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Alzheimer's disease (AD) includes a long asymptomatic stage, which precedes the formal diagnosis of dementia. AD biomarker models provide a framework for precision medicine approaches during this stage. However, such approaches have ignored the possible influence of sex on cognition and brain health, despite female sex noted as a major risk factor. Since AD-related changes may emerge in midlife, intervention efforts are being redirected around this period. Midlife coincides with several endocrinological changes, such as the menopausal transition experienced by women. In this narrative review, we discuss evidence for sex-differences in AD neuropathological burden and outline key endocrinological mechanisms for both sexes, focussing on hormonal events throughout the lifespan that may influence female susceptibility to AD neuropathology and dementia onset. We further consider common non-modifiable (genetic) and modifiable (lifestyle and health) risk factors, highlighting possible sex-dependent differential effects for the AD disease course. Finally, we evaluate the studies selected for this review demonstrating sex-differences in cognitive, pathological and health factors, summarising the state of sex differences in AD risk factors. We further provide recommendations for targeted research on female-specific risk factors, to inform personalised strategies for AD-prevention and the promotion of female brain health. • Biomarker models of Alzheimer's disease (AD) provide intervention frameworks but do not consider sex-dependent differences. • Female sex is an AD risk factor, and may interact with genetic, health and lifestyle factors to progress disease process. • Aging comprises a cascade of endocrinological events, which may further exaggerate sex-risk differences in AD onset. • Menopausal transition (mid-life), might constitute an "optimal window" for interventions to prevent or delay AD in females. • Understanding female-specific risk factors may promote precision medicine approaches for heterogenous AD expression. [ABSTRACT FROM AUTHOR]

• Patients with Alzheimer's disease had higher morning cortisol level than controls. • Clinically meaningful AD-related increases of morning cortisol level were quantified. • People with mild cognitive impairment had higher CSF cortisol than normal controls. • High cortisol is associated with accelerated cognitive decline in people with MCI. • Predictive value of cortisol for cognitive decline in preclinical adults is unclear. Morning cortisol levels have been reported to be elevated among patients with Alzheimer's disease (AD); yet no meta-analysis has been conducted to confirm the existence and magnitude of this association. It also remains unclear whether hypercortisolism is a risk factor for AD. PubMed, EMBASE, and PsycINFO were systematically searched for eligible studies. Cross-sectional data were pooled using random-effects meta-analyses; the differences in morning cortisol levels between patients and cognitively normal controls were quantified. Longitudinal studies were qualitatively synthesised due to methodological heterogeneity. 17,245 participants from 57 cross-sectional studies and 19 prospective cohort studies were included. Compared with cognitively normal controls, AD patients had moderately increased morning cortisol in blood (g = 0.422, P < 0.001; I2 = 48.5 %), saliva (g = 0.540, P < 0.001; I2 = 13.6 %), and cerebrospinal fluids (g = 0.565, P = 0.003; I2 = 75.3 %). A moderate elevation of morning cortisol was also detected in cerebrospinal fluids from patients with mild cognitive impairment (MCI) versus controls (g = 0.309, P = 0.001; I2 = 0.0 %). Cohort studies suggested that higher morning cortisol may accelerate cognitive decline in MCI or mild AD patients, but the results in cognitively healthy adults were inconsistent. Morning cortisol was confirmed to be moderately elevated in AD patients and may have diagnostic and prognostic values for AD. [ABSTRACT FROM AUTHOR]