Response to cholinesterase inhibitors affects lifespan in Alzheimer's disease

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by progressive impairment of cognitive abilities, such as memory, orientation, language, and executive performance, and gradual loss of the capacity to carry out activities of daily living (ADL) [1]. A later consequence of AD is higher mortality compared with the nondemented elderly population. The disease represents the fifth leading cause of death in the USA in individuals aged ≥ 65 years [2]. The mean lifespan after the time of AD diagnosis varies between 3 and 10 years, depending on the patient's age; however, individuals with AD can live considerably longer, up to 15-20 years [3]-[5]. Furthermore, the reduction of life expectancy compared with the general population ranges from 67% for patients diagnosed at 65 years of age to 39% for those diagnosed at 90 years of age [3].

Several studies have demonstrated a cholinergic deficit in AD [6],[7], which became a target for therapeutic interventions. The 'cholinergic hypothesis' led to the development of cholinesterase inhibitors (ChEIs), which are at present the main therapy used for mild-to-moderate AD. ChEIs prevent the degradation of acetylcholine (ACh) by the acetylcholinesterase enzyme, resulting in higher levels of ACh available in the synaptic cleft for receptor absorption. The treatment enhances the cholinergic transmission, thus improving the communication between neurons [8]. Multiple placebo-controlled randomised clinical trials have shown modest responses after 6 months of ChEI therapy regarding cognition, global performance, and ADL [9]. However, not every patient with AD benefits from ChEI treatment, because the level of response varies among individuals. In some AD studies, a more positive cognitive response to ChEI was observed in participants with a faster disease progression [10] or lower cognitive ability [11],[12] and in patients taking larger doses of ChEIs [12],[13]. Whether short-term response to ChEI alters the survival time in AD is not clear.

Many demographic and clinical factors decrease life expectancy in AD, such as male sex [14],[15], older age [3],[4],[14],[15], higher education [16], and greater cognitive impairment [14]. Moreover, cardiovascular disorders [14],[17] and psychotic symptoms [18] might shorten lifespan in dementia. Because co-morbidity often accompanies AD, it might be difficult to point out a direct relationship between the disease and survival time. Some AD studies have investigated the association between ChEI therapy and mortality and reported conflicting results regarding whether these drugs increase the length of life [15],[19]. Therefore, the influence of ChEIs and the complex impact of potential risk factors on survival warrant further investigation using multivariate statistical methods.

Expanded knowledge of the factors that affect mortality in AD, including the level of response to ChEI and drug dose, might provide a more accurate prognosis for the patients, which also represents essential information for their families and the clinicians. Moreover, a better understanding of predictors of survival in AD might be valuable for the community-based services, namely in the planning of care and of the economic resources available.

The aims of this study were 1) to examine the relationship between lifespan and the short-term response to ChEI treatment, 2) to investigate associations among survival time, drug agent and dosage of ChEI, and 3) to identify potential predictors that might influence these outcomes.

The socio-demographic and clinical characteristics of the 681 deceased AD patients are shown in Table 1. Their lifespan after the start of ChEI therapy (baseline) was 5.83 ± 2.76 years (mean ± standard deviation (SD)). Women had a significantly longer survival (6.25 ± 2.83 vs 5.13 ± 2.48 years; t (679) = −5.43; P < 0.001).

This observational AD study performed in clinical practice showed that a longer lifespan was independently related to a more favourable response in cognitive (MMSE model only), global, or functional ability after 6 months of ChEI therapy; female sex; no antihypertensive/cardiac or antidiabetic therapy; younger age; a lower level of education (not the CIBIC model); milder disease severity at the baseline; and higher dose of ChEI. APOE genotype did not affect mortality significantly. The patients who received a higher ChEI dose during the first 6 months had a mean survival time after the baseline that was more than 1 year longer than that of those receiving a lower dose.

AD reduces life expectancy in untreated individuals, particularly in those affected at younger ages [3]. Whether ChEI treatment has a beneficial or detrimental effect on mortality is unknown, as the few AD studies that have analysed this association have reported conflicting results [15],[19]. In this study, the mean survival of 5.83 years after the time of AD diagnosis (approximately the start of ChEI therapy) was similar to that of untreated patients [3],[14]. Rountree et al. [15] found that anti-dementia drug exposure was not significantly related to mortality in a community-based AD cohort that was followed for a mean period of 3 years. In a large-sample study of nursing-home residents with dementia, Gasper et al. observed that the survival rate after 2 years was higher in the ChEI-treated group compared with the untreated group. Nevertheless, individuals who are treated with ChEIs attend regular visits to their physician, and could also be receiving more aggressive pharmacological therapies against other co-morbid disorders, which might increase their length of life [19]. Both of the studies mentioned above included adjustment for a broad range of covariates, such as socio-demographic characteristics, dementia severity and major co-morbid illnesses. The patients with AD in the community-based cohort [15] were 10 years younger, on average, than the nursing-home residents [19] (73 vs 83 years). A recent study from our group that compared the SATS participants with untreated AD cohorts found no difference between these groups in patients aged < 85 years; however, a longer lifespan was observed among the ChEI-treated oldest old participants [5]. Older individuals may have less hereditary and aggressive forms of AD. In addition, their cognitive reserve capacity may be reduced, which could lead to the detection of the disease, diagnosis and ChEI therapy at an earlier stage. In another study from the SATS, older age was reported as an independent predictor of better cognitive short-term response to ChEI and longitudinal outcome [12]. These factors might imply a lower mortality rate in the oldest AD patients.

In the current study, the improved/unchanged participants, as measured by MMSE score after 6 months of ChEI treatment, exhibited a lifespan that was 0.5 years longer on average compared with the deteriorated group. Similarly, a worsening in the global CIBIC score suggested a 6-month shortening of life expectancy in AD. Individuals who demonstrated functional response, particularly in basic ADL, also had a significantly longer survival. No difference in mortality among the responder groups was observed when using the ADAS-cog scale. The ADAS-cog is a more complex cognitive measure than the MMSE test, and it includes a greater number of items. The proportion of patients who were categorized as improved/unchanged according to ADAS-cog was smaller compared with that categorized using the MMSE scale (49% vs 63%), which might be one explanation for this inconsistent result. Randomised clinical trials have demonstrated that ChEIs might delay both cognitive decline and loss of ADL [29]-[31]. A modest post-treatment improvement in cognitive rating scales for about 6-12 months before the score returned to baseline value was reported by previous AD studies [32]-[34]. Individuals who responded better to ChEI cognitively exhibited a lower cognitive ability at the baseline in several [11],[12],[31] but not all [35] studies. However, a subsequent faster deterioration over time was observed in the patients who were more severely impaired after their initial response to therapy [12]. A greater reversible cholinergic deficit in the more advanced stages of AD is a possible explanation for the finding mentioned above, suggesting that this subpopulation is more responsive to ChEI [36]. Another explanation might be that the change in the score on a certain assessment scale is expected to be larger at the level of function, e.g., moderate AD, at which the scale measures the person's abilities most accurately [37]. Articles stemming from the SATS reported that a higher cognitive status at the baseline was associated with better longitudinal outcome in cognition [12], and that individuals who initially exhibited a more positive functional response to ChEI therapy were less cognitively impaired at the baseline and showed a significantly higher ADL capacity after 3 years of treatment [38]. Therefore, the participants' cognitive and functional scores were included in our general linear models as independent predictors. Nevertheless, the responders exhibited a significantly longer survival. The above-mentioned findings indicate that response to ChEI, as measured using different scales, prolongs life by a few months in AD patients. A more preserved cognitive status at the start of therapy can lead to a better ability to maintain higher levels of cognitive and ADL performance over longer periods, which underscores the importance of initiation of anti-dementia drugs at an early stage of the disease. The effects of initial response to ChEI and the subsequent post-treatment delays in symptom progression suggest that the observed mean 6-month increase in lifespan occurs at a higher cognitive and functional level and not in the later, more advanced stages of AD.

Here, concomitant antihypertensive/cardiac therapy and antidiabetic therapy reduced the mean survival time by 6-8 months and ~1.5 years, respectively. Consistently, co-morbid disorders, particularly cardio/cerebrovascular and respiratory diseases, and diabetes, increase mortality in most dementia studies [14],[17],[39] and in the general population [40]. Because concomitant illnesses are commonly observed in elderly persons, it is difficult to investigate direct associations between AD and lifespan. In the present study, we adjusted the multivariate models for usage of different types of medications. Nevertheless, other factors related to co-morbidity might affect survival time in AD, such as severity and type of somatic disorders or psychiatric symptoms, which were not addressed by the variables included in the models. Moreover, a shorter life expectancy among males and older individuals was observed in this study and in most previous AD studies [14],[15], and in the general population [40]. Male sex, older age, and antihypertensive/cardiac/antidiabetic therapy were independent predictors of higher mortality in all of our statistical models, regardless of the scales used, which demonstrates the accuracy and consistency of the results.

The current study of ChEI-treated patients with AD showed that those with a higher education level have a shorter lifespan, similar to the findings of Stern et al. regarding untreated individuals [16]. However, most previous studies have demonstrated that the individuals' level of education does not affect life expectancy [3],[14],[15]. A faster cognitive decline among patients with a higher level of education has been reported in several [12],[41],[42] but not all [43],[44] ChEI-treated and untreated AD cohorts. Furthermore, a greater proportion of APOE ε4 carriers among those with a higher education level has also been observed [12]. In studies from the USA [3],[14],[15],[44], the majority of participants are highly educated, which might imply that the variance in the cohorts is too small to detect possible differences. Individuals with a high education level were assumed to have a more pronounced cognitive reserve and, therefore, would be less vulnerable to the effects of neurodegeneration. This might lead to better performance on cognitive tests and, consequently, later detection of the disease [41]. A higher level of education can be a risk factor for worse prognosis in AD, suggesting a more advanced disease at the manifestation of clinical symptoms and at treatment onset, a faster progression rate, and a shorter survival.

In the present study, the patients who received and tolerated a higher dose of ChEI, regardless of drug agent, exhibited a mean of 15 months of extension in lifespan. Higher doses have previously been related to more positive long-term cognitive and functional outcomes [12],[13],[21]. Moreover, a significant association between a higher dose of ChEI and a lower amount of home help services [45], and delays in the need for nursing home placement [28],[46], has been reported. These results show that a higher ChEI dose would be beneficial as long as the individuals can tolerate this medication. The slowing of disease progression and the postponed need of community-based services indicate that the possible increase in life expectancy occurs in a less advanced stage, when the AD patients are able to live in their own homes.

The advantages of the SATS are the 6-month, prospective, well-structured cognitive, global, and functional assessments after the start of ChEI therapy in a large AD cohort with co-morbidities and concomitant medications enrolled from memory clinics located across Sweden. Access to the Swedish health care system is publicly funded for residents; thus, not dependent on the patient's income or health insurance coverage [47]. This leads to the assumption that the SATS participants are representative of the general population. A limitation of the SATS is that, as in other long-term naturalistic studies, it is not placebo controlled because of ethical considerations, or randomised according to drug agent. Clinicians who are specialised in dementia disorders decided on the type of ChEI and the dose for each individual patient, in accordance with the standard routine in clinical practice. Another shortcoming of the study was that the clinical diagnosis of AD was not confirmed via autopsy. Additional factors that were not investigated in the SATS might also influence mortality. For example, a recent study reported by our group found that cerebral inflammation independently predicted an early death in AD. The effect of ChEI was not addressed in that study [48]. Furthermore, ChEI therapy could entail wide-spread effects beyond the central nervous system that might affect lifespan. ACh synthesis has been detected in various types of immune cells, muscle cells and epithelial cells (e.g., of the airways and of the alimentary and urogenital tracts) [49]. A review of the role of ChEIs in the modulation of the immune response reported that these drug agents might influence the immune system [50].

This is the first AD study to analyse the association between short-term response to ChEI therapy and survival. Additional studies are warranted to confirm our findings. Regardless of whether response to ChEIs prolongs life, other aspects that were not evaluated in the SATS, such as the patients' quality of life and the caregiver burden during this extended time, need to be investigated. An increased understanding of the impact of ChEI treatment on life expectancy is important for the estimation of the patients' prognosis by the treating physicians. Detailed information regarding factors that affect survival time in AD might be a valuable tool for the health authorities to investigate the effects and costs of the disease from a societal perspective. Knowledge of the potential effects of ChEIs on lifespan is necessary for the assessment of the effect of future disease-modifying therapies on mortality in AD.

In conclusion, the current study of response to ChEI after 6 months of treatment showed a few months prolonged lifespan among the improved/unchanged AD patients regarding cognition (MMSE score, but not ADAS-cog score), global performance, and functional capacity. A shorter survival time was observed in men, older individuals, and in those taking antihypertensive/cardiac or antidiabetic medications. These findings are consistent with those of other dementia studies and for the general population, thus showing consistency in our models. A higher level of education was also related to shorter life expectancy, which might reflect a more advanced disease at the point of seeking care and consequently a more rapid AD progression. The patients who could tolerate a higher dose of ChEI, regardless of drug agent, during the first 6 months of therapy exhibited a longer mean lifespan (by more than 1 year) than did those receiving a lower dose. Earlier reports of post-treatment delays in disease progression and a decrease in community-based service utilisation, lead to the assumption that this increase in the length of life occurs at a higher cognitive and functional level, with no increase in survival during the most debilitated stages of AD.

CW participated in the SATS, supervised the data collection, was responsible for the statistical design and for carrying out the statistical analyses, interpreted the results, and drafted the paper. EL participated in the study, assisted in the analysis and interpretation of the data, and revised the manuscript critically. LM was responsible for the design of the study, was the principal investigator, and revised the manuscript critically. All authors read and approved the final manuscript.