Long Term Outcome and Prediction Models of Cognition, Activities of Daily Living and Nursing Home Placement in Alzheimer’s Disease with Cholinesterase Inhibitor Treatment

Background Prospective longitudinal studies in Alzheimer's disease (AD) that include cholinesterase inhibitor (ChEI) treatment in routine clinical settings are scarce. The patients vary in severity of the disease, clinical course, rate of progression and response to treatment. Knowledge about the predicted course of the disease, sociodemographic and clinical factors affecting the outcome and the impact of ChEI therapy, could be valuable for clinicians and the social services. This information is also essential for clinical research and for evaluating new therapies. Aims Study aims are to investigate potential predictors of change, differences in long-term outcome and rates of decline, and the time to nursing home placement for ChEI-treated AD patients in clinical practice. Material Swedish Alzheimer Treatment Study - outpatients with a clinical dementia diagnosis, and probable or possible AD, were recruited from memory clinics across Sweden. Cognitive, global and Activities of Daily Living (ADL) assessments were performed at the start of ChEI treatment and every 6 months during the following 3 years. I. 435 donepezil-treated patients II. 843 patients treated with donepezil, rivastigmine or galantamine III. 790 patients treated with donepezil, rivastigmine or galantamine IV. 880 patients treated with donepezil, rivastigmine or galantamine Results I. Regression models predicted 3-year cognitive outcome in ChEI-treated patients with high accuracy at the group level, but not individual patient responses. II. A higher dose of ChEI, male gender, older age, absence of the APOE ε4 allele or usage of NSAIDs/acetylsalicylic acid were predictors of improved cognitive response to ChEI treatment after 6 months, and of a more positive long-term outcome. III. Lower cognitive status at baseline, older age, higher education level, and solitary living were identified as risk factors for faster decline in functional ability, whereas a higher dose of ChEI, regardless of drug agent, was related to a slower instrumental ADL decline. IV. The rate of functional, but not cognitive, deterioration was a strong risk factor for nursing home placement. The males living alone, patients with a substantial increase in adult day care or those receiving a lower mean dose of ChEI during the study exhibited shorter time to institutionalization. Conclusions Instrumental ADL ability is an essential measure for predicting longitudinal outcome and nursing home placement in AD. Patients with more cognitive impairment and older individuals exhibited a better response to ChEI therapy, stressing the importance of treating these groups as well. A higher ChEI dose, irrespective of drug agent, could possibly lead to more favorable cognitive and functional outcomes

Prediction Models for Assessing Long-Term Outcome in Alzheimer's Disease: A Review.

In Alzheimer's disease (AD), placebo-controlled long-term studies of cholinesterase inhibitors (ChEIs) are not permitted for ethical reasons. Therefore, in these studies, patients' outcomes on cognitive and functional assessment scales must be compared with mathematical models or historical data from untreated cohorts. PubMed and previously published long-term extensions of clinical trials and naturalistic studies of ChEIs were examined to identify empirical statistical models and other approaches, such as use of data from historical cohorts or extrapolated changes from extension studies, that were used to draw comparisons between ChEI-treated and untreated patients. The models and methods were described. It is essential to be aware of the limitations of comparisons made with these approaches. Prediction models based on ChEI-treated patients can be used in the studies of new treatments when those treatments are added to ChEIs. More sophisticated models that also accommodate patient-specific characteristics should be developed for comparisons in future long-term AD studies

The Influence of Level of Education on Instrumental Activities of Daily Living in Patients with Alzheimer’s Disease.

Background: According to the “brain-reserve hypothesis” in Alzheimer’s disease (AD), patients with more years of education are expected to have higher cognitive status during adulthood. Hence, they might have a relatively larger burden of AD pathology and a more advanced level of the disease when dementia is clinically evident. Higher educated people would also be expected to perform better on standardized cognitive tests that use a single threshold to identify dementia, such as Mini-Mental State Examination (MMSE). These factors might lead to a later manifestation of the typical symptoms of AD and detection of the disease. Thus, diagnosis and treatment might occur in a later stage, which may impair the results of AD therapy. The period in which higher educated individuals experience clinical AD might be shortened, with faster disease progression and earlier death. A higher education level has been associated with more rapid cognitive decline in several studies; however, the relationships between functional abilities and education are less investigated. Objectives: This long-term study aimed to investigate the potential associations between years of education and aspects of Instrumental Activities of Daily Living (IADL) capacity in AD. Methods: The Swedish Alzheimer Treatment Study (SATS) is a prospective, observational multicenter study used for assessing longitudinal effectiveness of cholinesterase inhibitor (ChEI) treatment in a routine clinical setting. Among the 1,258 outpatients clinically diagnosed with probable or possible AD, 1,021 had mild-to-moderate AD (MMSE score, 10–26) at the start of ChEI therapy (baseline). Of these, 767 individuals had lower (9 years) education level, and education level was missing for 2; thus, 1,019 patients were enrolled in the present study. Participants were assessed for cognitive (MMSE) and functional performance (IADL and Physical Self-Maintenance Scale [PSMS]) at baseline and every 6 months for 3 years. The date of death was recorded over 20 years. Cox proportional-hazards regression was used to determine characteristics that affected survival: sex, number of apolipoprotein E e4 alleles, solitary living, duration of AD, age at baseline, specific concomitant medications, and cognitive and functional abilities at baseline and their rates of deterioration. Results: The IADL status at baseline was worse in patients with lower education than those with higher education, mean (95% confidence interval [CI]) 16.3 (15.9–16.7) vs. 14.9 (14.2–15.6) points, p < 0.001. The higher educated group demonstrated faster IADL progression, but not cognitive decline, from the 24-month assessment and onwards (p < 0.011). The IADL capacity was already markedly impaired at baseline; about 45–65% of the participants with higher education and 55–75% of those with lower education were dependent on assistance to perform these activities (IADL score, 2–5). The percentage of patients with impairment in the individual IADL items: “ability to use telephone,” “shopping,” “mode of transportation,” and “responsibility for own medications” and “ability to handle finances,” was significantly lower at baseline in the higher educated cohort. After 3 years, the IADL capacity had deteriorated further; 70–90% of the remaining participants still living at home in both groups could not perform these tasks independently. No significant difference in any of the individual IADL items was found between the groups. Thus, the patients with higher education showed faster deterioration in the abovementioned tasks during the 3-year study.After 20 years of follow-up, 733 (96%) of the participants with lower education and 231 (92%) of those with higher education had died, p = 0.017. Patients with lower education were older at death than those with higher education, mean (95% CI) 82.9 (82.4–83.3) vs. 80.2 (79.2–81.2) years, p < 0.001). In the Cox regression models, risk factors for shorter lifespan in all individuals were male sex, older age, and faster basic ADL progression. In the lower educated cohort, use of antidiabetics or antihypertensive/cardiac therapy, worse cognitive or basic ADL capacity at baseline, and more rapid cognitive decline were independently observed to decrease survival time. In participants with higher education, lower IADL performance at baseline predicted shorter life expectancy. Conclusion: The present study highlights the clinical importance of functional evaluations in AD. Participants with lower education, who were ~2.5 mean years older, had worse functional status at baseline than those with higher education; however, the higher educated group deteriorated faster over a longer time in several individual IADL items. The patients with higher education were almost 3 years younger at death, on average. Common risk factors for death, such as use of antihypertensive/cardiac therapy or antidiabetics and cognitive impairment, were found in lower educated, but not in higher educated individuals. IADL capacity at baseline was an important predictor of survival in participants with higher education only. These results indicate that the consequences of dementia, such as cognitive and functional outcomes and comorbidities, have different impacts on the course of AD and prognosis in patients with various levels of cognitive reserve

Sex differences between early- and late-onset Alzheimer’s disease.

Objectives: To examine potential sex differences in longitudinal cognitive and activities of daily living (ADL) performance and life expectancy between early- and late-onset Alzheimer’s disease (AD). Methods: The Swedish Alzheimer Treatment Study is a prospective, observational, multicentre study that was used in a routine clinical setting including 1,017 patients diagnosed with mild-to-moderate AD at the initiation of cholinesterase inhibitor therapy. The participants were investigated using cognitive and functional assessment scales at baseline and every 6 months over 3 years. The date of death was documented for 20 years. Results: In late-onset AD (LOAD), but not in early-onset AD (EOAD), women exhibited a greater proportion of apolipoprotein E (APOE) ε4 carriers than men (71% vs. 58%, p<0.001). In women, but not in men, a larger frequency of solitary living (49% vs. 24%, p<0.001) and a lower education level (mean, 95% confidence interval; 9.1, 8.9–9.2 vs. 10.1, 9.5–10.8 years; p<0.001) were found in LOAD compared with EOAD. In only LOAD, men had worse instrumental ADL capacity at baseline than women (17.1, 16.5–17.7 vs. 15.9, 15.4–16.3 points; p<0.001). No difference in cognitive ability at baseline was detected. In only women, the deterioration per year in Alzheimer’s Disease Assessment Scale–cognitive subscale was faster in EOAD compared with LOAD (5.8, 3.9–7.8 vs. 3.0, 2.3–3.7 points; p=0.013). Functional rates of progression did not differ between the groups. In only LOAD, women demonstrated an older age at death than men (84.4, 83.9–84.8 vs. 82.9, 82.3–83.5 years; p<0.001). Conclusions: The higher proportion of APOE ε4 carriers in women with LOAD compared with men with LOAD suggests more hereditary forms of AD in older women. Women with EOAD showed almost twice as fast long-term cognitive decline than both LOAD groups (irrespective of sex), which might imply a more aggressive disease in younger women. In only LOAD, older age at death and longer survival time after AD diagnosis were observed in women compared with men. Thus, the common risk factor for earlier death, male sex, was not found in EOAD

The interaction effect of sex and apolipoprotein E genotype in Alzheimer’s disease—rates of progression and prognosis.

Objectives: To investigate the interaction effect of sex and apolipoprotein E (APOE) genotype on long-term cognitive and functional outcomes and survival in Alzheimer’s disease (AD). Methods: The Swedish Alzheimer Treatment Study (SATS) is a prospective, observational, multicentre study in clinical practice involving 999 participants diagnosed with mild-to-moderate AD at the start of cholinesterase inhibitor treatment (time of diagnosis). The patients were evaluated using Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS–cog), Instrumental Activities of Daily Living scale (IADL) and Physical Self-Maintenance Scale (PSMS) at baseline and semi-annually over 3 years, and date of death was recorded for 20 years. Results: The frequency of APOE ε4-carriers differed between sexes, 60% of males and 73% of females had 1 or 2 alleles (p < 0.001). The ε4-carriers were younger than non-ε4-carriers at the estimated onset of AD and at diagnosis in both sexes, and younger at death in males. After 3 years, decline in ADAS–cog was faster in both female APOE ε4-carriers, mean (95% confidence interval), 8.2 (6.5–9.8) and non-ε4-carriers 9.4 (6.4–12.3) points, than in male non-ε4-carriers 3.8 (0.9–6.7) points, (p = 0.036). Functional deterioration was faster in female non-ε4-carriers than in male non-ε4-carriers, IADL: 8.1 (6.8–9.4) vs. 4.9 (3.6–6.2) points (p = 0.007), and PSMS: 3.8 (3.0–4.7) vs. 2.2 (1.3–3.0) points (p = 0.033). These differences were not detected among ε4-carriers. Conclusions: The effect of APOE genotype differed between sexes in AD. Male ε4-carriers showed 2 years earlier death than male non-ε4-carriers. Female non-ε4-carriers demonstrated worse cognitive and functional prognosis than male non-ε4-carriers

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

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