for statistical analysis will be conducted independently by two reviewers using pre-defined forms and criteria, described in this protocol. All these steps will also be piloted and the forms and/or methods adapted if issues arise. Meta-analysis and assessment of the shape of the exposure-response functions will be conducted if four independent exposure-outcomes pairs are available, and the remainder of results will be synthesized in the forms of tables and via a narrative summary. Certainty in the body of evidence will be assessed using the OHAT approach. This protocol describes the planned analysis and synthesis a priori and serves to increase transparency and impact of this systematic review and meta-analysis.