Brain-derived neurotrophic factor or BDNF is a multi-functional neurotrophin released in the brain following neuronal activity that is involved in synaptic plasticity and long-term memory formation via its ability to lead to the differentiation and survival of neuronal connections (Bergen, 2020; Lewin & Carter, 2014). The role BDNF plays in neurogenesis and synaptic plasticity implies a potential relationship to disorders characterised by the progressive degradation of neuronal connections (Alzheimer's disease, dementia, Parkinson’s), as well as in normal aging (Brown et al., 2020). In support of this connection, BDNF serum levels have been found to decrease with age and to be lower in individuals with Alzheimer’s disease (AD), Parkinson’s disease, and multiple forms of dementia (Erickson et al., 2010; Ng et al., 2019; Scalzo et al., 2010; Ventriglia et al., 2013). Studies have found that reduced serum BDNF is associated with age-related hippocampal volume loss and decreased memory performance, and that healthy middle-aged individuals with higher BDNF serum levels have better cognitive performance (Erickson et al., 2010; Gunstad et al., 2008). Beyond this, individuals with Alzheimer’s disease who have higher levels of serum BDNF have been found to experience slower cognitive decline, and similarly, healthy individuals with lower levels of serum BDNF have been found to experience more rapid cognitive decline (Laske et al., 2011; Siuda et al., 2017). Collectively these findings suggest that serum BDNF may potentially be an important biomarker of cognitive aging and decline. Beyond a role in learning and memory, BDNF is also involved in the regulation of energy intake and expenditure, and is expressed in hypothalamic nuclei involved in feeding behavior and energy homeostasis (H. Yang et al., 2016). BDNF’s involvement in energy metabolism likely relates to findings of association between BDNF and BMI, principally in GWAS studies (Speliotes et al., 2010; Zhao et al., 2011) with mixed phenotypic findings in human studies, albeit in very small samples (Sandrini et al, 2018). Moreover, findings of BDNF and regular exercise/physical activity are fairly robust in phenotypic studies (Szuhany, Bugatti, & Otto, 2015; Huang, Larsen, Ried-Larsen, Møller, & Andersen, 2014; Gunstad et al., 2006; Shugart et al., 2009; Cotman et al., 2002; ). It is speculated that BDNF may play a role in BMI and physical activity by modifying related circuitry. This is similar to its mechanism in learning and memory, in which BDNF alters the synaptic plasticity of circuitry relevant to learning and memory processes (Noble et al., 2011). Interestingly, acute physical exercise has been shown to temporarily increase BDNF levels in the brain as reflected by increased serum BDNF levels (Schmidt-Kassow et al., 2012; Tang, Chu, Hui, Helmeste, & Law, 2008; Gold et al., 2003; Vega et al., 2006; Marquez, Vanaudenaerde, Troosters, & Wenderoth, 2015) while long term/consistent physical activity has been found to decrease serum BDNF levels (Chan, Tong, & Yip, 2008; Currie, Ramsbottom, Ludlow, Nevill, & Gilder, 2009; Nofuji et al., 2008; Babaei, Damirchi, Mehdipoor, & Tehrani, 2014; De la Rosa et al., 2019). The decreased levels in long term physical activity do not have a negative effect, however, as chronic physical activity has been found to increase the BDNF response to an acute bout of exercise (Szuhany et al., 2015). As explanation, both chronic exercise training (Fahimi et al., 2017; Kim et al., 2015) and BDNF overexpression (LeMaster et al., 1999) result in upregulation of the TrkB receptor, leading to improved BDNF function in the brain and lower basal levels (Walsh et al., 2020). A myriad of evidence shows that physical health, including physical activity, nutrition, and body weight, can influence cognitive aging (Depp, Harmell, & Vahia, 2011; Stanek et al., 2013). Physical activity, in particular, has been found to have a positive impact on cognitive health by activating circuitry which promotes synaptic plasticity and neuronal survival (Cotman, 2002; Baek, 2016). For this reason, researchers have been interested in the ability of exercise-induced increases in serum BDNF to improve brain health and ameliorate disease and age-related declines in learning and memory (Walsh & Tchaikovsky, 2018). Several studies have found physical activity to influence both serum BDNF and cognitive performance. Winter et al., (2007) found that in 27 healthy adults, not only were serum BDNF levels increased following aerobic interventions, but vocabulary learning was 20 percent faster (Winter et al., 2007). Similarly, Griffin and colleagues found that a short period of high-intensity cycling increased serum BDNF as well as performance on a face-name matching task in 47 healthy adult males (Griffin et al., 2011). However, most of the research between BDNF, physical activity and cognition focuses on acute exercise or shorter periods of exercise intervention on either healthy, young adults or older adults often with diseases such as Alzheimers. As mentioned by Walsh et al., 2020, a more systematic look at BDNF, exercise and cognition is needed, including the under studied middle-aged group which our data includes (Walsh et al., 2020). Given findings that long term, consistent physical activity influences baseline serum BDNF levels, it is of interest to investigate whether everyday, leisure time physical activity influences both serum BDNF and cognitive performance in healthy adults approaching midlife. Furthermore, almost all individuals experience declining memory abilities as they age to some degree, yet evidence shows that declines do not occur equally in all forms of memory (Cansino, 2009). For example, episodic memory has been found to be particularly sensitive to the aging process, while other forms of memory show less decline (Nilsson, 2003; Puckett & Stockburger, 1988; Craik & McDowd, 1987). Due to findings that BDNF is associated with altered hippocampal function and volume as well as age-related cognitive decline, most research in this area has focused on episodic memory (Hairi et al., 2003; Dennis et al., 2011; Kennedy et al., 2015; Bueller et al., 2006). However, as BDNF is expressed in other areas of the brain, including the prefrontal cortex, whether BDNF influences other forms of memory is of interest as well (Lipska, Khaing, Weickert, & Weinberger, 2001). As evidence of BDNF’s role in multiple forms of memory, decreased serum BDNF has been found to be associated with decreased episodic memory performance as well as executive function impairment, and animal studies suggest BDNF may play a role in various forms of memory, including working memory (Siuda et al., 2017; Jeon & Ho Ha, 2017; Papaleo et al., 2011; Cunha et al., 2009). However, while the BDNF val66met polymorphism, which decreases BDNF expression, has been found to be associated with poorer episodic memory in several studies, it has not as reliably been found to influence working memory and other aspects of executive function (Egan et al., 2003; Kennedy et al., 2015; Hansell et al., 2006; Gong et al., 2009). Many studies investigating BDNF’s relationship to episodic memory include aging or demented groups, while studies focused on working memory/executive function often include groups with disorders that tend to show working memory deficits (schizophrenia, bipolar disorder, major depressive disorder), for this reason more research on BDNF and specific memory processes in healthy subjects is needed as well (Man et al., 2018; Dias et al., 2009; Oral et al., 2012). In order to increase understanding of BDNF we will begin by investigating possible pathways by which BDNF may be associated. We will examine serum BDNF’s relationship with multiple measures of memory performance via physical activity and BMI pathways, considering phenotypic associations. We will accomplish this by testing a phenotypic mediational model in which serum BDNF may directly or indirectly cognition, specifically episodic memory (EM) and working memory (WM)/executive functioning (EF), considering BMI and physical activity as mediators. Furthermore, we will investigate genetic associations. Complex traits such as physical activity, BMI, and cognition are determined by many genes of small effect, making them polygenic (Sugrue & Desikan, 2019). The cumulative impact from the aggregate of these DNA variants is referred to as a polygenic score (PGS), generated using weights from large genome-wide association studies (GWAS) (Sugrue & Desikan, 2019). Of relevance to our current project, GWAS have been conducted on all of our traits of interest (BMI, physical activity, memory) as well as serum BDNF (Yengo et al., 2018; Klimentidis et al., 2018; Neale Lab, 2018; de la Fuente et al., 2020; Li et al., 2020). These GWAS will be used to form PGS for BMI, physical activity, episodic memory, working memory/EF and serum BDNF, and we will investigate the ability of these polygenic scores to account for phenotypic associations by including them in mediating pathways between BDNF and BMI and physical activity to memory performance.