The considerable total societal economic burden of AD includes direct costs (including both medical and non-medical costs) and indirect costs (largely informal care costs, but also lost productivity costs and intangible costs) [
7,
60,
61]. While the precise definitions of different cost categories varied across studies, it was generally the case that direct medical costs included costs for physician and other outpatient services, emergency department (ED) visits, hospitalizations, and/or pharmacy costs. By contrast, direct non-medical costs (often described as social care costs) included community care service costs, costs for consumables, costs for home modifications, and costs for institutionalization. Finally, indirect costs included lost productivity costs for patients and caregivers as well as informal care costs (i.e., the value of unpaid care provided by family members). The total societal burden of AD dementia was estimated at more than $307 billion in the USA in 2010, 91.4 billion renminbi (RMB) in China in 2010, €232 billion in Europe (European Union [EU] 28) in 2015, and $958 billion worldwide [
4‐
7]. By 2050, these costs are projected to increase by approximately 4.9-fold in the USA (to $1.5 trillion), 3.6-fold in China (to 332.5 billion RMB), 2.7-fold in Europe (to €633 billion), and 9.5-fold worldwide (to $9.1 trillion) [
4‐
7]. These estimated cost increases are driven by increases in the prevalence of AD dementia as a result of population aging as well as increased per-patient costs [
4‐
7]. Notably, the two models that provided cost breakdowns differed considerably in included cost inputs: the US model estimated that 41% of the 2010 total societal burden was due to informal care costs, whereas the Chinese model estimated that paid home caregivers accounted for 70% of the total cost burden and did not incorporate the contribution of unpaid, informal care by family members [
5,
7]. These findings are broadly consistent with a worldwide study evaluating the burden of dementia (i.e., not exclusively due to AD), which estimated a worldwide burden of $604 billion in 2010 and $818 billion in 2015, with informal care costs accounting for 36% of total costs in 2010 and 40% in 2015 [
62]. In this model, approximately 90% of total costs were incurred in high-income countries. The following sections report on per-patient costs associated with AD, including key cost drivers such as dementia severity, and on resource use by patients with AD. Total societal costs are considered as well as the underlying component costs.
Total Societal Cost of AD Dementia and Key Cost Drivers
Total societal costs per patient per month (PPPM) incurred by patients with clinically diagnosed AD dementia from six countries are reported in Table
2. Monthly costs reported in US dollars varied from $1595 (China) to $5941 (USA); those reported in euros varied from €1852 (France) to €5363 (one of two estimates from Spain) [
6,
7,
44,
63‐
66]. Two UK studies reported different monthly total cost estimates (£1160 and £1806), as did two studies conducted in Spain (€2190 and €5363) [
44,
64,
66,
67]. The substantial gap between the two studies conducted in Spain may be due to differences in dementia severity between populations, although the studies used different metrics for assessing severity, preventing direct comparisons [
44,
64]. Olazaran et al., who assessed dementia severity by MMSE score, reported that 38.4% of patients had moderate-to-severe AD dementia, whereas Darba et al. assessed severity by Clinical Dementia Rating (CDR) score and reported that 30.4% of patients had severe AD [
44,
64]. Of note, the analysis by Zissimopoulos et al. estimated that total societal costs were considerably higher among patients with AD than among those who did not have AD ($5941 vs. $1531) [
7].
Table 2
Total societal cost (PPPM) incurred by patients with AD dementia
Zissimopoulos, 2014* | USA | $5941‡ |
Henderson, 2019 (IDEAL) | UK | £1166†† |
Reed, 2017 (GERAS) | UK | £1806† (€2106)† |
France | €1852† |
Germany | €2122† |
Maresova, 2018 (meta-analysis) | France, Spain | €3895 |
Olazaran, 2017 (GERAS II) | Spain | €2190 |
Darba, 2015 | Spain | €5363** |
Nakanishi, 2020 (GERAS-J) | Japan | JPY 224,584 ($2101) |
Jia, 2018 | China | $1595‡ |
Potential drivers of total societal costs in patients with AD dementia include dementia severity, patient dependence level, cognitive and/or functional decline, institutionalization, and comorbidity burden.
Studies conducted in the USA, EU5 countries (France, Germany, Italy, Spain, and the UK), Japan, and China found that costs rise with increasing severity of AD dementia (Table
3). These studies included national cohorts from the GERAS (France, Germany, and UK), GERAS II (Spain and Italy), GERAS-J (Japan), and GERAS-US prospective studies as well as two cross-sectional studies (Spain, China), an analysis of baseline data from a randomized controlled trial (RCT) set in Italy, and a meta-analysis of three studies conducted in France and Spain [
63‐
66,
68‐
72]. In all studies reporting on dementia severity strata, patients with moderate-to-severe or severe dementia incurred higher total societal costs than those with mild or moderate dementia, and the difference between severity groups was statistically significant in all studies where significance was reported [
64‐
66,
68,
70,
71]. Of note, one study, conducted in Italy, found that among patients with AD, those with moderate dementia incurred lower total societal costs than those with mild dementia [
68].
Table 3
Total societal cost (PPPM) incurred by patients with AD, stratified by dementia severity
Robinson, 2020 (GERAS-US) | USA | $4243* | – | – | – |
$2653† | – | – | – |
Reed, 2017 (GERAS) | France | €1327‡ | €1878‡ | €2328‡ | NR |
Germany | €1445‡ | €2357‡ | €2830‡ | NR |
UK | €1676‡ | €2002‡ | €2822‡ | NR |
Lenox-Smith, 2016 (GERAS) | UK | £1437‡ | £1717‡ | £2420‡ | < 0.001 |
Maresova, 2018 (meta-analysis) | France, Spain | €2668 | – | €5270 | NR |
Rapp, 2018 (GERAS) | France | €1341‡ | €1905‡ | €2454‡ | < 0.001 |
Bruno, 2018 (GERAS II) | Italy | €1850 | €1552 | €2728 | < 0.001 |
Chiatti, 2015 | Italy | – | €1677** | – | NA |
Olazaran, 2017 (GERAS II) | Spain | €1514 | €2082 | €2818 | < 0.001 |
Darba, 2015*** | Spain | €2623†† | €5765†† | €8746††,‡‡ | < 0.001 |
Nakanishi, 2020 (GERAS-J) | Japan | JPY 158,454 ($1483) | JPY 211,302 ($1977) | JPY 294,224 ($2753) | NR††† |
Jia, 2018; Yan, 2019 | China | $1133** | $1399** | $2167**,‡‡ | < 0.001 |
Dependence level and cognitive or functional decline are associated with total societal costs in patients with AD dementia. Studies conducted in the USA, UK, and Spain found that as the level of functional dependence increased, total societal costs also rose [
73‐
75]. The three studies used different methods of assessing dependence level, with the UK study mapping dependence levels of 0 to 5 based on ADCS-ADL questionnaire responses (the cost difference from dependence level 1 to dependence level 5 was €2844 PPPM,
p < 0.001) and the other studies using Dependence Scale (DS) scores to stratify patients into four dependence levels (the Spanish study; cost difference from the lowest to highest dependence level was €7133 PPPM,
p < 0.001) or six dependence levels (the US study; cost difference from the lowest to highest dependence level was $5401 PPPM) [
73‐
75]. An analysis of patients from the GERAS study in France, Germany, and the UK found that those with cognitive decline (≥ 3-point decline from baseline MMSE score) or functional decline (decline in performance of ≥ 20% of ADCS-ADL items) exhibited significantly increased total societal costs compared to patients who did not experience such declines (for cognitive decline, €1653 vs. €1210,
p = 0.045; for functional decline, €1660 vs. €945,
p < 0.001) [
76]. An evaluation of cognitive decline in patients with mild AD (
n = 200) from the UK cohort of the GERAS study found that a 3.6-point reduction in MMSE score over the 18-month study period was associated with an increase in total societal costs of approximately £124 per month [
77]. In the French arm of the GERAS study, a 1-point reduction in MMSE score (indicative of worsening cognitive function) was associated with higher total societal costs (2.2% increase;
p < 0.01) [
70].
Institutionalization and comorbidity burden have also been associated with total societal costs in patients with AD dementia. A model evaluating the relationship between time to institutionalization and total societal costs estimated that total societal costs rose from £1900 at 5 years before institutionalization to £3160 at institutionalization [
78]. A study conducted in China reported that total societal costs rose as the number of comorbidities rose; PPPM costs rose from $1145 for patients with no comorbidities to $3196 for those with ≥ 5 (
p < 0.001) [
71]. The association between costs and comorbidity number was also observed in patients stratified by AD severity (
p < 0.001 for difference across mild, moderate, and severe dementia strata) [
71].
Total Direct Cost of AD Dementia and Key Cost Drivers
Direct costs PPPM incurred by patients with clinically diagnosed AD dementia from seven countries are reported in Table
4. Monthly total costs reported in US dollars varied from $1479 (China) to $3506 (USA), those reported in euros varied from €312 to €878 (both estimates from Spain), those reported in British pounds varied from £284 to £1339 (both estimates from UK), and a study from Japan reported a total cost of JPY (Japanese yen) 95,923 [
6,
7,
44,
64,
65,
67,
79‐
84]. Studies from six countries reported on direct medical costs, which varied from $531 (China) to $1473 (USA), €171 (Spain) to €313 (France and Spain), £365 (UK), and JPY 26,744 (Japan) [
6,
44,
63‐
65,
81,
85]. Finally, direct non-medical costs (i.e., social care costs such as home health assistance, community care, skilled nursing facility care, consumables), reported in five countries, were €141 to €589 (Spain), €1398 (meta-analysis of France and Spain), £975 (UK), $258 (China), and JPY 69,179 to JPY 81,970 (Japan) [
6,
44,
63‐
65,
81,
86]. Among studies reporting on direct medical and non-medical costs, three studies and a meta-analysis reported that non-medical costs were higher (£975 vs. £365 in a UK study, €589 vs. €289 in a Spanish study, JPY 69,179 vs. JPY 26,744 in a Japanese study, and €1398 vs. €313 in a meta-analysis), whereas two studies reported that direct medical costs were higher than non-medical costs (€171 vs. €141 in another Spanish study and $1055 vs. $424 in a Chinese study). The cause of these differences is unclear, but it may have to do with differences in cost classification or differences between study populations. Notable differences were also seen between a database study conducted in the USA, which reported a total cost direct burden of $1161 PPPM, and a US model, which estimated a considerably higher burden of $3506 PPPM. Among the five studies that reported on cost comparisons between patients with AD dementia and controls, all reported that direct costs were higher among patients with dementia. According to a recent retrospective database analysis conducted in the USA, which followed patients newly diagnosed with AD dementia (
n = 16,454) and matched controls, direct medical costs were comparable between groups for most of the 3 years prior to diagnosis, but rose considerably in the AD dementia group during the 6 months prior to diagnosis (AD dementia group: $1742 PPPM vs. control group: $806 PPPM;
p < 0.0001) [
87].
Table 4
Total direct cost (PPPM) incurred by patients with AD dementia
Chen, 2019 | USA | $1161* | – | – |
Zissimopoulos, 2014 | USA | $3506* | – | – |
Bayen, 2020 | USA | $1601* | – | – |
Pyenson, 2019 | USA | $1601* | – | – |
Desai, 2019‡‡ | USA | – | $1473*,**,‡‡ | – |
Bruggenjurgen, 2015 | Germany | €855* | – | – |
Henderson, 2019 (IDEAL) | UK | £284‡ | – | – |
Jones, 2015 | UK | £1339‡ | £365‡ | £975‡ |
Maresova, 2018 (meta-analysis) | France, Spain | – | €313 | €1398 |
Olazaran, 2017 (GERAS II) | Spain | €878†† | €289 | €589 |
Darba, 2020 | Spain | €449* | – | – |
Darba, 2015 | Spain | €312†,e | €171† | €141† |
Nakanishi, 2020 (GERAS-J) | Japan | JPY 95,923†† | JPY 26,744 | JPY 69,179 |
Takechi, 2019 | Japan | – | – | JPY 81,970 |
Jia, 2018; Yan, 2019 | China | $789*,†† | $531* | $258* |
Potential drivers of direct costs in patients with AD include dementia severity, patient dependence level/care need, cognitive and/or functional decline, institutionalization, comorbidity burden, treatment status, age, and agitation.
Studies conducted in the EU5 countries (France, Germany, Spain, and the UK), Japan, China, and the USA found that total direct costs rose with increasing AD severity (Table
5). These studies included national cohorts from the GERAS (France, Germany, and UK), GERAS II (Spain and Italy), and GERAS-J (Japan) prospective studies as well as two cross-sectional studies (USA, Spain) and a meta-analysis [
44,
63‐
65,
70,
88,
89]. Patients with moderate-to-severe or severe AD dementia tended to incur higher total direct, medical, and non-medical costs than those whose dementia was mild or moderate, although tests of statistical significance were often not conducted. Dementia severity was associated with direct non-medical costs in each of the three studies that assessed this (all
p < 0.001) but was associated with direct medical costs in only one of the three studies (
p = 0.02) [
44,
64,
88]. A systematic review identified seven studies that reported on total direct costs stratified by AD severity in Europe or the USA; of these, all but one study reported higher costs in patients with more severe AD dementia [
90].
Table 5
Total direct cost (PPPM) incurred by patients with AD, stratified by dementia severity
Total direct costs |
Ton, 2017‡‡,*** | USA | $2694* | $1672* | $4722*,†† | < 0.001 |
Rapp, 2018 (GERAS) | France | €644† | €903† | €1193† | NR |
Lenox-Smith, 2016 (GERAS) | UK | £559† | £805† | £1032† | NR |
Chiatti, 2015 | Italy | – | €545‡ | – | NR |
Olazaran, 2017 (GERAS II) | Spain | €464 | €844 | €1238 | NR |
Darba, 2015‡‡ | Spain | €183** | €333** | €427** | NR |
Nakanishi, 2020 (GERAS-J) | Japan | JPY 70,347 | JPY 94,812 | JPY 118,380 | NR |
Direct medical costs |
Rapp, 2018 (GERAS) | France | €285† | €395† | €451† | NR |
Lenox-Smith, 2016 (GERAS) | UK | £161† | £174† | £170† | 0.624 |
Maresova, 2018 (meta-analysis) | France, Spain | €280 | – | €278 | NR |
Olazaran, 2017 (GERAS II) | Spain | €272 | €236 | €346 | 0.320 |
Darba, 2015‡‡ | Spain | €151** | €151** | €225** | 0.02 |
Nakanishi, 202 0 (GERAS-J) | Japan | JPY 27,441 | JPY 26,309 | JPY 26,649 | NR |
Direct non-medical costs |
Rapp, 2018 (GERAS) | France | €359† | €508† | €742† | NR |
Lenox-Smith, 2016 (GERAS) | UK | £398† | £631† | £862† | < 0.001 |
Maresova, 2018 (meta-analysis) | France, Spain | €619 | – | €1705 | NR |
Olazaran, 2017 (GERAS II) | Spain | €192 | €608 | €892 | < 0.001 |
Darba, 2015‡‡ | Spain | €32** | €183** | €202** | < 0.001 |
Nakanishi, 2020 (GERAS-J) | Japan | JPY 42,906 | JPY 68,503 | JPY 91,731 | NR |
Dependence level and cognitive decline have been associated with direct costs [
70,
73‐
75,
81,
86]. Studies conducted in France, Spain, Japan, the UK, and the USA found that as the level of functional dependence increased, direct costs also rose [
70,
73‐
75,
81,
86]. In the US study, which used the DS to stratify the patient population into six dependence levels from very mild to very severe, total direct, direct medical, and direct non-medical (i.e., social care) costs rose with increasing dependence, with the steepest rise seen in the non-medical costs related to long-term care [
75]. A UK study, which focused on direct medical costs, found that those costs increased significantly (
p < 0.001) over five levels of dependence; the magnitude of the increase (from €295 to €616 PPPM) was lower than that seen in the US study ($377 to $1120 PPPM) [
74,
75]. Another UK study also found that non-medical costs accounted for most of the direct cost increase in patients at higher dependence levels (increase from highest to lowest dependence, PPPM £136 in direct medical costs vs. £2166 in non-medical costs) [
81]. By contrast, the study conducted in Spain found that dependence was associated with significant increases in both medical (from €625 to €1722,
p < 0.001) and social care (from €138 to €1432,
p < 0.001) costs [
73]. An analysis of the French cohort of the GERAS study found that cognitive decline (1-point decrease in MMSE score) during the 18-month study was associated with a 2.5% increase in patient costs (
p < 0.001) [
70]. A study conducted in Japan found that when patients were stratified by care need, monthly social care costs rose with increasing need, from JPY 11,529 to JPY 233,584 (
p < 0.001) [
86].
Institutionalization and the cost impact of treatment have also been associated with direct costs [
78,
91,
92]. A model evaluating the relationship between time to institutionalization and total societal costs estimated that total monthly direct costs rose from £770 at 5 years before institutionalization to £1529 at institutionalization, with healthcare costs accounting for relatively little of the increase (£283 to £348) [
78]. Two retrospective database analyses conducted in the USA found that direct costs were higher among patients with clinically diagnosed AD dementia aged 65 to 100 years who received a Food and Drug Administration (FDA)-approved treatment compared with those who did not [
91,
92]. One study found that total direct costs were significantly higher among untreated patients (PPPM costs $2509 vs. $2152,
p = 0.0162) [
91,
92]. The other analysis, which also stratified patients by age and timing of treatment initiation, found that patients aged 65 to 100 years who were not treated incurred higher costs than those who were treated (PPPM costs: untreated: $2744, treated: $2029 to $2706 depending on timing of treatment initiation) [
92]. Similar findings were seen among patients with AD dementia aged 50 to 64 years (PPPM costs: untreated: $3807, treated: $1754 to $2303 depending on timing of treatment initiation), although the difference between treated and untreated patients was more pronounced [
92].
An analysis of data from a prospective study conducted in the UK found that agitation was a key driver of direct costs (including medical and social costs) in patients with AD dementia (
n = 695) [
93]. Patients with no agitation incurred a monthly cost of £2415, whereas those with agitation incurred significantly greater monthly costs of £2600 to £4572 (costs adjusted for demographic and medical characteristics) (
p = 0.01) [
93].
Total Indirect Cost of AD Dementia and Key Cost Drivers
Total PPPM informal care costs (i.e., costs associated with unpaid caregiving, typically by family members) incurred by patients with AD dementia from five countries are reported in Table
6. Other indirect costs (i.e., patient or caregiver lost productivity costs and intangible costs due to mental suffering and unexpected injuries) were not well reported. Monthly costs reported in US dollars varied from $786 (China) to $2436 (USA), and those reported in euros varied from €1312 to €5539 (two estimates from Spain and one from a meta-analysis of studies conducted in France and Spain) [
6,
7,
44,
63,
64]. One UK study reported a monthly cost of £864 and a study in Japan reported a monthly cost of JPY 128,661 [
65,
67]. Only two studies reported on other types of indirect costs, a Chinese study which found that patients incurred $47 per month in intangible costs and a Spanish study that found an indirect cost of €77 per month due to lost caregiver productivity [
6,
64]. The US analysis was based on a model in patients with AD dementia who were ≥ 70 years of age; this analysis estimated that monthly costs in patients who did not have AD were considerably lower than in those with AD dementia ($247 vs. $2436) [
7].
Table 6
Total informal care and other indirect cost (PPPM) incurred by patients with AD dementia
Zissimopoulos, 2014** | USA | $2436* | NR |
Henderson, 2019 (IDEAL) | UK | £864‡ | NR |
Maresova, 2018 (meta-analysis) | France, Spain | €1556 | NR |
Olazaran, 2017 (GERAS II) | Spain | €1312 | NR |
Darba, 2015 | Spain | €5539† | €77† |
Nakanishi, 2020 (GERAS-J) | Japan | JPY 128,661 | NR |
Jia, 2018 | China | $760* | $47*,†† |
Potential drivers of informal care costs in patients with AD dementia include dementia severity, patient dependence level, and comorbidity burden.
Studies conducted in EU countries (France, Italy, Spain, and the UK) and Japan found that informal care costs rose with increasing dementia severity (Table
7). These studies included national cohorts from the GERAS (France, and UK), GERAS II (Spain and Italy), and GERAS-J (Japan) prospective studies as well as a cross-sectional study (Spain), an analysis of baseline data from an RCT (Italy), and a meta-analysis [
44,
63‐
65,
68‐
70,
88]. In all studies, patients with moderate-to-severe or severe AD dementia incurred higher informal care costs than those with less severe dementia, and the difference between groups was significant in the five studies that assessed significance. Of note, one study, conducted in Italy, found that patients with moderate AD dementia incurred lower informal care costs than those with mild AD dementia [
68]. A systematic review identified six studies that reported on total indirect costs (related to caregiving and lost productivity) stratified by AD dementia severity in Europe or the USA, each of which reported higher costs in patients with more severe dementia [
90].
Table 7
Informal care cost (PPPM) incurred by patients with AD, stratified by dementia severity
Lenox-Smith, 2016 (GERAS) | UK | £871* | £945* | £1371* | < 0.001 |
Rapp, 2018 (GERAS) | France | €698* | €1002* | €1261* | < 0.001 |
Maresova, 2018 (meta-analysis) | France, Spain | €1027 | – | €1996 | NR |
Bruno, 2018 (GERAS II) | Italy | €1370 | €1223 | €2223 | < 0.001 |
Chiatti, 2015 | Italy | – | €1677† | – | NA |
Olazaran, 2017 (GERAS II) | Spain | €1050 | €1239 | €1580 | 0.013 |
Darba, 2015†† | Spain | €2760 | €5983 | €8817‡,** | < 0.001 |
Nakanishi, 2020 (GERAS-J) | Japan | JPY 88,107 | JPY 116,488 | JPY 175,845 | NR |
Dependence level and behavioral symptoms have also been associated with informal care costs in patients with AD dementia. Studies conducted in the USA and Spain found that as the level of functional dependence (as assessed by the DS scale) increased, informal care costs also tended to rise [
73,
75]. In the US study, which stratified the patient population into six dependence levels from very mild to very severe, informal care costs (PPPM) rose from $46 among patients with very mild dependence to a peak of $2705 among those with moderate dependence. Informal care costs were lower among patients with severe ($2051) and very severe dependence ($1763), which may reflect a transition from informal to formal care at the highest dependence levels [
75]. By contrast, the study conducted in Spain, which stratified patients into four dependence levels, found that dependence was associated with significant increases in monthly informal care costs (from €2311 to €9639,
p < 0.001) costs [
73]. An analysis of data from the GERAS study cohorts in France and Germany, for which the follow-up period was extended to 36 months, found that functional loss (as assessed by ADCS-ADL scores at baseline and at 18 months) was associated with increased informal care costs [
94].