AbstractBackgroundWe previously published data showing that olfactory test performance changes on the University of Pennsylvania Smell Identification Test (UPSIT) following an intranasal ‘challenge’ with the anticholinergic atropine (an ‘Olfactory Stress Test’, (OST)) were significantly correlated with measures of cognition, hippocampal volume and APOE genotype in a small (n = 56) convenience sample of elders. The results suggested that this procedure might unmask incipient Alzheimer’s disease.Here, we present data from two new studies, including an attempted replication of the above findings.MethodIn study one, the full 40 item UPSIT was administered to the left nostril to 56 individuals. Data from this study were used to determine the relationship between scores on the first 20 items (booklets 1+2) with those on the second 20 items (booklets 3+4) of the UPSIT.The second study comprised 296 elders (aged 65 or older) who underwent olfactory testing, including the OST, assessment of cognition with the Audio Recorded Cognitive Screen, APOE genotyping, and hippocampal volume (in a subsample). In this study the first 20 items of UPSIT were always administered before and the second 20 items always after intranasal atropine and regression analyses were conducted to investigate for any association of the adjusted (see below) UPSIT change score following atropine with memory or hippocampal volume.ResultIn study 1, the mean score on the first 20 items of the UPSIT was 1.53 (SD 2.07) greater than the second 20 items (t = 5.55, p<.001). An appropriate adjustment factor derived from these data were used to scale the study 2 raw post atropine scores (from UPSIT booklets 3+4) into equivalent scores on booklets 1+2. These post‐atropine adjusted scores were then used in the calculation of the change in (adjusted) UPSIT following atropine.In a series of stepwise linear regression analyses, after controlling for age, gender and education, the adjusted UPSIT change score did not predict any additional variance in memory scores or hippocampal volume.ConclusionIn this larger study, we failed to replicate our earlier findings. The ’Olfactory Stress Test’ is unlikely to aid in the early detection of AD.