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Introduction: Knowledge of longitudinal progression in mild Alzheimer's disease (AD) is required for the evaluation of disease-modifying therapies. Our aim was to observe the effects of long-term cholinesterase inhibitor (ChEI) therapy in mild AD patients in a routine clinical setting., Methods: This was a prospective, open-label, non-randomized, multicenter study of ChEI treatment (donepezil, rivastigmine or galantamine) conducted during clinical practice. The 734 mild AD patients (Mini-Mental State Examination (MMSE) score 20 to 26) were assessed at baseline and then semi-annually over three years. Outcome measures included the MMSE, Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Clinician's Interview-Based Impression of Change (CIBIC) and Instrumental Activities of Daily Living (IADL) scale., Results: After three years of ChEI therapy, 31% (MMSE) and 33% (ADAS-cog) of the patients showed improved/unchanged cognitive ability, 33% showed improved/unchanged global performance and 14% showed improved/unchanged IADL capacity. Higher mean dose of ChEI and lower educational level were both predictors of more positive longitudinal cognitive and functional outcomes. Older participants and those with a better IADL score at baseline exhibited a slower rate of cognitive decline, whereas younger participants and those with higher cognitive status showed more preserved IADL ability over time. Gender and apolipoprotein E (APOE) genotype showed inconsistent results. Prediction models using the abovementioned scales are presented., Conclusions: In naturalistic mild AD patients, a marked deterioration in IADL compared with cognitive and global long-term outcomes was observed, indicating the importance of functional assessments during the early stages of the disease. The participants' time on ChEI treatment before inclusion in studies of new therapies might affect their rate of decline and thus the comparisons of changes in scores between various studies. An increased understanding of expected disease progression in different domains and potential predictors of disease progression is essential for assessment of future therapies in AD.

Introduction: Patients with Alzheimer's disease (AD) are currently treated with cholinesterase inhibitors, such as galantamine, without actual knowledge of its concentration in plasma. Our objective was to analyse potential relationships between galantamine concentration, galantamine dose, socio-demographic characteristics, body weight, body mass index (BMI), and treatment response., Methods: Eighty-four patients with AD recruited from the Memory Clinic, Malmö, Sweden, and treated with galantamine were included in the study. Efficacy measures, including cognition (Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog)) and instrumental activities of daily living (IADL), were evaluated at baseline, 2 months after treatment initiation (MMSE only) and semi-annually over 3 years. At these assessments, blood samples were obtained for the analysis of the galantamine concentration, and body weight, BMI, drug dose and time from drug intake were recorded., Results: All patients had a measurable concentration of galantamine at all assessments. The mean plasma concentration of the drug exhibited a positive linear association with dose (r = 0.513, P < 0.001). The dose did not differ between sexes. Negative linear associations between the galantamine plasma concentration and BMI (r = -0.454, P = 0.001) or body weight (r = -0.310, P = 0.034) were found exclusively in the male group. When mixed-effects models were used, the dose of galantamine (P < 0.001), time from drug intake (P < 0.001), and BMI (P = 0.021) or weight (P = 0.002) were factors that predicted the concentration, whereas sex, age, and cognitive and functional changes were not., Conclusions: High compliance to galantamine treatment was found among all patients in this naturalistic AD study. The impact of BMI or body weight on the plasma concentration of galantamine was important only among males. No relationship was observed between concentration and short-term treatment response or progression rate in terms of cognitive and functional abilities.

Background: Activities of daily living (ADL) are an essential part of the diagnostic criteria for Alzheimer's disease (AD). A decline in ADL affects independent living and has a strong negative impact on caregiver burden. Functional response to cholinesterase inhibitor (ChEI) treatment and factors that might influence this response in naturalistic AD patients need investigating. The aim of this study was to identify the socio-demographic and clinical factors that affect the functional response after 6 months of ChEI therapy., Methods: This prospective, non-randomised, multicentre study in a routine clinical setting included 784 AD patients treated with donepezil, rivastigmine or galantamine. At baseline and after 6 months of treatment, patients were assessed using several rating scales, including the Instrumental Activities of Daily Living (IADL) scale, Physical Self-Maintenance Scale (PSMS) and Mini-Mental State Examination (MMSE). Demographic and clinical characteristics were investigated at baseline. The functional response and the relationships of potential predictors were analysed using general linear models., Results: After 6 months of ChEI treatment, 49% and 74% of patients showed improvement/no change in IADL and in PSMS score, respectively. The improved/unchanged patients exhibited better cognitive status at baseline; regarding improved/unchanged PSMS, patients were younger and used fewer anti-depressants. A more positive functional response to ChEI was observed in younger individuals or among those having the interaction effect of better preserved cognition and lower ADL ability. Patients with fewer concomitant medications or those using NSAIDs/acetylsalicylic acid showed a better PSMS response., Conclusions: Critical characteristics that may influence the functional response to ChEI in AD were identified. Some predictors differed from those previously shown to affect cognitive response, e.g., lower cognitive ability and older age predicted better cognitive but worse functional response.

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.

Background: In the absence of long-term, placebo-controlled studies of cholinesterase inhibitors in Alzheimer's disease (AD), analysis of the results of open-label trials becomes crucial. This study aimed to explore the three-year effects of galantamine treatment, as well as subgroups of response and adherence to treatment., Methods: Two hundred and eighty patients with a clinical diagnosis of AD were included in the prospective, open-label, multicenter Swedish Alzheimer Treatment Study, and received galantamine treatment. Efficacy measures included cognitive tests, ie, the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-cog), functional rating (Instrumental Activities of Daily Living Scale [IADL]), and global rating. Assessments were carried out before treatment and every six months for a period of three years. K-means cluster analysis was used to identify response subgroups., Results: After three years of treatment, the mean change from baseline was 2.6 points in MMSE and 5.6 points in ADAS-cog scores. Globally, half of the patients improved or remained unchanged for two years. Cluster analysis identified two response clusters. Cluster 1 included patients with low ability in ADAS-cog and IADL scores at baseline. Even though the patients in cluster 1 were older and less educated, they responded better at six months compared with patients in cluster 2. Cluster 2 included patients with better ADAS-cog and IADL scores at baseline. Patients in cluster 2 had a higher frequency of the APOE ɛ4 allele, a slower pretreatment progression rate, and remained in the study longer than those in cluster 1. Three-year completers (n = 129, 46%) received higher doses of galantamine compared with dropouts., Conclusion: AD patients who received long-term galantamine treatment were cognitively and globally stabilized. Subgroup response analysis identified a better short-term response in older patients with lower cognitive and functional abilities at baseline, a faster pretreatment progression rate, and a lower incidence of the APOE ɛ4 allele. The galantamine dose was higher in the population of completers.

Early-onset dominantly inherited forms of Alzheimer's disease (AD) are rare, but studies of such cases have revealed important information about the disease mechanisms. Importantly, mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1) and PSEN2, alter the APP processing and lead to an increased amyloid β-peptide (Aβ) 42/40 ratio. This, together with other studies on pathogenic mechanisms, show that Aβ42 is a major player in the etiology of AD. Here, we present a clinical and neuropathological description of a Swedish family with an I143T mutation in the PSEN1 gene, which gives rise to a severe form of AD. We also performed an extensive investigation on the concentration and distribution of Aβ species of different lengths in six brain regions from two mutation carriers. Our study showed that Aβ42 and a longer peptide, Aβ43, were present both in plaque cores and in total amyloid preparations, and were each clearly more frequent than Aβ40 in all examined regions, as shown by both mass spectrometry and immunohistochemistry.

Background: The objective was to identify separate cognitive domains in the standard assessment tools (MMSE, ADAS-Cog) and analyze the process of decline within domains during three years in Alzheimer's disease (AD) patients with donepezil treatment., Method: AD patients (n = 421) were recruited from a clinical multi-centre study program in Sweden. Patients were assessed every six months during three years. All patients received donepezil starting directly after study entry. After dropouts, 158 patients remained for analyses over three years. Data for the other patients were analysed until they dropped out (4 groups based on length in study)., Results: Factor analyses of all items suggested that there were three intercorrelated factors: a General, a Memory and a Spatial factor for which we constructed corresponding domains. Overall there was a cognitive improvement at six months followed by a linear drop over time for the three domains. Some group and domain differences were identified. Patients who remained longer in the study had better initial performance and a slower deterioration rate. The early dropouts showed no improvement at six months and many dropped out due to side effects. The other groups displayed a performance improvement at six months that was less pronounced in the Memory domain. Before dropping out, deterioration accelerated, particularly in the Spatial domain., Conclusion: The course of illness in the three domains was heterogeneous among the patients. We were not able to identify any clinically relevant correlates of this heterogeneity. As an aid we constructed three algorithms corresponding to the cognitive domains, which can be used to characterize patients initially, identify rapid decliners and follow the course of the disease.