Background and ObjectivesLoneliness is common, and its prevalence is rising. The relationship of loneliness with subsequent dementia and the early preclinical course of Alzheimer disease and related dementia (ADRD) remains unclear. Thus, the primary objective of this study was to determine the association of loneliness with 10-year all-cause dementia risk and early cognitive and neuroanatomic imaging markers of ADRD vulnerability.MethodsThis was a retrospective analysis of prospectively collected data from the population-based Framingham Study cohorts (September 9, 1948-December 31, 2018). Eligible participants had loneliness assessed and were dementia-free at baseline. Loneliness was recorded with the Center for Epidemiologic Studies Depression Scale, defined conservatively as feeling lonely ≥3 days in the past week. The main outcomes were incident dementia over a 10-year period, cognition, and MRI brain volumes and white matter injury.ResultsOf 2,308 participants (mean age 73 [SD 9] years, 56% women) who met eligibility in the dementia sample, 14% (329 of 2,308) developed dementia and 6% (144 of 2,308) were lonely. Lonely (versus not lonely) adults had higher 10-year dementia risk (age-, sex-, and education-adjusted hazard ratio 1.54, 95% CI 1.06-2.24). Lonely participants <80 years of age without APOE ϵ4 alleles had a 3-fold greater risk (adjusted hazard ratio 3.03, 95% CI, 1.63-5.62). Among 1,875 persons without dementia who met eligibility in the cognition sample (mean age 62 [SD 9] years, 54% women), loneliness associated with poorer executive function, lower total cerebral volume, and greater white matter injury.DiscussionOver 10 years of close clinical dementia surveillance in this cohort study, loneliness was associated with increased dementia risk; this tripled in adults whose baseline risk would otherwise be relatively low on the basis of age and genetic risk, representing a majority of the US population. Loneliness was also associated with worse neurocognitive markers of ADRD vulnerability, suggesting an early pathogenic role. These findings may have important clinical and public health implications given observed loneliness trends.Classification of EvidenceThis study provides Class I evidence that loneliness increases the 10-year risk of developing dementia.