Abstract
INTRODUCTION
The old age population has progressively increased over the last decades and, therefore, management of chronic diseases, such as dementia, is becoming a main public health problem. Alzheimer’s disease (AD) represents the most frequent cause of dementia, characterized by multiple cognitive deficits, decline of functional capacity, and presence of neuropsychiatric symptoms [1]. Since a curative therapy is not available yet, and it is widely accepted that a cholinergic defect plays a central role in cognitive impairment, cholinesterase inhibitors (ChEIs)— such as donepezil, galantamine, and rivastigmine— currently represent the only therapeutic approach considered effective by many randomized clinical trials [2]. However, although the prevalence of dementia increases markedly along with aging, therapeutic indications can be uncertain in very old subjects affected by AD. Despite onset at a younger age predicting a more severe and aggressive course of the disease, with a faster rate of cognitive and functional decline compared with later onset [3, 4], AD response to ChEI treatment has been shown to differ among age ranges. Bullock and colleagues [5] demonstrated that younger patients (≤75 years old) have a better response in term of cognitive and functional abilities as compared with the older ones. Moreover, the fact that some guidelines recommend discontinuation of treatment in patients without an initial response, as evaluated three or six months after the introduction of ChEI therapy, complicates the clinical approach [6, 7]. Thus, when a patient deteriorates on a global, cognitive, or functional status, he/she is considered as a “non-responder” and discontinuation of treatment is strongly recommended. For example, in Italy, ChEI therapy is subject to prescribing restrictions by the Agenzia Italiana del Farmaco (AIFA; Italian Medicines Agency), which, with a restrictive note (n.85; http://www.agenziafarmaco.gov.it/it/content/nota-85) controls the use of ChEIs. Accordingly, ChEIs may be prescribed only to subjects with mild to moderate AD and with a Mini-Mental State Examination (MMSE) score above 10. Patient response is reviewed after three months of treatment and then every six months. Continued reimbursement is contingent on proof of benefit based on cognitive stabilization or improvement as demonstrated by MMSE score after three months. These observations and limitations make questionable the use of these drugs but the evidence that it is appropriate to drop treatment in subjects considered as non-responders after three months is limited.
Very recently, it has been shown that discontinuing treatment solely on the absence of an initial response on cognitive functions is inappropriate. In fact, in a large population of patients with a mean age of 80 years, the authors showed that those considered as non-responders after six months of therapy had a slower rate of cognitive decline during the subsequent years of treatment as compared with subjects with a positive initial response [8]. Although ChEIs are widely used for treating AD, there is a lack of practice guidelines in case of absence of perceived effect. Most of the published research on this topic have strong limitations: for example, many studies evaluated the change in cognitive functions using the absolute score from the MMSE and not the rate of decline; another bias is that patients included in clinical trials usually are highly selected and therefore not representative of a typical geriatric population. Understanding the relationship between the initial response to ChEI treatment and the subsequent course of the disease is extremely important for the potential negative consequences of stopping a therapy that might be more efficacious along with time, especially in the old age population. Thus, evaluating more in detail the effect of age on the response to short and long lasting ChEI treatment is valuable. In light of such evidence, with this study we aimed to investigate the relationship between the initial cognitive and functional response to treatment with ChEIs and the subsequent long-term course in subjects with AD stratified by age ranges in a “real life” setting.
MATERIALS AND METHODS
Study design
This is a retrospective longitudinal study of subjects with AD treated with ChEIs (donepezil, rivastigmine, or galantamine) over three years in a “real life” setting. Since, according to most of the studies, the three available ChEIs do not differ in efficacy but only in safety [9, 10], we evaluated the effect of the pharmacological class. The sample was divided in two groups according to age: the “young-old” (≤75 years of age) and the “old-old” (≥76 years of age). Subjects were considered as “responders” if their MMSE score remained unchanged or increased after 3 months of treatment, and “non-responders” if their MMSE score decreased in the same period. Assuming that the natural history of untreated AD is characterized by an annual average decrease of 1.5–3.3 MMSE points [11, 12], we operatively defined progression of disease as a loss of ≥2 points peryear.
Setting and subjects
We retrospectively evaluated data of 628 old age subjects with mild or moderate AD followed at the Memory Clinics in Perugia (n = 466) and in Lamezia Terme (n = 162). All patients, diagnosed in accordance to standard clinical criteria [13, 14], were 65 years old or older and started, after the first evaluation, treatment with ChEIs. Since the definition of response is based on the change in MMSE score at baseline and after three months of treatment, patients considered in the study had to have both assessments. Patients who did not fulfill the diagnostic criteria for AD or with contraindications to ChEI treatment were excluded from the study. Subjects were evaluated in a well-structured follow-up program, which assessed cognition and functional capacity at the initiation of treatment, after three months and then every six months for a period of almost three years. After recruitment and baseline evaluation, patients were prescribed ChEIs according to the approved product recommendations. The choice of treatment (donepezil, rivastigmine, or galantamine) was left entirely to physician’s discretion and professional judgment. The ChEI dose was recorded after three months of treatment and then every six months. All patients and/or caregivers gave their written informed consent to participate in the study, which was conducted according to the provisions of the Helsinki Declaration and was approved by the Ethics Committees at our Institutions.
Assessment
Cognitive performances were evaluated with the MMSE, as test of general cognition, with a range from 0 to 30, in which a lower score indicates more impaired cognition [15]. Functional status was evaluated using the Katz Index of Independence in Activities of Daily Living (ADL) (from 0, worst to 6, best performance) [16] and Lawton-Brody Instrumental Activities of Daily Living (IADL) (from 0, worst to 8, best performance) [17]) scales. To avoid the underestimation of self-rated level of functional capacity, an informant-based rating of functional status was carried out.
Calculations and statistical analyses
The observed data were normally distributed (Shapiro-Wilk W-Test) and are presented as mean±standard deviation (SD). Statistical comparisons were performed with Student’s t test for continuous variables. Pearson χ2 was used to compare relative frequencies. Repeated-measure ANOVA was used to assess the efficacy of treatment, considering evaluation time as a within-subject factor and group as a between-subject factor. Logistic regression analyses were performed to estimate predictors of responsiveness. The IBM Statistical Package for the Social Sciences (SPSS) software (version 21.0; IBM Corporation, Armonk, NY, USA) was used to perform statistical analyses. The level of significance was defined as p < 0.05.
RESULTS
Descriptive analyses
628 patients with available follow up after three months were included in the study. All subjects were old (mean age 75.5±8.6) with a greater proportion of women (444 F/184 M). MMSE, ADL, and IADL at baseline were 18.9±4.4, 4.8±1.3, and 3.4±2.2, respectively. Women (70.7%) were older (76.1±7.8 versus 74.1±10.1 years; p = 0.008), had a lower education (4.9±3.2 versus 6.2±3.8 years; p < 0.0001), a later onset of the disease (74.7±8.3 versus 72.6±11.0 years; p = 0.011), a lower MMSE score at baseline (18.5±4.3 versus 19.8±4.4; p = 0.001), and a higher IADL score at baseline (3.7±2.3 versus 2.8±1.8; p < 0.0001), as compared with men. No significant differences on ADL score at baseline and disease duration were found between genders.
Clinical characteristics of all sample population stratified by age range (young-old ≤75; old-old ≥76) are displayed in Table 1. Old-old subjects had a lower education, a later onset as well as a lower duration of the disease, had a higher MMSE score, lower ADL and IADL scores at baseline, and a shorter time of follow up. No differences were found in gender distribution.
The most used treatment was donepezil, for 390 subjects (62.1%), then rivastigmine, for 201 (32.0%) and galantamine, for 37 (5.9%). During the first three months of treatment, the mean±standard deviation (SD) doses of donepezil was 8.07±2.43 (range: 5–10 mg), of rivastigmine 7.30±3.0 (range: 3–12 mg) and of galantamine 14.81±6.38 mg (range: 8–24 mg). No differences in drug type (χ2 = 4.103, p = 0.392) were found between young-old and old-old (p = 0.127). During the follow up, memantine was added in 99 (15.8%) patients and none included in the repeated measures analysis. 10 (1.5%) patients switched to monotherapy with memantine and excluded from repeated measures analysis.
Cognitive and functional outcomes: Responder versus non-responder groups
All treated subjects were divided into two groups according to the response after three months of ChEI treatment: unchanged/improved (defined as patients with a Δ MMSE ≥0 after three months of treatment with ChEIs) indicated as “responder” (n = 351, 55.8%), and declined (defined as Δ MMSE <0 after three months of treatment with ChEIs) indicated as “non-responder” (n = 277, 44.2%). The socio-demographic and clinical characteristics of the two groups are displayed in Table 2. The responder group was mostly represented by women, younger subjects, with a younger age at onset of the disease, higher education, and, at baseline, lower MMSE but higher ADL and IADL scores. No difference in ChEI type (p = 0.222) was detected between responders and non-responders at baseline.
A logistic regression analysis having ‘response to treatment after three months’ as dependent variable, revealed that a younger age, independently of multiple covariates, was associated with a higher probability of response (Table 3). A positive association was found also for higher educated subjects, with a lower MMSE at baseline and higher ADL score. To investigate whether there was a difference in the course of the disease in cognitive and functional status between responders and non-responders, we applied repeated measures analyses developed for longitudinal continuous data. Repeated-measure ANOVA, after correction for age, gender, and education, was performed in a subgroup of 247 subjects who had six follow-up evaluations (namely after 3, 9, 15, 21, 27, and 33 months from baseline) as within-subject factors and the group-distinction (responders, n = 143 versus non-responders, n = 104) as between-subject factors. Three separate analyses were performed for each variable: MMSE, ADL, and IADL scores (Fig. 1). ANOVA showed a significant main effect of time (F = 11.603, p < 0.0001) and between groups (F = 14.830, p < 0.0001) in MMSE. During the three years of observation the MMSE score of the non-responders was lower than that of the responders but with a mean annual decline of 1.0 point versus 1.6 points (p < 0.0001). A significant main effect of time in ADL decline was found (F = 6.187, p < 0.0001) but it did not differ significantly between groups (F = 1.237, p = 0.267). The ADL score of non-responders was similar to that of responders with a mean annual ADL decline of 0.52 points versus 0.60 points, respectively (p = 0.698). A significant main effect of time (F = 16.738, p < 0.0001) but not between groups (F = 1.504, p = 0.221) in IADL was found. During the three years the IADL score was similar between groups with a mean annual IADL decline of 0.72 points versus 0.69 points in non-responders and responders, respectively(p = 0.782).
Cognitive and functional outcomes: Exploring the age effect
To better clarify the role of age in ChEI response, we performed a repeated-measure ANOVA after correction for gender and education in the subgroup of 247 patients considering the seven clinical evaluations along with time (baseline, 3, 9, 15, 21, 27, and 33 months) as within-subject factors, and the group-distinction (young-old n = 98 and old-old n = 149) as between-subject factors for MMSE, ADL, and IADL variables (Fig. 2). The analysis showed a significant main effect of time (F = 22.571, p < 0.0001) and between groups (F = 4.697, p = 0.031) in MMSE. During the three years of observation, the rate of decline in MMSE score (adjusted for gender and education) of the old-old subjects was lower as compared with the young-olds, with a mean annual MMSE decline of 1.0 points versus 1.32 points, respectively (p = 0.004).
The ANOVA showed a significant main effect of time (F = 43.720, p < 0.0001) and between groups (F = 18.131, p < 0.0001) in ADL. During the three years of follow-up the fitted ADL score of the old-old subjects was lower as compared with the young-olds with a mean annual ADL decline of 0.45 points versus 0.59 points respectively (p = 0.038). A significant main effect of time (F = 50.317, p < 0.0001) and between groups (F = 23.839, p < 0.0001) in IADL also were found. During the three years, the fitted IADL score of old-olds was lower than young-olds with a mean annual IADL decline of 0.60 points versus 0.77 points, respectively (p = 0.028).
Stratifying all subjects as responders and non-responders according to the age group, repeated-measure ANOVA showed, during the three years, a significantly slower progression of the disease [as shown by MMSE adjusted for gender and education (p < 0.0001), ADL (p < 0.0001), and IADL (p < 0.0001)] in the old-old non-responders as compared with other groups. In detail, old-old non-responders (n = 73) had a mean annual decline in MMSE score of 0.86; young-old non-responders (n = 31) of 1.34; old-old responders (n = 76) of 1.31; and young-old responders (n = 67) of 1.90. On ADL, old-old non-responders had a mean annual decline of 0.42; young-old non-responders of 0.69; old-old responders of 0.50; and young-old responders of 0.64. On IADL, old-old non-responders had a mean annual decline of 0.57; young-old non-responders of 0.87; old-old responders of 0.61; and young-old responders of 0.79.
Indeed a logistic regression having progression of disease (indicated as the decrease at MMSE of ≥2 points each year) as dependent variable, showed that older age was associated with a lower probability of progression of the disease independently of multiple covariates including gender, education, MMSE, ADL, and IADL scores at baseline, and, overall, the initial response to treatment (Table 4).
DISCUSSION
Data from randomized controlled trials with ChEIs, in addition to poorly reflecting real world situation, provide little information about their long-term effects, especially among old aged subjects. To our knowledge, this is one of the largest studies examining the relation between the initial response to ChEI treatment and long-term course in cognition and functional abilities in a “real world” cohort of old age subjects affected by AD.
According to previous findings [18], our results show that younger age, independently of multiple covariates, is associated with a higher probability of early response to treatment (as evaluated after three months) (Table 3). This finding further support the hypothesis that younger age may be associated with better anatomical and functional conditions of the brain that may positively act on this short-term effect [5, 19]. A positive association with a response after three months is found also in higher educated subjects, with lower MMSE and higher ADL scores at baseline. This is in accordance with results from studies identifying factors affecting ChEI treatment, showing that patients with a lower MMSE score as well as highly educated [18] are more likely to response. A potential explanation is that subjects with a lower MMSE score have a more severe cholinergic deficit [20] and the effect of increasing cholinergic levels with ChEIs in these patients is larger [21]. Education could take place through the maintenance and enhancement of brain and cognitive reserve protecting the substrate the drug acts on. Brain reserve refers to neuroprotective brain capacity, which can be induced by long-lasting training and enhancement of mental activity [22]. Previous studies on Italian populations also investigated whether a short-term response (three months) on cognitive functions as evaluated with absolute MMSE score was predictive of cognitive outcome at long term (twenty-one months) [23–26]. These studies showed that subjects with a positive short-term response had a better cognitive outcome at endpoint as compared with patients without an initial response. Our results confirm these findings as shown by the mean MMSE score of responders that is higher than that of non-responders during the follow-up (Fig. 1). On this basis, it would be reasonable to hypothesize that if cognitive improvement is not detectable during the first three months, treatment should be dropped out. In agreement, previous findings demonstrated that effectiveness of ChEIs on cognitive symptoms in mild to moderate AD was modest, with an evident improvement only in that subgroup of patients who had demonstrated a positive short-term response to treatment [26]. However, when we looked at the rate of cognitive decline, we found that those subjects defined as non-responders just after three months of treatment have a slower rate of cognitive decline during the subsequent three years as compared with those initially defined as responders. Therefore, our findings suggest that, despite the absence of a short-term response, treatment with ChEIs can be beneficial in reducing the rate of decline in cognition in the long run. As far as functional abilities, we did not find a significant difference in the rate of decline between responder and non-responder groups. In agreement, a recent prospective study of ChEI treatment in subjects with mild AD in a routine clinical setting demonstrated that cognitive ability was more preserved than functional status [27]. Moreover, we need to take into account that, in older patients, the functional response might be significantly influenced by physical disability, impaired senses, or medical conditions not related to AD.
It has been shown that AD pathogenesis and disease progression differ with age [5]. Early onset AD (below the age of 70 years) predicts a more severe and aggressive course of the disease as compared with the late onset form. From a meta-database of eighteen studies from the Alzheimer’s Disease Cooperative Study and the Alzheimer’s Disease Neuroimaging Initiative [28], it has been demonstrated that change on cognitive parameters between older and younger participants are substantially greater than differences expected between experimental drugs and placebo in clinical trials or differences between marketed cholinesterase inhibitors and placebo. Thus, wondering whether age may affect the therapeutic response, we stratified our sample in old-old and young-old patients. Results show that subjects over 75 years of age have a slower rate of cognitive and functional decline during the subsequent three years as compared with younger subjects (Fig. 2). The fact that younger patients with AD have a more widespread and severe cholinergic deficit and increased neuronal loss, as compared with older patients [22], could in part explain the better response on cognitive functions in the short but not in the long term. Again, baseline differences likely accounted for some of the effect on decline since older patients had better initial cognitive scores, a predictor of slower progression. During the three years of follow-up, the rate of decline in ADL and IADL scores of the old-old group are significantly lower as compared with the young-old. This finding has important clinical and economic implications: despite the similar rate of decline between responder and non-responder groups, old-old subjects have a significantly slower rate of decline in global functioning. Functional impairment, independently of cognitive status, is the main cause of placement in nursing home of patients with AD [29, 30]. Moreover, functional impairment is a strong predictor of community-based help services, which significantly affect health system costs.
Finally, we found a slower decline in cognitive and in functional status in old-old non-responder patients (Fig. 3). Old-old patients had a higher MMSE score at baseline as compared with the young-old group, which may in part explain this finding. The final regression analysis (Table 4) confirms that older age is associated with slower progression of the disease during the 3-year follow-up, independently of the initial response. This is in agreement with a recent study exploring cognitive functions in patients with AD evaluated for three years that demonstrated that older age was associated with a slower cognitive decline [31]. The same study also showed that initial response to treatment was associated with a significant higher probability of disease progression as compared with patients without an initial positive response, independently of multiplecovariates.
The fact that we used only one measure of cognitive performance (the MMSE) may represent a potential limitation of the study. However, during follow up, the adoption of more refined cognitive instruments is commonly very time-consuming, and contradicting the philosophy of the “real world”. In this view, the MMSE, which is easy and quick to administer, represents the ideal tool to assess cognition reliably in clinical practice.
Our study has several strengths, including the relatively large number of subjects, the adjustment for multiple potential confounders, and the use of repeated measures analysis developed for longitudinal dependent data. The major strength of this study is the “real world” setting, avoiding bias of clinical trial population while the retrospective nature represents its main limitation and further research is needed to confirm our results.
In conclusion, we found that the long-term cognitive and functional decline in patients without an initial response to ChEI treatment is slower as compared to patients with a positive initial response. The oldest age is associated with a slower progression of the disease independently of the initial response during subsequent three year of treatment. Thus, discontinuing ChEI treatment solely for the absence of initial response is not appropriate, and age per se cannot be considered as a limit in starting and maintaining this kind of therapy.
DISCLOSURE STATEMENT
Authors’ disclosures available online (http://j-alz.com/manuscript-disclosures/16-0904r1).