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•What is the primary question addressed by this study?Does neuropsychiatric symptoms and depression symptoms, Alzheimer disease (AD) biomarkers (cerebrospinal fluid or Positron Emission Tomography imaging) increase the risk of cognitive impairment among cognitively normal older adults?•What is the main finding of this study?Neuropsychiatric symptoms, not depression symptoms, increase the risk of cognitive impairment independently of AD biomarkers. There were no statistically significant interactions between neuropsychiatric symptoms and AD biomarkers.•What is the meaning of the finding?Change in neuropsychiatric symptoms is a significant risk factor for incident cognitive impairment among healthy, community-residing older adults.

Alzheimer’s disease (AD) pathology accumulates for decades before the onset of cognitive decline. Cognitively normal individuals with biomarker evidence of AD brain pathology (i.e. biomarker + or preclinical AD) can be differentiated from individuals without AD brain pathology based on naturalistic driving data, such as hard acceleration or braking and speeding, measured using in-vehicle dataloggers. Older adults are at increased risk of injury and death from motor vehicle crashes and driving cessation is also linked to negative health outcomes. Identifying potentially modifiable risk factors that increase driving risk may prolong safe driving in old age. Sleep apnea is associated with adverse driving behaviors across the age span. In this study, we hypothesized that high-risk driving behaviors would be associated with increased sleep apnea severity and AD pathology. We found that higher sleep apnea severity measured by a home sleep apnea test was associated with a higher incidence of adverse driving behaviors even after controlling for multiple confounders (β= 0.24 ± 0.09, p< 0.01). This association was independent of AD biomarker positivity (i.e. increased t-tau/Aβ 42ratio). Increasing age was associated with a higher likelihood of high-risk driving behaviors in individuals with AD brain pathology (β= 0.12 ± 0.04, p< 0.01), but a lower likelihood in individuals without AD brain pathology (β= −0.06 ± 0.03, p< 0.05). These findings suggest that adverse driving behaviors linked to a higher rate of traffic crashes in older adults are associated with sleep apnea severity and AD pathology even in cognitively unimpaired individuals. Further studies are needed to determine if treatment of sleep apnea decreases high-risk driving behaviors and therefore motor vehicle crashes.

The lack of reliable molecular markers for normal differentiated epithelial cells limits understanding of human gastric carcinogenesis. Recognized precursor lesions for gastric adenocarcinoma are intestinal metaplasia and spasmolytic polypeptide expressing metaplasia (SPEM), defined here by ectopic CDX2 and TFF2 expression, respectively. In mice, expression of the bHLH transcription factor MIST1, normally restricted to mature chief cells, is down-regulated as chief cells undergo experimentally induced metaplasia. Here, we show MIST1 expression is also a specific marker of human chief cells. SPEM, with and without MIST1, is present in human lesions and, akin to murine data, likely represents transitional (TFF2+/MIST1+= “hybrid”-SPEM) and established (TFF2+/MIST1−= SPEM) stages. Co-visualization of MIST1 and CDX2 shows similar progressive loss of MIST1 with a transitional, CDX2+/MIST1−hybrid-intestinal metaplasia stage. Interinstitutional analysis and comparison of findings in tissue microarrays, resection specimens, and biopsies (n400 samples), comprising the entire spectrum of recognized stages of gastric carcinogenesis, confirm MIST1 expression is restricted to the chief cell compartment in normal oxyntic mucosa, rare in established metaplastic lesions, and lost in intraepithelial neoplasia/dysplasia and carcinoma of various types with the exception of rare chief cell carcinoma (∼1%). Our findings implicate MIST1 as a reliable marker of mature, healthy chief cells, and we provide the first evidence that metaplasia in humans arises at least in part from the chief cell lineage.