Currently, the main therapy used for mild-to-moderate AD is cholinesterase inhibitor (ChEI) treatment. ChEIs prevent the breaking down of acetylcholine by the acetylcholinesterase enzyme, resulting in increased levels in the synaptic cleft available for receptor absorption. This enhances cholinergic transmission and improves the communication between neurons [6]. Randomized AD trials have demonstrated that ChEIs are effective in slowing functional decline compared with placebo-treated controls [7-9], and “real world” studies have reported positive long-term effects of ChEI on ADL [10,11]. The expected effect of ChEI on function may slow or delay the deterioration rather than promote the regaining of lost abilities [12]. The clinical value of these drugs is still controversial among physicians. One study reported that the prevalence of ChEI treatment was lower among older than it was among younger AD patients [13].

Factors that might influence the short-term functional response to ChEI therapy in AD patients in naturalistic studies have not been investigated previously. In a recent paper, our group analysed the socio-demographic and clinical factors that might affect the long-term functional outcome in AD. A slower decline in ability to perform ADL after 3 years of ChEI therapy was associated with higher cognitive status at baseline, younger age, and the interaction effect of lower education and a longer time in the study. Moreover, a higher dose of ChEI, regardless of the drug used, or living with a family member predicted a better longitudinal outcome in IADL [10]. Some shorter naturalistic studies have observed different results in functional outcome between the three ChEI drugs [14,15].

The short-term cognitive response to ChEI therapy has been reported as heterogeneous among individuals with AD. Some studies have focused on different cognitive responses to ChEIs based on socio-demographic and clinical characteristics. A better cognitive response to treatment was observed in patients with a fast pre-treatment progression rate [16,17], in patients who were more cognitively impaired [9,18,19], in males [19,20], and in patients taking larger doses of ChEIs [19,21]; however, these results were not conclusive [22,23]. Inconsistent results have been described regarding age [14,24] and apolipoprotein E (APOE) genotype [9,25].

The identification of subgroups of functional responses to ChEI may provide valuable prognostic information to clinicians and social service providers and treatment recommendations for clinical practice, as well as increased knowledge regarding counselling patients and their families about the treatment effect.

ADL performance in AD shows a moderate linear association with cognitive ability (r = 0.4–0.7) among both untreated [32,33] and treated patients [34]. Therefore, ADL scales are a complement and an essential part of the assessment of the patient and might produce a more complete understanding of the effect of AD therapies [35]. The pharmacological therapeutic drugs available currently, ChEIs, have yielded improvements, on average, in cognition in several 6-month randomised clinical trials [36] and have shown positive cognitive effects in longer-term naturalistic studies [26,37]. Conversely, ChEIs tend to provide a slowing or delay of functional decline, on group level, rather than an improvement over the first 6 months of treatment.

Patient characteristics that might affect the short-term effect of ChEI treatment on ADL ability have not been investigated in previous naturalistic AD studies. Our group has recently published a paper on the socio-demographic and clinical predictors that influence the long-term functional outcome in ChEI-treated AD patients [10]. The 6-month response of ADL demonstrated a weak-to-moderate linear relationship with functional status after 3 years. Thus, the factors that might predict the short-term ChEI response are not necessarily equal to those that predict the longitudinal outcome. Higher cognitive ability and younger age at baseline were both independent predictors of better functional short-term response to ChEI and long-term treatment effect. In the present study, fewer medications at baseline or NSAID/acetylsalicylic acid therapy predicted a more positive 6-month basic ADL response to ChEI; these variables were not addressed in our previous analyses of the 3-year functional outcome. A higher dose of ChEI and living with a family member were independent predictors of better long-term IADL ability, but not of the short-term response of IADL. The difference in the results of ChEI dose might reflect the regular dose titration that always takes place during the first weeks of treatment, which inevitably led to a lower mean dose of ChEI in the first 6 months. The current study shows that the patients in both the improved/unchanged IADL and PSMS groups after 6 months of ChEI therapy received a higher mean dose of ChEI during the following years than did the deteriorated groups and demonstrated better ADL status at the end of the 3-year study. This might imply that the individuals who responded and could tolerate higher doses exhibited a more positive long-term functional outcome. The faster IADL deterioration among solitary living AD patients observed over a longer period of time might reflect symptoms of depression, apathy and social isolation [10]. The heterogeneity in functional response to the initiation of ChEI therapy highlights the importance of identifying specific subgroups of patients with differential response to treatment. Rapidly progressing patients require more resources from caregivers and social services [33].

A significant interaction between cognitive and functional abilities at baseline regarding response to ChEI treatment was identified in this study of mild-to-moderate AD patients. Higher cognitive status and lower ADL ability implied increased functional response to ChEI therapy. Therefore, the effects of these domains should not be interpreted separately. The present study only demonstrated a weak linear association between cognitive and ADL response after 6 months; thus, the predictors of response might differ between the domains. Previous studies from our group [19] and from others [9,38], but not all [22], observed that more cognitive impaired individuals exhibited a better 6-month cognitive response to ChEI treatment, emphasizing the importance of not excluding this group from treatment opportunities.

Prior work has reported that cognitive deficits are a risk factor for functional impairment among the elderly, even after adjusting for socio-demographic and medical characteristics [39]. Bullock & Lane [40] reported improved executive function and attention among patients with dementia that responded to rivastigmine therapy. Moreover, a relationship between executive dysfunction and diminished instrumental and basic ADL was observed [41]. Better function in the above-mentioned cognitive abilities might lead to a more positive response in ADL. A recent 6-month study of donepezil [22] showed that the mild AD group (MMSE ≥ 21) exhibited significantly less decline in ADL compared with the moderate group (MMSE < 21), which agrees with our findings. In contrast, subsequent analyses of donepezil [42] and rivastigmine [38] clinical trials showed that the functional benefit of the drug compared with the placebo was greatest in the moderate and moderately severe AD groups. However, those studies did not address the cognitive-functional interaction effect or the multivariate impact of other background variables.

In the present paper, significantly fewer AD patients in the improved/unchanged basic ADL group used anti-depressants. This type of medication also tended to affect the IADL response negatively in the multivariate model (p = 0.058). Depression is considered as a characteristic of fronto-subcortical pathology. Patients with a significant burden of this pathology, concomitant with a heavier load of AD pathology, may show a more aggressive course of disease [40]. Furthermore, Atchison et al. [43] observed that the rapidly declining AD patients, as measured using basic ADL ability, had higher levels of self-reported depressive symptoms at the initial evaluation. Although significance was borderline in the current study, the findings indicate that depression, even if treated pharmaceutically, might be related to faster functional deterioration and less response to ChEI.

This study also demonstrated that individuals using NSAIDs/acetylsalicylic acid responded better to ChEI regarding basic, but not instrumental, ADL. A recent study from our group suggested that this category of medication was also a predictor of a more positive cognitive response to ChEI [19]. In contrast, a recent placebo-controlled randomised trial of NSAID treatment has failed to show any positive effects on cognition or function in AD [44]. One explanation might be the shorter treatment period in that clinical trial compared with the longer perspective of the naturalistic SATS patients. Furthermore, NSAID/acetylsalicylic acid therapy implies a symptomatic effect on pain, which in cognitively impaired elderly individuals may be more difficult to assess and recognize [45]. Under-treated pain can have adverse functional consequences and, therefore, analgesics might positively influence the response of ADL.

The predictors younger age or fewer concomitant medications (basic ADL only) independently demonstrated a better functional response to ChEI therapy in the present study; these individuals exhibited less ADL impairment at the start of treatment. In older patients, the functional response might be more influenced by physical disability, impaired senses or medical conditions not related to AD [46]. A linear association between cognitive status and number of medications at baseline was not observed in the present study. This agrees with another multivariate study from our group, in which concomitant medications were not a significant predictor of response regarding cognition [19]. In that study, older patients exhibited better 6-month cognitive response and long-term outcome. In contrast, older age predicted more rapid longitudinal decline in both instrumental and basic ADL abilities [10]. A more pronounced decline in daily function because of the natural aging process in older individuals, compared with cognition, might negatively affect the functional response observed in the present paper.

The advantages of the SATS are the 6-month, prospective, well-documented cognitive and functional evaluations after ChEI exposure in a large cohort of AD patients. The inclusion of everyday patients with co-morbidities and concomitant medications provides an essential supplement to data generated in clinical trials. The SATS, like other long-term naturalistic studies, is limited because it is not placebo controlled (because of ethical aspects) or randomised with respect to drug use. The treating physician, specialized in dementia disorders, decided the type of ChEI and the dose according to the standard routine in clinical practice. To minimize possible differences between the treatment groups, multivariate models that took into account demographic and baseline clinical factors were used. Other medical conditions, such as concomitant somatic diseases that may influence ADL ability, were not evaluated in the SATS programme. Therefore, the number of medications was used as an indicator of co-morbidity. The functional response to ChEI therapy might be complex among elderly AD patients in clinical practice. The inclusion of additional predictors, not assessed in the SATS, might influence the multivariate models and affect the individual’s outcome in ADL. However, the shorter follow-up time analysed in the present paper might imply less influence of factors associated with, e.g., multimorbidity in comparison with longer-term studies.