Neurodegenerative diseases such as multiple sclerosis (MS) and Alzheimer's dementia (AD) demonstrate an ever-evolving disease continuum. The presymptomatic phase of neurodegenerative diseases provides a window of opportunity to detect disease-specific changes and abnormalities early on and potentially intervene right away, before clinical symptoms occur. Age and sex are key modifiers of the presymptomatic phase of neurodegenerative diseases. In presymptomatic MS, younger age and male sex are main risk factors for transition to symptomatic MS, whereas older age and male sex are important predictors of the direct transition from presmyptomatic MS to primary progressive MS. In cognitively unimpaired adults, age is the strongest risk factor for AD and the lifetime AD risk after>65 years is higher in women versus men. The prevalence and future disease severity of AD is further modified by factors such as apolipoprotein Eɛ4, ovarian hormones, and menopause in women. Biomarkers are instrumental in detecting and monitoring abnormalities and underlying disease mechanisms in vivo, that are already present in the presymptomatic phase. Evaluating the influence of age and sex on presymptomatic phase of neurodegenerative diseases, particularly through biomarkers, contributes to the enhanced patient selection for clinical trials, optimization and individualization of patient management and development of new therapeutics.