Table 4.

Sex differences in neurological disease.

Disease	Sex Bias	Evidence for the role of hormones	Evidence for the role of genetics	Other factors affecting sex differences in disease
Alzheimer's Disease (AD)	Women demonstrate higher AD prevalence at older ages [143; 144].	Gonadal hormones implicated in gender-related cognitive deficits of AD but the interaction is complex [145]	APOE allele type [146; 147] (i.e. Less and slower rate of amyloid plaque formation in men due to APOE ε2 [148])	Greater degeneration in areas of orbitofrontal cortex, middle and posterior cingulate cortex, hypothalamus, and mammilary bodies in men, and anterior thalamic in women [149].
Parkinson's disease (PD)	Overrepresented in males [150; 151] Age at onset is later in women [152]. Pathological symptoms of PD differ among males and females [153; 154; 155]	Most women manifest PD after menopause [156] Estrogen affecting BDNF secretion [157] Early life estrogen decline seems to be more important [158; 159; 160]	Linkage to X chromosome markers in 362 families, and to Xq28 in 443 discordant sibling pairs [161; 162] Val66met polymorphism in BDNF in women [163]	Environmental factors [164] Anatomical and structural differences in dopaminergic systems among males and females [107]
Autism	There is a high male to female ratio in the prevalence of autism [165]	Gonadal hormones affecting oxytocin (OT) and arginine vasopressin (AVP) receptors [166; 167]	Single nucleotide polymorphisms in the OT receptor in the Chinese Han [168] and American Caucasian population [169], SNPs in the vasopressin receptor (V1aR) gene [170; 171] X-chromosome has effects on cognition and social aspects [172; 173]	Alterations in oxytocin or arginine vasopressin activity, and differential processing of the oxytocin precursor [174; 175; 176]
Addiction	Drug addiction more frequent in men [12] Higher relapse rates, faster progression of compulsive drug abuse and dependence have in women [177; 178])	Estradiol levels correlate with drug induced reinforcing behavior whereas progesterone levels are negatively associated with addiction [179; 180; 181]	Genes encoded on sex chromosomes can affect sex-related differences in addiction (the four core genotype mice) [182]	Neuroanatomical differences in motivation systems among males and females [107] Sex-related alterations in the cortico-limbic-striatal system that mediates reward processing [183]
Depression	Women are twice as likely as men to develop depression during reproductive years [184]	Low estrogen levels in female rats mediated by influences on neurotransmitter levels [185] Low testosterone levels associate with risk for depression in young and middle aged-men [186; 187]	Heritability rates estimated to be 70% [188] Polymorphisms in serotonin gene, estrogen receptor 1 (ESR1) polymorphism in the presence of Val/Val genotype of the Val158Met polymorphism in the Catechol-O-methyl transferase (COMT) gene, longer CA repeats of human estrogen receptor 2 (ESR2), short CAG repeats in androgen receptor gene [189]	Maladaptive coping, pessimism, dependency, low self- esteem, victimization, sexual abuse, comorbid anxiety disorder more common in depressed women [190] Early life events increase depression rates in adult women [191]
Anxiety disorders	The rate of anxiety disorders is higher in females [55]. The high comorbidity of these disorders with major depression helps account for the sex difference in depression [192].	States of anxiety and panic have been reported to be affected by the menstrual cycle and pregnancy, implicating a role for estrogen and progesterone [55]. Pregnancy and lactation seem to alter brain neurochemical system that affect anxiety and fear [193].	TheVal158alleleof COMT is associated with panic disorder in Caucasian women but not men [194]. In Asians, Met158 is associated with panic disorder in women but not men [194]. 5HTTLPR is a polymorphism associated with anxiety in humans. The orthologous polymorphism in rhesus macaques interacts with early adversity in a sexually dimorphic manner [195].	Animal studies indicate females undergo less neurobiological changes in response to stress compared to males [193]. It is speculated that this indicates increased adaptability in males and hence lower prevalence of affective illness [193].
Schizophrenia	more common in men than in women [196] Age at onset is later in women, another smaller peak of onset during peri- and post-menopause [196; 197] Pathological symptoms of schizophrenia differ among males and females (males experience more negative symptoms, greater decrease in emotion expression and recognition,, greater paranoid delusions in women) [198] Lower chances of full recovery, and a poorer prognosis in men [196; 197] Anatomical brain differences between male and female patients	This disease is not common before adolescence and puberty [199] Male schizophrenics have higher levels of Luteinizing Hormone (LH) and testosterone than healthy subjects, and female schizophrenics higher levels of LH and lower levels of estrogen [200]	Eight ultra-rare variants in eight distinct miRNA genes in 4% of analyzed males with schizophrenia [201] Relatives of females with schizophrenia demonstrate higher levels of the psychotic forms whereas relatives of schizophrenic men express lower rates of psychosis suggesting the presence of genetic heterogeneity [202] Higher rate of CAG repeat expansions among families of female patients and not male patients [203]	Anatomical and structural brain differences among males and females [198] Higher cortical levels in males as compared to females according to some studies [198] Higher sensitivity of the dopamine system in men as compared to women (Normal males produce more striatal dopamine in response to an amphetamine challenge as compared to females) [204]