Background: A growing confluence of evidence demonstrates that heavy episodic drinking (HED) during adolescence can alter neurodevelopment. Alcohol use has a well- established and strong association with academic functioning. The extent to which this association is mediated by neuropsychological decrements remains a critical gap in the research literature. Aims: Aim 1: Articulate an adaptable conceptual and procedural approach to guide research on the joint study of HED, neuropsychological functioning, and academic performance. Aim 2: Examine the utility of applying factor analysis frameworks to the measurement of neuropsychological functioning to optimize the evaluation of HED effects. Aim 3: Evaluate the potential mediating role of neuropsychological functioning in the association between adolescent alcohol use and academic performance. Methods: Aim 1 was addressed with a critical review of the literature used by public health, social sciences, behavioral sciences, biological sciences, and philosophy to guide the use of theory in scientific investigations. Measurement models for the neuropsychological assessment used in this project were established through comparative confirmatory factor modeling as a means to address Aim 2. Causal models based on propensity score weighting were used to assess the association between HED attributable decrements in neuropsychological function and changes in academic performance. Aims 2 and 3 were addressed with data obtained from the NCANDA study, which is a longitudinal study of youth (ages 14-18, n = 419). Results: Challenges to current approaches to the use of theory were identified, and solutions, including paratheoretical framing and abductive inference, were outlined. The conceptually based Gur+ and 8-Factor models were found to be adequate representations of the factor structure and applicable to the investigation of the effects of HED on neuropsychological functioning. Prior reports of the association between neuropsychological functioning and grade point average were corroborated. Causal effects of HED mediated through neuropsychological changes on academic performance were not detected. Conclusions: Although causal effects were not detected, the theoretical and analytical paradigms developed in this project are applicable to future investigations, including the parent study of this project as more NCANDA participants escalate their drinking exposures.