Alzheimer’s Disease (AD) is the leading cause of dementia, observed at a higher incidence in women compared with men. Treatments aimed at improving pathology in AD remain ineffective to stop disease progression. This makes the detection of the early intervention strategies to reduce future disease risk extremely important. Isolation and loneliness have been identified among the major risk factors for AD. The increasing prevalence of both loneliness and AD emphasizes the urgent need to understand this association to inform treatment. Here we present a comprehensive review of both clinical and preclinical studies that investigated loneliness and social isolation as risk factors for AD. We discuss that understanding the mechanisms of how loneliness exacerbates cognitive impairment and AD with a focus on sex differences will shed the light for the underlying mechanisms regarding loneliness as a risk factor for AD and to develop effective prevention or treatment strategies.