8

AD disorders, such as schizophrenia(4). However, little is known about the influence of vitamin D on psychotic symptoms among patients with AD/ADRD. The article by Wang et al.(5) makes an important contribution to growing knowledge regarding the association of vitamin D with onset of late-life psychological symptoms and specifically addresses a possible role of vitamin D in mitigating psychosis in AD. The study participants were well-characterized members of an AD Research Center cohort, and data from knowledgeable informants was used to classify psychotic symptoms on the Behavioral Rating Scale (BRS). The authors used a data-driven approach to identify medications that differed among AD with psychosis (AD+P) vs. AD without psychosis (AD-P), and they found that only vitamin D showed a significantly higher frequency of use in AD-P vs. AD+P. Furthermore, given that the prevalence of NPS increases with duration of illness (approaching 100% at end-stage)(1), applying survival methods to address time-to-AD+P – rather than focusing only on presence (yes/no) of psychosis in AD – was another advantage in the study design. Finally, using gene expression data and enrichment approaches, the authors identified genes and transcriptional targets related to vitamin D, including its vitamin D receptor (VDR), that may inform possible mechanisms. While vitamin D was associated with delay in time-to-onset of psychosis, there was no relation of vitamin D use to rate of cognitive decline – which might suggest that any effects of vitamin D on psychosis may be independent of pathways related to cognitive decline. Current treatment approaches for AD+P rely frequently on antipsychotic treatments that were developed for other disorders, such as schizophrenia. However, efficacy is questionable in many patients and side effects are common, especially for older adults. Thus, the study by Wang and colleagues addresses a critical need in AD therapeutics to identify novel medications for AD+P. While still preliminary, these results appear to provide a promising lead for the development of drugs that can address psychosis in AD. Furthermore, this research may point toward AD+P treatment options that may be more focused and specific to the biology of AD, rather than broadly addressed at an array of neurotransmitter systems(6). Although speculative at this stage, one can imagine future approaches that involve use of vitamin D combined with other therapeutics, such as memantine (also identified as related to AD psychosis in this study), that may mitigate symptoms or slow progression of impairments(7). However, this would require rigorous investigation in future clinical trials. The pharmacogenomics findings contribute to the literature on potential molecular mechanisms of vitamin D in NPS. Vitamin D receptors are widely distributed in the brain, and vitamin D may exert neuroprotective or neurotrophic effects, including in hippocampus. Wang et al. positied that vitamin D may regulate AD- and psychosis-related genes through the VDR, to which vitamin D binds. However, important biological questions remain regarding the vitamin D findings. In particular, it was surprising that ergocalciferol (vitamin D2), and not cholecalciferol (vitamin D3), was identified as the form of vitamin D that differed in AD+P vs. AD-P. Cholecalciferol is generally considered to be the more potent form of vitamin D with regard to raising blood 25-hydroxyvitamin D (25-OH-D) levels and is the preferred form of supplementation – although some controversy remains; the two forms of vitamin D also appear to differ in their affinities for the VDR(8, 9), which may have therapeutic implications. The authors were also admittedly limited in their ability to probe effects of dose and/or cumulative drug exposure, to measure correspondence of vitamin D use with peripheral nutrient biomarker levels, or to address the variable nutrient composition of supplements used by participants. In future work, investigators may wish to scrutinize the molecular and genetic origins of potential differences in the associations of ergocalciferol vs. cholecalciferol with AD+P. Further study is also needed to determine

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18