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To compare the real-world clinical effectiveness and long-term clinical trajectory in patients with Alzheimer disease (AD) treated with combination (COMBO) therapy consisting of cholinesterase-inhibitor (CI) plus memantine (MEM) versus CI alone versus no treatment with either.Three hundred eighty-two subjects with probable AD underwent serial clinical evaluations at a memory disorders unit. Cognition was assessed by the Information-Memory-Concentration subscale of the Blessed Dementia Scale (BDS) and function was assessed by the Weintraub Activities of Daily Living Scale (ADL) at 6-month intervals. One hundred forty-four subjects received standard care without CI or MEM (NO-RX), 122 received CI monotherapy, and 116 received COMBO therapy with CI plus MEM. Mean follow-up was 30 months (4.1 visits) and mean cumulative medication treatment time was 22.5 months. Rates of decline were analyzed using mixed-effects regression models, and Cohen's d effect sizes were calculated annually for years 1 to 4.Covarying for baseline scores, age, education, and duration of illness, the COMBO group had significantly lower mean annualized rates of deterioration in BDS and ADL scores compared with the CI (P<0.001; Cohen's dBDS=0.10−0.34 and dADL=0.23−0.46 at 1 to 2 y) and NO-RX groups (P<0.001; Cohen's dBDS=0.56−0.73 and dADL=0.32−0.48 at 1 to 2 y). For the COMBO group, Cohen's d effect sizes increased with treatment duration. Similar comparisons significantly favored the CI over the NO-RX group on the BDS.COMBO therapy slows cognitive and functional decline in AD compared with CI monotherapy and no treatment. These benefits had small-to-medium effect sizes that increased with time on treatment and were sustained for years.