Long-term observational clinical cohort studies the following site performed in naturalistic settings with prospectively collected data show similar patterns to RCTs, and demonstrate Level II grade, generalisable evidence that favours combination treatment over monotherapy, and monotherapy over placebo/no anti-dementia medication treatment [32-34]. Long-term combination therapy with memantine added to a ChEI has, in the clinical setting, been observed to significantly reduce cognitive and functional decline, and to delay time to nursing home admission compared to ChEI monotherapy and to standard care without a ChEI or memantine [32,33]. Furthermore, the benefits of combination therapy increase with time on treatment, and are sustained for years [32].

The latter observation is further supported by Rountree and colleagues who found that benefits of treatment with a ChEI and/or memantine significantly increased with treatment persistence and were observable across multiple symptom domains and stages of disease, including moderate and severe AD [37]. Finally, the recent REAL.FR cohort study, which followed 686 patients with mild to moderate AD in 16 specialised memory clinics in France (89% used ChEI monotherapy at baseline, 26% used ChEI and memantine combination therapy by year 4), reported significantly less decline in this cohort over 4 years compared to untreated historical cohorts [38]. Clinical worsening In the MOD-SEV subgroup, the occurrence of marked clinical worsening in patients receiving memantine added to donepezil was less than half that of those receiving placebo added to donepezil (8.

5% versus 18.9%; P = 0.003; OC; MMSE 5 to 19). This rate is similar to the rate reported in patients receiving any concurrent ChEI (donepezil, galantamine, or rivastigmine) previously reported in a pooled clinical worsening analysis using data from the same two studies (9.8% versus 18.3%; P < 0.01; OC; MMSE 5 to 19) [6]. In the present study, the occurrence of marked clinical worsening in the MOD subgroup was also observed to be less than half for those treated with memantine added to donepezil versus placebo added to donepezil. Previous reports have considered the occurrence of clinical worsening in memantine and donepezil monotherapy studies [6,13]. In data pooled from four memantine monotherapy studies, a significantly lower occurrence of marked clinical worsening was observed for memantine versus placebo (11.4% versus 23.0%; OC; week 24/28; P < 0.001; MMSE < 20) [6]. Brefeldin_A In data pooled from three donepezil monotherapy studies, a significantly lower occurrence of any worsening (any concurrent sellectchem decline in cognition, function, and global status) was observed for donepezil versus placebo (14.4% versus 30.9%; OC; week 24; P < 0.0001; MMSE 10 to 17) [13].