•Aging promotes modifications in brain due to estrogen decline, mainly in females.•Adult exposure to estrogens and androgens regulate AD development in women and men.•Sex effect on both neuroimaging and fluid biomarkers of AD was explored.•Sex representation in basic/clinical neuroscience, in clinical trials, is inadequate.•A “sex-stratified pathway-based therapy” framework needs to be introduced. Neurodegenerative diseases (ND) are among the leading causes of disability and mortality. Considerable sex differences exist in the occurrence of the various manifestations leading to cognitive decline. Alzheimer’s disease (AD) exhibits substantial sexual dimorphisms and disproportionately affects women. Women have a higher life expectancy compared to men and, consequently, have more lifespan to develop AD. The emerging precision medicine and pharmacology concepts – taking into account the individual genetic and biological variability relevant for disease risk, prevention, detection, diagnosis, and treatment – are expected to substantially enhance our knowledge and management of AD. Stratifying the affected individuals by sex and gender is an important basic step towards personalization of scientific research, drug development, and care. We hypothesize that sex and gender differences, extending from genetic to psychosocial domains, are highly relevant for the understanding of AD pathophysiology, and for the conceptualization of basic/translational research and for clinical therapy trial design.