The present study estimated the economic burden of AD in adult patients in Spain according to disease severity stage. Results show that the average annual cost per patient with AD ranges between €42,336.4 (scenario 1) and €70,445.1 (scenario 2). The greatest proportion of the cost is attributed to DNHC, ranging between €36,364.8 (scenario 1) and €64,473.5 (scenario 2), followed by DHC (€3647.1), DSCC (€1957.1), and IC (€367.4). Taking AD severity stage into account, the costs associated with moderate and severe stages are greater than those associated with milder stages.

The total annual costs estimated in the present study are similar to those reported in recent studies in Spain [13, 14]. In those studies, DNHC (mainly informal care) also accounted for the greatest proportion of TC. Regarding informal care, Darbà et al. (2015) estimated an average cost per patient of €32,177.3 for a 6-month period, using the cost per hour of a professional caregiver (€15.71) as a proxy to calculate the cost of informal care. Extrapolated to 1 year, informal care estimated by this study closely resembles that of scenario 2 in the present study, in which the average cost per hour of home help service (€14.81) was used as a proxy of the cost per hour of informal care. Similarly, Lopez-Bastida et al. (2006) reported a DNHC of €28,198 per patient, which resembles that of scenario 1 in the present study. In both cases, the hourly rate per hour of unskilled work established for domestic employees (€7.55/h) was used as a proxy for the cost per hour of informal care. Regarding DHC and IC, the results of our study are in line with those of Darbà et al. and Lopez-Bastida et al., with IC having the lowest weight on the TC [13, 14].

High AD costs have also been reported for other European countries. Reed et al. (2017) explored 18-month resource utilization and differences in costs of AD between France (€33,339), Germany (€38,197), and the UK (€37,899) [16]. In line with our results, informal care contributed the most (between 54% and 65%) to the TC in these three countries. Differences in costs among these countries were attributed to different unit costs as well as variations in resource consumption and availability associated with each specific healthcare system. Regarding unit costs, those applied to informal care in the UK were lower than in Germany and France. Moreover, regarding resource consumption and availability, French patients used more community care services and, thus, caregivers spent less time on informal care. In contrast, German patients were less likely to be institutionalized or use temporary accommodation. Therefore, the availability of community care services influences the time that caregivers spend on informal care, which in turn has a direct impact on the TC of AD. In our study, costs are higher than those estimated for these three European countries, which could be explained by the cost of informal care, as DNHC contributed 86% (scenario 1) to 92% (scenario 2) to TC and informal care costs were the largest proportion of DNHC. Similar to these findings, in the US, the greatest part of the cost associated with mild AD was explained by informal caregiver costs (45%) [18].

The large contribution of informal care costs to AD TC has been broadly acknowledged in the literature [15,16,17,18, 43, 44]. It has been estimated that in Spain approximately 80% of patients with AD are cared for by their families [9, 19]; moreover, it is suggested that these families cover 88% of the TC of the disease [45]. A study found that, on average, informal caregivers spend 80 h/week in caregiving activities, with disease severity and level of dependency being strongly correlated with the number of caregiving hours [19]. Accordingly, in our study 84% of patients live with the caregiver and caregivers spend an average of 71 h/week caring for the patient. This leads to an undeniable high psychological and economic burden on the caregivers and families. Indeed, in this study, 77% of the caregivers reported a high strain and workload involved in the care provided to the patients. The overload on the families is influenced by factors such as the presence of behavioral disorders and functional disruption in the patients as well as the lack of social support for the caregivers [9].

The results of this study show that the costs of AD increase with disease progression. More specifically, the annual TC associated with moderate (€42,315.9 [scenario 1]; €72,676.9 [scenario 2]) and severe stages of AD (€47,894.6 [scenario 1]; €77,597.2 [scenario 2]) are significantly higher compared with the mild stage (€25,725.8 [scenario 1]; €42,014.2 [scenario 2]) (p < 0.01). In line with the results of this study, several studies have found that the costs associated with AD are higher in more severe stages of the disease [13,14,15, 17, 43, 46, 47]. A literature review study among European countries shows that in general, despite methodological differences among the studies (inclusion criteria, method of follow-up or cost items, among others), there is a strong association between costs of care and disease severity, with costs being higher for more severe stages of the disease [46]. Other studies have shown that this is also the case in Spain [13,14,15, 47]. Results from our multivariate analysis are in line with these findings, as moderate and severe disease stages, along with greater caregiver burden, are associated with higher costs. Patients at an advanced stage of disease have a lower ability to perform activities of daily living [48]. It has been found that greater impairments in activities of daily living are associated with greater informal caregiving time and higher AD costs [48]. These associations shed light upon the differences in costs depending on the severity of the disease. In this line, slowing disease progression seems to be a way to reduce social and economic burden associated with AD.

Although annual TC differ among disease stages, no statistically significant differences are found for DHC specifically. Evidence from other studies in Spain is mixed, with some showing significant differences in DHC among disease stages [14], while others state no differences [15, 47]. In this study, DHC represent a relatively small proportion of the total annual costs (8.6% [scenario 1]; 5.2% [scenario 2]); similarly, in these other studies, DHC stay low in proportion to the TC [14, 15, 47].

A challenge of AD burden studies is the difficulty of recruiting patients within the mild severity stage, due to the high rates of underdiagnosis. A study performed on the Spanish population found that 70% of patients with dementia had not been previously diagnosed by healthcare services, especially those patients with mild dementia [49]. Moreover, it has been observed that at the time of the diagnosis, 64% of Spanish patients showed scores of moderate AD (Mini-Mental State Examination [MMSE] score 10–20) and 6% showed scores of advanced AD (MMSE < 10) [30]. The patients in our study had on average 1.8 ± 2.3 years of diagnosis delay, that is, the time elapsed between first symptoms experienced and diagnosis. Similarly, a previous study has reported an average diagnosis delay of 28.4 ± 21.3 months [30]. It is important that healthcare systems prioritize the early detection and treatment of AD to prevent disease progression. In turn, this would have an impact on health outcomes, the quality of life of patients and their families, and society at large.

The current Spanish national strategy for AD and other dementias places early diagnosis as a primary objective. Lines of action include an opportunistic screening in primary care settings, training health professionals for the detection of early disease signs and symptoms, development and implementation of protocols for up-to-date diagnostic assessment, and streamlining coordination between healthcare levels to reduce waiting times, among others [27]. In addition, and considering the high strain of AD on the caregivers, efforts should also be made to prevent disease progression. Apart from the need of innovative pharmacological solutions, non-pharmacological alternatives such as cognitive stimulation therapies should also be considered. One of the goals of the mentioned Spanish national strategy is to increase the rate of patients receiving these types of therapies [27]. Healthcare professionals recognize the benefits of cognitive stimulation, including improvements in the quality of life of AD patients and caregivers [50]. However, access to these options is currently very limited, and there is significant misinformation among healthcare professionals, patients, and families [27]. Some data suggest that 36% of caregivers are unaware of memory maintenance workshops or programs, and for 15%, these are not available in their area [50].

One of the main strengths of the present study is the classification of patients according to AD severity stage, providing a greater understanding of how disease-related costs vary according to disease progression. Moreover, a wide range of resources was considered to estimate the costs associated with the disease (i.e., healthcare, social care, non-healthcare, and labor productivity losses). Finally, data collection was performed jointly with CEAFA, allowing the inclusion of patients and informal caregivers from different regions in Spain and contributing to obtaining a more representative sample of the Spanish population. Moreover, CEAFA actively provides training and information to its members, which contributes to greater health literacy and, therefore, greater validity of the data provided by the caregivers in this study.

Some limitations should be considered when interpreting the results of the present study. The estimates of resource consumption over the previous 12 months were based on data collected from a questionnaire completed by proxy informants (i.e., informal caregivers). Consequently, results may carry a recall and/or question misinterpretation bias; however, this method is commonly used in burden studies and, more specifically, in AD socioeconomic impact studies [13,14,15]. Moreover, when comparing responses between patients and caregivers, several studies have shown that the latter are capable of reporting valid healthcare information on the patient [51,52,53]. Similarly, disease severity was indicated by the caregivers based upon the last clinical report, which can also be susceptible to recall bias. Moreover, the estimation of disease severity can be confounded by the fact that there is a lack of a standard staging system used in clinical practice. In addition, the sample of the present study is relatively small, with a sampling error of 7.5%. Consequently, the survey results may not be fully representative of all AD patients in Spain and should be interpreted (and used) with caution. Nevertheless, information was collected from most regions in Spain, accounting for healthcare and social variability between regions. Moreover, a low proportion of patients in the sample had a mild disease severity. The overall average cost per patient could be potentially inflated given that most of the patients included in the study had moderate and severe disease stages. However, it is not uncommon in AD studies to have a lower proportion of participants with mild disease severity, considering the underdiagnosis of AD and the difficulty of finding patients with mild symptoms, as they do not frequently join patient associations. Nevertheless, statistical power was increased by combining patients with mild cognitive impairment and those in the mild AD severity stage.

The present study highlights the importance of understanding the economic burden of AD according to the type of cost and disease severity. Specifically, informal care represents the largest proportion of the TC associated with AD. Understanding the burden of AD is not only being aware of its social and economic impact from different perspectives, but visualizing potential benefits that could arise from preventing disease progression, hence, improving early diagnosis and treatment. In addition, this may further contribute to the design of equitable and efficient AD prevention and management policies.