Early- versus late-onset Alzheimer's disease in clinical practice: cognitive and global outcomes over 3 years

Abstract

Background: Whether age at onset influences Alzheimer's disease (AD) progression and the effectiveness of cholinesterase inhibitor (ChEI) therapy is not clear. We aimed to compare longitudinal cognitive and global outcomes in ChEI-treated patients with early-onset Alzheimer's disease (EOAD) versus late-onset Alzheimer's disease (LOAD) in clinical practice.

Methods: This 3-year, prospective, observational, multicentre study included 1017 participants with mild to moderate AD; 143 had EOAD (age at onset < 65 years) and 874 had LOAD (age at onset ≥ 65 years). At baseline and semi-annually, patients were assessed using cognitive, global and activities of daily living (ADL) scales, and the dose of ChEI was recorded. Potential predictors of decline were analysed using mixed-effects models.

Results: Six-month response to ChEI therapy and long-term prognosis in cognitive and global performance were similar between the age-at-onset groups. However, deterioration was significantly faster when using the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) over 3 years in participants with EOAD than in those with LOAD; hence, prediction models for the mean ADAS-Cog trajectories are presented. The younger cohort had a larger proportion of homozygote apolipoprotein E (APOE) ε4 allele carriers than the older cohort; however, APOE genotype was not a significant predictor of cognitive impairment in the multivariate models. A slower rate of cognitive progression was related to initiation of ChEIs at an earlier stage of AD, higher ChEI dose and fewer years of education in both groups. In LOAD, male sex, better instrumental ADL ability and no antipsychotic drug use were additional protective characteristics. The older patients received a lower ChEI dose than the younger individuals during most of the study period.

Conclusions: Although the participants with EOAD showed a faster decline in ADAS-Cog, had a longer duration of AD before diagnosis, and had a higher frequency of two APOE ε4 alleles than those with LOAD, the cognitive and global responses to ChEI treatment and the longitudinal outcomes after 3 years were similar between the age-at-onset groups. A higher mean dose of ChEI and better cognitive status at the start of therapy were independent protective factors in both groups, stressing the importance of early treatment in adequate doses for all patients with AD.

Keywords: Cholinesterase inhibitors; Cognition; Early-onset Alzheimer’s disease; Late-onset Alzheimer’s disease; Longitudinal study; Mixed-effects models; Predictors.

Fig 1

Cognitive outcome over 3 years of cholinesterase inhibitor (ChEI) treatment. The mean changes in Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS-Cog) score with 95% CI from the start of ChEI therapy (baseline) over 3 years, by age at onset of Alzheimer’s disease (AD). The patients with early-onset Alzheimer’s disease showed a more rapid rate of cognitive decline from baseline after 12 months (p = 0.045), 18 months (p = 0.035) and 30 months (p = 0.019) of treatment

Fig 2

Global outcome over 3 years of cholinesterase inhibitor (ChEI) treatment. The proportion of patients is shown according to differences in treatment response in global performance (Clinician Interview-Based Impression of Change (CIBIC)) from the start of ChEI therapy over 3 years for early-onset Alzheimer’s disease (EOAD) versus late-onset Alzheimer’s disease (LOAD). No significant differences in global response were observed between the two groups, except after 24 months (p = 0.005) of treatment. CIBIC scores 1–3 were considered as improvement, 4 as unchanged, and 5–7 as deterioration