The considerable public health and care burden of dementia is well documented.(1) While the 22 age-standardised prevalence and incidence of dementia may be declining,(2-4) because of 23 population ageing, the absolute number of people with dementia worldwide is projected to triple combined the terms dementia OR alzheimer* AND "forced expiratory volume" OR "expiratory 40 volume" OR FEV OR "forced vital capacity" OR "vital capacity" OR FVC OR "peak expiratory 41 flow" OR "peak flow" OR PEF OR ((pulmonary OR lung OR respiratory) AND function) OR 42 asthma OR COPD OR "respiratory disease" or COAD or "airways disease" OR "lung disease" 43 OR pneumonia AND longitudinal OR prospective OR cohort. We also scrutinised the reference 44 sections of retrieved papers and searched our own files. TCR screened the search results using 45
Covidence (https://www.covidence.org/) and extracted data from included articles. The review 46 We identified eleven prospective studies in which investigators had explored the association 139 between respiratory disease and later dementia ( Table 2) . Mean age at which disease was 140 ascertained varied from 50.6 to 82.9 years but was over 65 years in six of the 11 studies. the study-specific estimates were heterogeneous, they all favoured risk factor status. Excluding a 150 study which investigated the association between atopic illnesses(29) (asthma, eczema, or rhinitis 151 -only one of which is likely to have a substantial effect on pulmonary function) and dementia 152 reduced the magnitude of the effect observed (1.28, 1.03, 1.60) as well as heterogeneity 153
(I 2 =78.2%) but did not alter our conclusion. individual studies. Face-to-face assessment by a clinician combined with brain imaging is a robust 201 method to ascertain incident dementia cases, but is resource-intensive and differential 202 participation in the screening process by different groups can introduce bias. (36) Linkage to 203 electronic medical records has been shown to identify only part of a known cohort of people 204 with dementia, particularly if multiple sources are used, although mild and undiagnosed cases are 205 not captured. (14, 37) Death certification has been criticised as a methodology for identifying 206 dementia cases but reporting of dementia on death certificates seems to be becoming 207 increasingly comprehensive: for instance, a recent investigation found that, in a memory clinic The point in time at which risk factors are measured seems to be important for their ability, or 286 lack of it, to predict later dementia or cognitive decline: There was some evidence of be an age-287 dependent association with stronger links seen for midlife than old age respiratory function and 288 respiratory disease. Further research is needed to clarify whether this reflects the longer exposure 289 period among younger individuals or a critical period in which poor respiratory function is 290 particularly damaging. 291 292
Pulmonary function alone is likely to have relatively low sensitivity and specificity as a predictor 294 of cognitive decline and dementia and therefore may not be a useful predictor of dementia in the 295 absence of a range of other predictive factors. Further research is needed to examine this. One 296 way forward is examination of pulmonary function and pathology as a contributor to risk factor 297 algorithms -such as the modified CAIDE risk score(54) -given the reported associations 298 between pulmonary function and dementia which remained after adjustment for cardiovascular 299 risk factors. To date, there is some evidence to suggest that such risk scores predict cognitive 300 function(89) and decline, (90) although there is less evidence for prediction of dementia. ( 
Therefore there is, as yet, no risk score including lung function which can be used in clinical 302
In addition to risk stratification and early identification of risk groups, further work is also 305 required to confirm or refute the importance of pulmonary function as a risk factor amenable to 306 modification and thus a target for prevention. Extended follow up of studies where the initial 307 focus was treating respiratory illness might be a pragmatic place to start. It would be difficult to 308 conduct a powered randomised, controlled trial on this topic given the long follow-up from mid-309 life into later life needed and the large sample size required to obtain a sufficient number of 310 incident dementia cases. Therefore, in order to reduce confounding and reverse causation bias, 311
Mendelian randomization studies with genetic variants related to lung function as an instrument 312 would provide one avenue to pursue. These results were presented in preliminary form as a poster at the AAIC 2017.
This work was unfunded. The authors have no conflicts of interest to disclose.
Newman 