This review will highlight advances in sex differences in AD in human populations with a focused perspective on epidemiology, biomarkers, and clinical trials. A thorough and concise overview of sex differences reviewed here indicates varying vulnerabilities in men and women. This review examines several lines of recent and strong evidence that collectively indicate the following (1) men die faster with AD, (2) more women live with AD, (3) both sexes show similar risk of developing AD until advanced ages when women show increased risk, (4) both sexes show largely similar AD biomarker burden with notable exceptions for higher tau levels in subgroups of women with high amyloid, (5) women show brain reserve and resilience to tau pathology, (6) both sexes are vulnerable to the genetic risk of carrying APOE4, with women showing higher risk, and (7) neither sex has shown clear benefit of hormone replacement for AD or dementia risk in randomized clinical trials to date.Sex differences in behavior, and whether these behavioral differences are related to sex differences in brain development, has been a longstanding topic of debate. Presumably, sex differences can provide critically important leads for explaining the etiology of various illnesses that show (i) large sex differences in prevalence and (ii) have an origin before or during adolescence. The general aim of this chapter is to provide an overview of scientific studies on sex differences in normative brain and behavioral development across puberty and adolescence, including the (sex) hormone-driven transition phase of puberty. Moreover, we describe the literature on brain and behavioral development in gender dysphoria, a severe and persistent incongruence between the self-identified gender and the assigned sex at birth. From the literature it becomes clear there is evidence for a specific link between pubertal maturation and developmental changes in arousal, motivation, and emotion. However, this link is rather similar between boys and girls. Moreover, although there is substantial evidence for sex differences in mean brain structure, these have not always been linked to sex differences in behavior, cognition, or psychopathology. Furthermore, there is little evidence for sex differences in brain development and thus, studies so far have been unable to explain sex differences in cognition. Suggestions for future research and methodologic considerations are provided.Neuroinflammation is implicated in contributing to a variety of neurologic and somatic illnesses including Alzheimer's disease (AD), Parkinson's disease (PD), and depression. In this chapter, we focus on the role of neuroinflammation in mediating these three illnesses and portray interactions between the immune response and the central nervous system in the context of sex differences in disease progression. The majority of this chapter is supported by clinical findings; however, we occasionally utilize preclinical models where human studies are currently lacking. We begin by detailing the pathology of neuroinflammation, distinguishing between acute and chronic inflammation, and examining contributions from the innate and adaptive immune systems. Next, we summarize potential mechanisms of immune cell mediators including interleukin-1 beta (IL-1β), tumor necrosis factor α, and IL-6 in AD, PD, and depression development. Given the strong sex bias seen in these illnesses, we additionally examine the role of sex hormones, e.g., estrogen and testosterone in mediating neuroinflammation at the cellular level. Systematically, we detail how sex hormones may contribute to distinct behavioral and clinical symptoms and prognosis between males and females with AD, PD, or depression. Finally, we highlight the possible role of exercise in alleviating neuroinflammation, as well as evidence that antiinflammatory drug therapies improve cognitive symptoms observed in brain-related diseases.This chapter reviews the current information about sex differences in epilepsy and potential mechanisms underlying sex differences in seizure susceptibility and epilepsy. The susceptibility to and occurrence of seizures are generally higher in men than women. There is gender-specific epilepsies such as catamenial epilepsy, a neuroendocrine condition in which seizures are most often clustered around the perimenstrual or periovulatory period in adult women. Structural differences in cerebral morphology, the structural and functional circuits may render men and women differentially vulnerable to seizure disorders and epileptogenic processes. Changes in seizure sensitivity are evident at puberty, pregnancy, and menopause, often attributed to circulating steroid hormones and neurosteroids as well as neuroplasticity in receptor systems. An improved understanding of the sexual dimorphism in neural circuits and the neuroendocrine basis of sex differences or resistance to protective drugs is essential to develop sex-specific therapies for seizure conditions.Experiences throughout the life course lead to unique phenotypes even among those with the same genotype. Genotype sets the substrate on which physiologic processes, which communicate with the brain, mediate the effects of life experiences via epigenetics. Epigenetics modify the expression of genes in the brain and body in response to circulating hormones and other mediators, which are activated to facilitate survival responses through a process called allostasis.  https://www.selleckchem.com/products/AP24534.html  Epigenetic signatures can even be inherited, resulting in transgenerational effects. This chapter addresses epigenetics in the context of sex differences, discussing the intersection between genetics and gonadal hormones and their effect in the brain at discrete developmental periods.Sex hormones have organizational and activational effects on the human brain and can interact with the neurotransmitter systems. These biologic mechanisms may have a far-reaching impact, with both behavioral consequences and structural as well as functional brain modulation. The impact of cycling hormone levels throughout the menstrual cycle on cognitive and emotion processing has especially received some attention recently. Therefore, the aim of this chapter is to give an overview of findings regarding the effects of estradiol and progesterone, but also testosterone, on functional brain domains comprising cognition, emotion, and reward processing.