Early- versus late-onset Alzheimer's disease: 3-year outcomes of cholinesterase inhibitor treatment in routine clinical practice

Abstract

Background: Alzheimer’s disease (AD) is an insidiously progressive neurodegenerative disorder that is characterized by multiple cognitive impairments and gradual loss of independence in carrying out activities of daily living (ADL). Currently, the predominant therapy for mild-to-moderate AD is cholinesterase inhibitors (ChEIs), which have been shown to have positive effects on symptoms compared with placebo in randomized clinical trials. There is an increased interest in dominantly inherited and early-onset AD, and in new treatments aimed at blocking the course of the disease. Therapies that are expected to modify disease progression should be assessed thoroughly over many years, and advances in understanding of the expected long-term outcomes for individuals with different ages at the onset of AD require well-designed observational studies. This study aimed to identify potential differences in clinical characteristics, longitudinal outcomes, and endpoints in patients with early- vs late-onset AD in routine clinical practice. Methods: The Swedish Alzheimer Treatment Study (SATS) is a prospective, open, nonrandomized multicenter study for the assessment of ChEI treatment in a routine clinical setting. In total, 1,258 outpatients with a clinical diagnosis of probable or possible AD were included. Of these, 1,021 participants were defined as having mild-to-moderate AD (Mini-Mental State Examination (MMSE) score, 10–26) and were enrolled in the present study. The age at AD onset was estimated by a clinician who specialized in dementia disorders. The age at onset was younger than 65 years in 143 individuals (14%) and 65 years or older in 874 (4 missing data). Patients were assessed using cognitive tests (MMSE and Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog)) and functional capacity scales (Instrumental Activities of Daily Living scale (IADL) and Physical Self-Maintenance Scale (PSMS)) at baseline, after 2 months (MMSE only), and every 6 months for 3 years. Eventual dates of nursing home placement and death were recorded. Results: The presence of apolipoprotein E (APOE) e4-alleles was more frequent among the early-onset AD patients (2 e4-alleles, 29%; 1 e4-allele, 46%; 0 e4-alleles, 25%) vs late-onset patients (2 e4-alleles, 13%; 1 e4-allele, 54%; 0 e4-alleles, 33%; P < 0.001). At the start of ChEI therapy, the mean age was 62.7 years (95% confidence interval (CI), 61.8–63.6) for the early-onset patients compared with 77.3 years (95% CI, 77.0–77.6) for the late-onset patients (P < 0.001). The duration of illness was longer in the early-onset group than in the late-onset group (4.1 years (95% CI, 3.6–4.7) vs 2.9 years (95% CI, 2.8–3.0); P < 0.001). The early-onset group had more years of education compared with the late-onset group (10.1 years (95% CI, 9.6–10.5) vs 9.3 years (95% CI, 9.2–9.5); P = 0.004). In the entire cohort, 64% were females and the cognitive ability at baseline was assessed as a mean MMSE score of 21.4 points (95% CI, 21.2–21.6) and ADAS-cog score of 20.8 points (95% CI, 20.2–21.3); these values did not differ significantly between groups. Individuals with early-onset AD exhibited less functional impairment compared with those with late-onset AD (IADL score, 13.9 points (95% CI, 13.0–14.8) vs 16.3 points (95% CI, 15.9–16.7); P < 0.001 and PSMS score, 6.7 points (95% CI, 6.5–6.9) vs 7.6 points (95% CI, 7.5–7.8); P < 0.001)) and took fewer concomitant medications (1.8 (95% CI, 1.5–2.0) vs 3.1 (95% CI, 3.0–3.3); P < 0.001). During the study, the mean annual deterioration in ADAS-cog score from baseline for the early- and late-onset groups was 5.0 points (95% CI, 3.7–6.4) vs 2.9 points (95% CI, 2.4–3.5; P = 0.003). The corresponding declines/year for the entire cohort were 1.3 points (95% CI, 0.9–1.8) for MMSE score, 2.7 points (95% CI, 2.4–2.9) for IADL score, and 1.2 points (95% CI, 1.1–1.4) for PSMS score; these did not differ significantly between groups. Twenty-three percent of all patients were admitted to nursing homes during the study, and 38% completed the 3-year SATS; these values did not differ significantly between groups. After 3 years, 6% of the early- and 15% of the late-onset individuals had died (P = 0.002). The ChEI dose received during the study did not differ between groups. Conclusion: This AD study performed in a routine clinical setting shows that more sensitive cognitive measures such as ADAS-cog are required to detect the potential faster decline among early-onset AD patients. Despite better functional performance and fewer concomitant medications at the start of ChEI treatment, early-onset patients had a similar rate of deterioration in ADL and need for institutionalization to the late-onset group. This emphasizes the clinical importance of functional assessments even among younger patients. The possibility of younger individuals living longer after a diagnosis of AD raises questions about the need to provide 24-hour care adapted specifically for this group. (Less)