Date Published: August 31, 2017
Publisher: BioMed Central
Author(s): Carina Wattmo, Åsa K. Wallin.
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.
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. 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. 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.
People who have a clinical onset of Alzheimer’s disease (AD) before the age of 65 years are diagnosed with early-onset Alzheimer’s disease (EOAD). The prevalence of patients with EOAD is low, but it varies in studies from 6% to 16% [1–3]. Some observations suggest that EOAD might be a separate, more severe entity than late-onset Alzheimer’s disease (LOAD). Researchers in neuropathological studies have reported that younger patients with AD exhibited higher burdens of neuritic plaques and neurofibrillary tangles, as well as greater synapse loss, than older individuals . Moreover, patients with AD who died before 80 years of age had a more widespread and severe cholinergic deficit with abnormalities in other neurotransmitters (e.g., noradrenaline) compared with those who died at older ages . Regarding cognition, the patients with EOAD demonstrated more impairment in language and concentration, whereas the LOAD cohort showed difficulties in memory and orientation . Clinical diagnosis of AD is often missed in individuals with early onset because of the atypical symptoms and non-amnestic presentations . Younger persons are often more educated than older individuals and have a higher cognitive reserve capacity that could also lead to a delayed diagnosis . Therefore, antidementia therapy might be initiated in a later stage of the disease, which may impair the efficacy of treatment in EOAD.
In this study performed in routine clinical practice, the 6-month cognitive and global responses to ChEI therapy and the longitudinal outcomes after 3 years were similar between the age-at-onset groups; however, a somewhat faster decline in the EOAD group at some time points was detected when we used the ADAS-Cog scale. Homozygote APOE ε4 carriers were more frequent among the younger patients, but APOE genotype did not significantly affect disease progression in the multivariate models. The EOAD cohort received a higher ChEI dose than the LOAD group over the study period. A higher mean dose of ChEI, better cognitive status at the initiation of treatment and lower level of education were independent protective factors for a more favourable long-term cognitive performance in both groups. Risk factors for worse prognosis in LOAD were female sex, younger age, more impaired IADL capacity and use of antipsychotics.
A comparison of various aspects of disease progression between EOAD and LOAD was performed in this observational study. After 3 years, the cognitive and global rates of decline were similar between the age-at-onset groups; however, the more sensitive ADAS-Cog scale tended to exhibit a faster worsening among the younger individuals over this period. This information is necessary for the interpretation of results from clinical trials to evaluate the effectiveness of and provide realistic expectations for new potentially disease-modifying therapies (as add-ons to ChEIs) directed at AD cohorts of various ages. In addition, male sex, better IADL performance and no use of antipsychotics in the LOAD group, as well as fewer years of education in both groups, were protective factors of a more positive longitudinal cognitive outcome. Although the patients with EOAD included a larger proportion of carriers of two APOE ε4 alleles, this observation did not influence progression rate using multivariate models. The socio-demographic and clinical composition of an AD cohort under study may be one explanation for the heterogeneity of results presented in a number of reports. A higher mean dose of ChEI (regardless of drug agent) was associated with slower cognitive decline in both onset groups, but the older participants received a lower dose during most of the 3-year study period. This finding stresses the importance for clinicians to optimise the ChEI dose in AD, regardless of the individual’s age at onset, to improve treatment effectiveness. In summary, our results suggest that EOAD and LOAD are not separate entities. The younger patients’ longer time to AD diagnosis, higher level of education and thus cognitive reserve capacity might explain most of the differences detected between the groups.