Early- versus Late-Onset Alzheimer’s Disease—Differences in Functional Impairment.

Background: Persons with clinical onset of Alzheimer’s disease (AD) before 65 years of age are diagnosed with early-onset AD (EOAD). The prevalence of EOAD is low, but varies among studies from 6% to 16%. Most individuals with EOAD are still working, have an active social life, and might have children living at home. Therefore, the consequences of being diagnosed early with a disease that implies progressive deterioration of cognitive performance and activities of daily living (ADL), and personality and behavior changes, are enormous. These individuals may also have a decreased average life expectancy of 15–18 years. Some studies suggest that EOAD might be a separate, more severe entity than late-onset AD (LOAD). Neuropathological studies have found that younger patients exhibit a higher burden of AD pathology and a larger, more widespread cholinergic deficit than older patients. A faster cognitive progression among patients with EOAD has also been described. The clinical diagnosis of AD in younger persons can be difficult because of atypical symptoms and/or nonamnestic presentations. The present study aimed to investigate the functional outcomes in EOAD versus LOAD, and potential predictors of nursing home placement (NHP). Methods: The Swedish Alzheimer Treatment Study (SATS) is a 3-year, prospective, observational, multicenter study that investigated the long-term effectiveness of cholinesterase inhibitor (ChEI) treatment from various perspectives, e.g., cognition, ADL, and community-based service usage. Among the 1,258 outpatients clinically diagnosed with probable or possible AD, 1,021 had mild-to-moderate AD (Mini-Mental State Examination [MMSE] score, 10–26) at the start of ChEI therapy (baseline). Of these, 143 patients were defined as having EOAD (onset =65 years), and age at onset was missing for 4; thus, 1,017 patients were enrolled in the present study. Participants were assessed for cognitive ability (MMSE) and functional capacity (Instrumental Activities of Daily Living [IADL] scale and Physical Self-Maintenance Scale [PSMS]). The NHP date was recorded if this occurred during the study. Binary logistic regression was used to determine the patient characteristics that affected NHP. Potential predictors were investigated, including: sex, apolipoprotein E e4 carrier status, solitary living, years of education, duration of AD, age at baseline, specific concomitant medications, and cognitive and functional abilities at baseline and their rates of decline. Results: A significant difference in mean (95% confidence interval) IADL score at the start of ChEI treatment was observed between participants in the EOAD and LOAD groups, 13.9 (13.0–14.8) vs. 16.3 (15.9–16.7) points, p<0.001. The corresponding PSMS scores were 6.7 (6.5–6.9) vs. 7.6 (7.5–7.8) points, p<0.001. The IADL capacity was already markedly impaired at baseline; about 40–65% of the participants with EOAD and 55–75% of those with LOAD were dependent on assistance to perform these activities (IADL score, 2–5). The percentage of participants with impairment in the individual IADL items was significantly lower at baseline in the EOAD cohort, except for the “ability to handle finances” task. After 3 years, the IADL capacity had deteriorated further; 70–90% of the remaining participants in both groups could not perform these tasks independently. Thus, younger individuals showed a faster decline in some tasks including “ability to use telephone,” “shopping,” “food preparation,” and “housekeeping.” However, the participants with LOAD still showed worse capacity in “laundry,” “mode of transportation,” and “responsibility for own medications.”Except for physical ambulation (more than 50% of the individuals with LOAD needed assistance; PSMS score, 2–5), most participants could manage their basic ADL independently at baseline. A significantly larger percentage of the participants with LOAD were impaired in the ADL items: “toilet,” “physical ambulation,” and “bathing.” After 3 years, 35–55% of the remaining participants needed assistance in “dressing,” “grooming,” and “bathing.”The mean time from commencing ChEI therapy to institutionalization for participants with EOAD (n=26) and LOAD (n=205), was 22.3 (18.7–25.8) vs. 19.3 (18.0–20.7) months (p=0.156), and the survival time in nursing homes was 4.6 (3.4–5.8) vs. 4.0 (3.6–4.4) years (p=0.352), which were similar between the groups. In a logistic regression model, NHP risk factors for all participants were solitary living, worse IADL capacity at baseline, and faster IADL decline during the study. In the EOAD cohort, more years of education and use of antihypertensives/cardiac therapy, were independent predictors of a lower risk of institutionalization. Conclusion: The present study highlights the clinical importance of functional evaluations for individuals with EOAD. Patients in the LOAD group had significantly worse functional ability at baseline than those with EOAD; however, younger patients deteriorated faster in some individual items. Performance in IADL, but not cognitive ability, predicted NHP in both groups. A similar need for NHP and survival time in nursing homes might be expected for both groups, which is important knowledge for community-based services. Among patients with EOAD, higher education or antihypertensives/cardiac therapy might predict less risk of institutionalization

Functional response to cholinesterase inhibitor therapy in a naturalistic Alzheimer's disease cohort

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

Activities of daily living - Outcome during two years in galantamine treated Alzheimer patients

122 patients with Alzheimer's disease receiving galantamine in the Swedish Alzheimer Treatment Study were studied with respect to longitudinal change in cognition (MMSE and ADAS-cog) and function (IADL, PSMS and FAST). Particularly the FAST mean change from baseline showed a linear relationship with cognitive mean change and the strength of the relationship increased over time. The IADL scale demonstrated a faster decline of function, but significantly less than expected by using the mathematical model by Green et al. A cluster analysis was performed to reveal any natural groupings of the patients based on the functional scores at baseline. The two-cluster solution was significant; patients in cluster 1 were more cognitively impaired at baseline, they were less apt to carry the APOE e4 allele and declined faster in the outcome of PSMS score compared to the other group

Risk Factors for Nursing Home Placement in Cholinesterase Inhibitor Treated Naturalistic Alzheimer Patients.

Aims: To analyse which factors influence nursing home placement (NHP) and time until NHP in long-term cholinesterase inhibitor treated patients with Alzheimer’s disease (AD). Methods: The Swedish Alzheimer Treatment Study (SATS) is an open, on-going, non-randomized, multicentre study in a routine clinical setting. Patients with the diagnosis of AD, living at home at the time of inclusion, receive treatment with donepezil, rivastigmine or galantamine. They are assessed with MMSE, ADAS-cog, IADL and PSMS at baseline and every 6 months over the course of 3 years. The first 883 subjects that had the opportunity to complete the full study were investigated concerning NHP; 210 of these patients were admitted to nursing homes. The following risk factors for the event NHP (Chi-square and T-tests) and the time until NHP (Cox regression) were investigated: gender, APOE e4-carrier, living alone or with spouse, education level, age, illness duration, cognitive and functional level at baseline and decline in cognition and function prior to NHP. Results: Females (p=0.002), patients living alone (p<0.001), older age (p=0.002), longer illness duration (p=0.004) and lower cognitive and functional status at baseline (p<0.001) are risk factors for admission to a nursing home. The distribution of time until NHP was significantly affected by gender (p=0.048), living alone (p<0.001) and MMSE and IADL score at baseline (p<0.001). Conclusions: Female gender, patients living alone and lower cognitive or functional ability at baseline demonstrated larger risk of early NHP. Cognitive or functional decline prior to NHP did not influence time until NHP

Living Alone in Alzheimer’s Disease—The Influence of Functional Impairment.

Background: A large number of individuals with Alzheimer’s disease (AD) live alone and receive little or no help from family members, which implies an additional pressure on the increasing societal costs of dementia care. Their adult children, if any, might have very limited ability to assist by providing informal help because of social structural changes, such as full-time work for most women and sometimes a place of residence located far away from the parents’ home. About half of the informal help received has been reported to consist of surveillance, diversion from repetitive or dangerous activities, and management of behavioral disturbances. Lack of help in monitoring these expressions of AD might lead to safety issues for individuals who live alone. Moreover, difficulties in detecting increasing impairments in their cognitive and functional abilities could affect negatively the opportunities of solitary-living individuals to receive necessary formal help. Living alone with dementia is also a strong factor for nursing home placement. This study aimed to describe the cognitive and functional abilities of solitary-living AD patients, as well as the potential predictors of usage of community-based home help services (HHS). Methods: The Swedish Alzheimer Treatment Study (SATS) is a prospective, open, nonrandomized, multicenter study that was undertaken the investigation of the long-term effectiveness of cholinesterase inhibitor (ChEI) treatment from various perspectives, such as cognition, activities of daily living (ADL), and usage of community-based services. Among the 1,258 outpatients with a clinical diagnosis of probable or possible AD in the SATS, 1,021 had mild-to-moderate AD (Mini-Mental State Examination (MMSE) score, 10–26) at the start of ChEI therapy (baseline). Three hundred fifty-five (35%) of these individuals were living alone at the baseline, with or without HHS, and were included in the current study. Patients were assessed regarding cognitive ability (MMSE), functional capacity (Instrumental Activities of Daily Living (IADL) scale and Physical Self-Maintenance Scale (PSMS)), and the amount of HHS (hours/week), at baseline and every 6 months for a total period of 3 years. Binary logistic regression was used to determine the individuals’ characteristics that affected the use of HHS at baseline. The following potential predictors were investigated: gender, APOE 4 carrier status, years of education, illness duration, age, number of medications, and cognitive and functional abilities at baseline. Results: At the start of ChEI therapy, 267 (75%) of the solitary-living patients were in the mild stage of AD (MMSE score, 20–26). HHS was used by 85 (32%) of the mild and 48 (55%) of the moderate (MMSE, 10–19) AD patients (P < 0.001). The mean hours of HHS used per week was 5.7 (95% confidence interval (CI), 5.0–6.5); no difference in this parameter was detected among the disease stages. The IADL capacity was already markedly impaired at baseline: 50–65% of the individuals were dependent on assistance to perform these activities (IADL score, 2–5). Regarding basic ADL, most patients were able to manage themselves independently, with the exception of physical ambulation (almost 60% of individuals needed some assistance; PSMS score, 2–5). A significant difference in mean IADL score at the start of ChEI treatment was observed between the mild and moderate AD patients: 14.6 points (95% CI, 13.9–15.2) vs 19.2 points (95% CI, 18.1–20.3; P < 0.001). The corresponding PSMS scores were 7.5 points (95% CI, 7.2–7.7) vs 8.9 points (95% CI, 8.2–9.6; P < 0.001). No difference in age or number of medications at baseline was found among the disease stages. In a logistic regression model, the variables IADL score (OR, 1.27; 95% CI, 1.17–1.38; P < 0.001) and number of medications at baseline (OR, 1.19; 95% CI, 1.07–1.33; P = 0.002) correctly classified 80.2% of the patients with AD regarding whether they used HHS at the start of ChEI therapy. After 3 years of ChEI treatment, 89 AD patients (25%) were still living alone in their own home. Of those, 65 individuals used a mean of 9.5 hours (95% CI, 7.8–11.3) of HHS per week. The cognitive ability of the solitary-living patients varied appreciably, but 80–90% could not carry out IADL tasks independently. In addition, more than 50% of the individuals needed assistance in performing the basic ADL items of grooming and physical ambulation. Conclusions: A substantial number of AD patients, predominantly females, with severe cognitive and functional impairments live alone, which might lead to safety risks for these vulnerable individuals. The amount of HHS used did not reflect disease severity. Functional, but not cognitive, ability predicted the need for home help, suggesting that HHS meets the needs related to cognitive deterioration to a lesser extent. Increased knowledge about how community-based services can better accommodate the care needs of recipients with cognitive impairment is essential

Activities of Daily Living – Outcome During Three Years in Donepezil Treated Alzheimer Patients.

Objectives: To analyse and present the outcome of longitudinal change and possible subgroups with respect to Activities of daily living (ADL) function measured by different scales (PSMS, FAST and IADL) in patients treated with donepezil for three years (n=435). Methods: The Swedish Alzheimer Treatment Study (SATS) is an open, 3-year, multicentre study in a routine clinical setting. The patients were assessed with several rating scales including ADL at baseline and every 6 months for a total period of three years. IADL scores were compared to the expected change in untreated patients based on a mathematical model by Green et al. A two-step cluster analysis was performed to reveal any natural groupings (clusters) of the patients based on the ADL scores at baseline. Results: After three years of donepezil treatment the total mean change in PSMS score was 3,2 ± 3,6 and in FAST 1,8 ± 2,1 points. The three-year change in IADL-score was 6,1 ± 5,4 points whereas the expected change using the mathematical model was 15,8 ± 5,6 points. The different ADL scales were linearly correlated with each other and with cognition measured by MMSE and ADAS-cog at all assessment points. However, the strength of the relationship increased over time with p-values < 0,000 from 18 months and onwards. The three scales showed no significant difference between gender at baseline but after three years the IADL mean decline from baseline was significantly worse among women. A cluster analysis showed two subgroups that significantly differed in age (p<0,000), duration (p<0,05) and cognition (p<0,000) at baseline. No significant difference in gender, APOE e4-carriers or mean dose of donepezil was observed. The two subgroups also deviated significantly in the long-term outcome of ADL score particularly measured by the PSMS scale (0,000<p<0,05). Conclusions: Increasing strength in the linear correlation between the three ADL scales as well as cognition was observed during the three years of the study. The IADL scale showed a decline of function less than expected compared with untreated patients in a mathematic model. Long term IADL scores deteriorated significantly more in the female gender than in the male. Cluster analysis based on ADL scores at baseline, identified two subgroups: with different mean age and cognitive ability and dissimilar rate of change in functional decline predominantly shown by the PSMS scale

Galantamine treatment in Alzheimer’s disease: response and long-term outcome in a routine clinical setting

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

Plasma concentration of galantamine - influence of dose and body mass index in Alzheimer’s disease.

Background/objectives: Patients with Alzheimer’s disease (AD) are at present treated with galantamine without actual knowledge of plasma concentration levels. The aim of this presentation is to analyse the relationship between galantamine plasma concentration, dose, demographics and body mass index (BMI). Methods: A total of 84 AD patients recruited at the Memory Clinic in Malmö, Sweden, treated with galantamine were included in this study. The patients were investigated at baseline, at 2 months and every 6 months for a period of three years. Blood samples were obtained at 180 of these investigations for the analysis of plasma galantamine concentration. Efficacy measures including cognitive tests (MMSE), functional ratings (IADL) and BMI were simultaneously evaluated. The dose as well as the time from drug intake to plasma extraction was investigated. Results: The mean galantamine plasma concentration demonstrated a strong positive linear association with dose (r=0.51, p<0.001). Moreover, patients with separate doses of galantamine (8, 16 and 24 mg daily) differed significantly in plasma concentration (p<0.001). No gender differences regarding dose were observed. There was no linear relationship between galantamine plasma concentration and BMI in the entire cohort. When investigating the impact of gender, a negative linear association (r=-0.45, p=0.001) between concentration and BMI was found in the male group but not in the female. Age did not influence the plasma concentration level. In a multivariate general linear model with concentration as the dependent variable, gender (p=0.010) and BMI (p=0.038) but not age (p=0.540) were predictive factors. Conclusion: Galantamine plasma concentration demonstrated a strong relationship with dose. The dose did not differ between genders, whereas the impact of body mass index on plasma concentration was important only among the males

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

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