Nonlipogenic ABCA1 Inducers (NLAI) for Alzheimer's Disease Validated in a Mouse Model Expressing Human APOE3/APOE4.

Therapeutics enhancing apolipoprotein (APOE) positive function are a priority, because APOE4 is the major genetic risk factor for Alzheimer's disease (AD). The function of APOE, the key constituent of lipoprotein particles that transport cholesterol and lipids in the brain, is dependent on lipidation by ABCA1, a cell-membrane cholesterol transporter. ABCA1 transcription is regulated by liver X receptors (LXR): agonists have been shown to increase ABCA1, often accompanied by unwanted lipogenesis and elevated triglycerides (TG). Therefore, nonlipogenic ABCA1-inducers (NLAI) are needed. Two rounds of optimization of an HTS hit, derived from a phenotypic screen, gave lead compound 39 that was validated and tested in E3/4FAD mice that express human APOE3/4 and five mutant APP and PSEN1 human transgenes. Treatment with 39 increased ABCA1 expression, enhanced APOE lipidation, and reversed multiple AD phenotypes, without increasing TG. This NLAI/LXR-agonist study is the first in a human APOE-expressing model with hallmark amyloid-ß pathology.

APOE2 Heterozygosity Reduces Hippocampal Soluble Amyloid-ß42 Levels in Non-Hyperlipidemic Mice.

APOE2 lowers Alzheimer's disease (AD) risk; unfortunately, the mechanism remains poorly understood and the use of mice models is problematic as APOE2 homozygosity is associated with hyperlipidemia. In this study, we developed mice that are heterozygous for APOE2 and APOE3 or APOE4 and overexpress amyloid-ß peptide (Aß) (EFAD) to evaluate the effect of APOE2 dosage on Aß pathology. We found that heterozygous mice do not exhibit hyperlipidemia. Hippocampal but not cortical levels of soluble Aß42 followed the order E2/2FAD > E2/3FAD≤E3/3FAD and E2/2FAD > E2/4FAD < E4/4FAD without an effect on insoluble Aß42. These findings offer initial insights on the impact of APOE2 on Aß pathology.

Psychometric properties of the generalised version of the Screener for Substance and Behavioural Addictions (SSBA-G): A comprehensive screening tool for substance-related and behavioural addictions.

Assessing addictive behaviours comprehensively and efficiently is a challenge in both research and clinical practice. Consequently, we tested the psychometric properties of the Generalized Screener for Substance and Behavioural Addictions (SSBA-G), a novel, brief screening tool measuring functional impairment resulting from both substance and behavioural addictions. The SSBA-G was developed from the Screener for Substance and Behavioural Addictions (Schluter et al., 2018) and tested in four samples including university students in Canada (n = 481) and the US (n = 164) as well as community adults in Canada (n = 301), and Hungary (n = 79). Confirmatory factor analysis supported the hypothesized bifactor model of the SSBA-G. Receiver-operation characteristic analyses revealed high differentiation accuracy (AUC=0.86-.95), as well as identical ideal cut points across the Substance Addiction (SSBA-G-S) and Behavioural Addiction (SSBA-G-B) Subscales. Results indicated good-to-excellent sensitivity and moderate-to-good specificity. The SSBA-G demonstrated excellent internal consistency and test-retest reliability as well as promising concurrent validity in relation to the original SSBA and additional questions regarding addiction-related impairment. The SSBA-G also showed good convergent and divergent validity with indicators of general mental health. These results indicate that the SSBA-G is a psychometrically sound and efficient measure of addiction-related impairment across substances and excessive behaviours.

A narrative systematic review of the gender inclusivity of measures of harmful drinking and their psychometric properties among transgender adults.

BACKGROUND AND AIMS: Experiencing higher rates of stigma, marginalization and discrimination puts transgender individuals at risk for alcohol use and associated harms. Measures of harmful drinking were designed with cisgender people in mind, and some rely on sex- and gender-based cut-offs. The applicability of these measures for gender diverse samples remains unknown. The present study had two aims: (i) identify gender-non-inclusive language and cut-offs in measures of harmful drinking, and (ii) systematically review research reporting psychometric properties of these measures in transgender individuals. METHODS: We reviewed 22 measures of harmful drinking for gendered language and sex- and gender-based cut-off values and provided suggestions for revision when warranted. We also conducted a systematic narrative review, including eight eligible studies, summarizing the psychometric properties of measures of harmful drinking in transgender populations. RESULTS: Six of 22 measures of harmful drinking were not gender inclusive, because of gendered language in the measure itself or use of sex- or gender-based cut-off scores. Only eight published studies reported psychometric data for these measures in transgender people. Apart from in one study, the Alcohol Use Disorders Identification Test (AUDIT) and Alcohol Use Disorders Identification Test Consumption (AUDIT-C) appear reliable for transgender adults (Cronbach's α: AUDIT [0.81-0.87] and AUDIT [0.72-0.8)]). There is initial support for using uniform cut-offs for transgender people for the AUDIT-C (≥3) and binge drinking (≥5 drinks in a sitting). CONCLUSIONS: Most existing measures of harmful drinking appear to be gender inclusive (containing gender neutral language and uniform cut-off scores across sex and gender groups) and some that are not easily adapted to be gender inclusive.