Medication management requires complex cognitive functioning, and therefore, difficulty taking medications might be an early sign of cognitive impairment and could be a risk factor for Alzheimer's disease and related dementias (ADRD). Accordingly, people with difficulty taking medications may benefit from more detailed cognitive screening, potentially aiding in the diagnosis of ADRD, which is underdiagnosed. We are unaware of evidence on medication management difficulties that precede a real-world ADRD diagnosis in the USA. Examine the association between difficulty taking medications and subsequent real-world ADRD diagnoses. Case-control study, using Health and Retirement Study (HRS) survey data linked to Medicare claims. A total of 1461 HRS respondents with an ADRD diagnosis observed from 1993 to 2012 (cases), matched by year of birth, wave of HRS entry, and sex to 3771 controls with no ADRD diagnosis. We examined the association between diagnosis of ADRD and self-reported difficulty taking medications in the preceding years (1-2 and 3-4years prior to case definition). Control individuals were assigned the index date from their matched case. Conditional logistic regressions adjusted for age, sex, race, education, and comorbidities. Compared with matched controls, cases had higher prevalence of difficulty taking medications 1-2years prior to diagnosis (11.0% versus 2.3%), and 3-4years prior to diagnosis (5.8% versus 2.3%). Adjusted analyses showed that compared with individuals without ADRD, those with an ADRD diagnosis had more than four times higher odds of difficulty taking medications 1-2years prior (OR = 4.56 (CI 3.30-6.31)), and more than two times higher odds of difficulty taking medications 3-4years prior (OR = 2.41 (CI 1.61-3.59)). Odds of medication difficulty 1-2years prior were more than four times greater for individuals with ADRD diagnoses compared with those without ADRD. Medication management difficulties may prompt further cognitive screening, potentially aiding in earlier recognition of ADRD.