Predictors of long-term cognitive outcome in Alzheimer's disease

Abstract

Introduction: The objective of this study was to describe the longitudinal cognitive outcome in Alzheimer's disease (AD) and analyze factors that affect the outcome, including the impact of different cholinesterase inhibitors (ChEI).

Methods: In an open, three-year, nonrandomized, prospective, multicenter study, 843 patients were treated with donepezil, rivastigmine, or galantamine in a routine clinical setting. At baseline and every six months, patients were assessed using several rating scales, including the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and the dose of ChEI was recorded. Sociodemographic and clinical characteristics were investigated. The relationships of these predictors with longitudinal cognitive ability were analyzed using mixed-effects models.

Results: Slower long-term cognitive decline was associated with a higher cognitive ability at baseline or a lower level of education. The improvement in cognitive response after six months of ChEI therapy and a more positive longitudinal outcome were related to a higher mean dose of ChEI, nonsteroidal anti-inflammatory drug (NSAID)/acetylsalicylic acid usage, male gender, older age, and absence of the apolipoprotein E (APOE) ε4 allele. More severe cognitive impairment at baseline also predicted an improved response to ChEI treatment after six months. The type of ChEI agent did not influence the short-term response or the long-term outcome.

Conclusions: In this three-year AD study performed in a routine clinical practice, the response to ChEI treatment and longitudinal cognitive outcome were better in males, older individuals, non-carriers of the APOE ε4 allele, patients treated with NSAIDs/acetylsalicylic acid, and those receiving a higher dose of ChEI, regardless of the drug agent.

Figure 1

Cognitive outcome and gender. a) MMSE, prediction of outcome for different baseline scores divided by gender Three-year mean outcomes with 95% confidence intervals predicted by the mixed models for patients with different Mini-Mental State Examination (MMSE) scores (15, 20, and 25 were used as arbitrary examples), at the start of ChEI treatment and according to gender. Males demonstrated a better six-month treatment response compared with females (P = 0.010). The calculated outcomes were based on a 75-year-old patient who did not receive NSAID/acetylsalicylic acid treatment, had nine years of education, exhibited an IADL baseline score of 16, and received 65% of the maximum recommended dose of ChEI. b) ADAS-cog, prediction of outcome for different baseline scores divided by gender. Three-year mean outcomes with 95% confidence intervals predicted by the models for patients with different Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) scores (20, 30, and 40 were used as arbitrary examples), at the start of treatment and according to gender. Male subjects showed a better response to treatment compared with females. An interaction effect of ADAS-cog baseline score × Gender was detected (P = 0.015), that is, the difference between genders increased with lower baseline scores. The calculated outcomes were based on a 75-year-old patient who was an APOE ε4 carrier, did not receive NSAID/acetylsalicylic acid treatment, had nine years of education, exhibited an IADL baseline score of 16, and received 65% of the maximum recommended dose of ChEI.

Figure 2

Cognitive outcome and age. a) MMSE, prediction of outcome for different baseline scores and ages. Three-year mean outcomes with 95% confidence intervals predicted by the mixed models for patients with different Mini-Mental State Examination (MMSE) baseline scores (15, 20, and 25) and ages (65, 75, and 85 years), used as arbitrary examples. Older subjects with a baseline MMSE score < 22 exhibited a better six-month treatment response compared with younger patients (P < 0.001). In addition, the interaction MMSE score × Age at the start of ChEI treatment showed a more pronounced age difference at lower baseline scores (P < 0.001). The calculated outcomes were based on a male patient who did not receive NSAID/acetylsalicylic acid treatment, had nine years of education, exhibited an IADL baseline score of 16, and received 65% of the maximum recommended dose of ChEI. b) ADAS-cog, prediction of outcome for different baseline scores and ages. Three-year mean outcomes with 95% confidence intervals predicted by the models for patients with different Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) baseline scores (20, 30, and 40) and ages (65, 75, and 85 years), used as arbitrary examples. Older individuals exhibited a better response to treatment compared with younger subjects (P = 0.043). The interaction ADAS-cog score × Age at the start of treatment showed a greater age difference at lower baseline levels (P < 0.001). The calculated outcomes were based on a male patient who was an APOE ε4 carrier, did not receive NSAID/acetylsalicylic acid treatment, had nine years of education, exhibited an IADL baseline score of 16, and received 65% of the maximum recommended dose of ChEI.