Differences in Depressive Patterns According to Disease Severityin Early-Onset Alzheimer’s Disease

Abstract

Background & Objective: Depression frequently combines with dementia, including early-onset Alzheimer’s disease (EOAD). We investigated differences in prevalence and characteristics of depressive symptoms according to dementia severity in EOAD patients.

Methods: The 15-item Korean version of the Geriatric Depression Scale (GDS-15) was administered to 412 EOAD patients. Factor analysis was used to assess GDS-15 factor structure. We subdivided participants into three groups by disease severity, then compared the frequencies and scores of individual GDS-15 items and performed logistic regression analysis to assess associations between depressive symptoms and EOAD stage.

Results: Factor analysis yielded three factor categories: 1) “hopelessness and ominousness” (symptoms no. 6, 8, 12, 14, 15); 2) “unhappiness and dissatisfaction” (no. 1, 3, 5, 7, 11); and 3) “monotony and lack of energy” (no. 2, 4, 9, 10, 13). Factor 2 depressive symptoms (no. 1, 5, 11) were less common in moderate EOAD. The risk of Factor 1 symptoms: no. 12 (OR, 2.04; 95% CI, 1.19–3.50; p = 0.010) and 14 (OR, 1.84; 95% CI, 1.07–3.16; p = 0.028) was higher in mild than very mild EOAD. The risk of Factor 2 symptoms: no. 9 (OR, 2.69; 95% CI, 1.08–6.71; p = 0.033) and 13 (OR, 2.12; 95% CI, 1.02–4.40; p = 0.043) was higher in moderate than mild EOAD.

Conclusion: We confirmed that depressive symptoms differ according to EOAD severity. When assessing depressive symptoms related to dementia progression, we recommend focusing on “hopelessness and ominousness” in very mild EOAD and “unhappiness and dissatisfaction” in mild EOAD.

Keywords

Alzheimer’s disease depression disease progression early-onset geriatric depression scale prediction

INTRODUCTION

Depression is one of the most frequent neuropsychiatric symptoms in the elderly, as well as in patients with dementia, including those with Alzheimer’sdisease (AD). Cognitive impairment is more common in depressed elderly individuals, and numerous studies have reported a relationship between depression and cognitive decline [1 –4]. Impairments in the speed of information processing, attention/concentration, and executive function are the most important cognitive features in geriatric depression [5]. However, it is not clear whether depression is a true risk factor for dementia or simply represents a prodromal clinical phase of the neurodegenerative changes occurring in AD. Depression may increase the risk of mild cognitive impairment (MCI) [6], vascular dementia [7], and AD [2 , 8–10] and negatively affect the cognitive outcome of patients with MCI [11, 12] and AD [13]. Conversely, depressive symptoms might be an early manifestation of, rather than a risk factor for, dementia [14], or depression could be a subjective reaction to cognitive impairment in MCI and mild AD patients, thus suggesting that patients’ awareness of cognitive changes may determine the type and extent of depressive symptoms [15]. Knowledge of the course of depressive symptoms may be useful for predicting disease progression of patients because neuropsychiatric symptoms vary considerably. Previous studies have reported contrasting results regarding the time course of depression: Some have noted that depression decreases in prevalence and severity over time [16 –18], whereas others have found that depression remains constant [19, 20].

Several studies have concluded that early-onset AD (EOAD) has different clinical manifestations, courses, neuroimaging, and neuropathologic findings compared to late-onset AD (LOAD). These studiesreported not only more severe impairment in attention, language, apraxia, and visuospatial function and relative sparing of memory function in patients with EOAD [21 –24], but also severe neuropsychiatric symptoms [25], such as more anxiety or depression (which might be related to dementia severity and more rapid progression [26]) and apathy [21] in those with EOAD. Furthermore, much evidence from neuroimaging studies has demonstrated consistent differences between EOAD and LOAD. Compared to patients with LOAD, those with EOAD at a similar stage of AD have greater diffuse cortical atrophy, particularly in the lateral parietal and precuneus; greater neuritic plaque and neurofibrillary tangle burden in the bilateral frontal and parietal lobes; lower synaptophysin concentrations, reflectinggreater synapse loss; and lower brain weight. In addition, EOAD patients exhibited less functional connectivity in the dorsolateral prefrontal network than those with LOAD [27 –33]. Researchers have highlighted the cognitive reserve theory to explain the differences between the two groups of AD patients and lengthening of the prodromal phase of illness in EOAD [27 , 34]. However, whether depression is related to dementia severity in EOAD remains unknown. Moreover, it is uncertain which depressive symptoms are related to disease progression.

Thus, the purpose of our study was to analyze the frequency and pattern of depressive symptoms according to disease severity in EOAD. Furthermore, we investigated which depressive symptoms are associated with disease progression in patients with EOAD.

MATERIALS AND METHODS

Participants

This study was performed as part of an ongoing,nationwide multicenter study of dementia, the Clinical Research Center for Dementia of South Korea (CREDOS) study (identifier on Clinical Trials: NCT01198093). At baseline, all patients underwent standardized dementia assessments, including basic demographics, informant-based history, past medical history, physical/neurological examination, comprehensive neuropsychological tests, laboratory tests, and brain magnetic resonance imaging. Apolipoprotein E (APOE) genotyping was performed for patients who consented. The diagnosis of AD was established according to the National Institute of CommunicableDiseases and Stroke-Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria for clinically probable AD [35]. Age at onset was determined using information from interviews with caregivers at the first visit. The classification of “early onset” was based on the age at onset: Patients with disease onset prior to age 65 were classified as EOAD patients. The details of other assessment processes are described in previous papers [21, 36]. Consecutive 412 EOAD patients attending 31 memory clinics of university-based hospitals were recruited from December 2005 to January2012. General disease severity was classified by clinical dementia rating (CDR) [37]. CDR 0.5 represents very mild stage disease, CDR 1 represents mild stage, and CDR 2 represents moderate stage.

Assessment of depression

The Geriatric Depression Scale (GDS) is one of the most widely used instruments in the world to screen for depression in the elderly [38]. The GDS has already been translated into many languages, and it has been validated in many countries, includingKorea [39, 40]. To simplify this screening tool for depression, Sheikh et al. developed a GDS-short form, which was created from the original 30-item GDS [41]. In this study, depressive symptoms were rated according to the 15-item Korean version of the GDS (GDS-15) [42] based on the GDS-short form. GDS-15 was used as a self-report instrument, in which neuropsychologists asked the questions and recorded the patients’ responses. A GDS-15 score≥8, which was the cutoff value in the validation study for the Korean version [42], was used to characterize patients as having clinically significant depression.

Statistical analysis

We analyzed the frequencies and mean values of the variables. Chi square analyses were used for categorical data. To compare differences in mean scores of individual items and total GDS-15 between the three CDR groups, analyses of covariance for adjusting confounding factors (such as age, gender, and education) were performed. Differences in frequency of each GDS-15 item were compared using the Kruskal-Wallis test. Factor analysis was conducted with all 15 individual GDS items entered simultaneously. Cross-sectional associations between the presence of depressive symptoms and each stage of EOAD at baseline were assessed using logistic regression models. For each of these models, the score on the individual GDS-15 item was the dependent variable, with group status, age, gender, and education entered as the independent variables. The statistical analyses were performed using SPSS version 16.0 (SPSS Inc., Chicago, IL, USA). The cutoff value for statistical significance was set at p < 0.05.

RESULTS

The baseline demographics of participantsaccording to CDR group are listed in Table 1. No significant differences were detected between the three groups except for the prevalence of diabetes. As expected, scores on the Korean version of the Mini-Mental State Examination, CDR sum of boxes, and scores on the Seoul instrumental activities of daily living worsened according to the CDR group.

Factor analysis

Factor analysis of the GDS-15 yielded three factors that accounted for 54.0% of the variability (Table 2). Factor 1 included five items (“afraid something bad is going to happen,” “often feel helpless,” “feel pretty worthless,” “situation is hopeless,” and “most people are better off than you”) and accounted for 21.2% of the total variance. We named this factor “hopelessness and ominousness.” Factor 2 included five items (“satisfied with life,” “life is empty,” “in good spirits most of the time,” “feel happy most of the time,” and “wonderful to be alive”) and accounted for 18.6% of the total variance. We named this factor “unhappiness and dissatisfaction.” Factor 3 included five items (“dropped many activities and interests,” “often get bored,” “prefer to stay at home,” “more problems with memory than others,” and “full of energy”) and accounted for 14.2% of the total variance. We named this factor “monotony and lack of energy.”

Analysis of individual depressive symptoms according to CDR

The prevalence of depression (defined by the GDS-15≥8 cutoff value) was highest in the mild EOAD group and lowest in the moderate EOAD group: 37.2% in CDR 0.5, 44.4% in CDR 1, and 23.1% in CDR 2 (p = 0.045). However, the mean total GDS-15 scores did not differ significantly between the three groups (Table 1). Based on factor analysis, only the mean scores for Factor 2 differed significantly between the three groups, with the score being significantly lower in the CDR 2 group than in the CDR 1group (p = 0.021) (Table 3).

The frequencies and mean scores for each GDS-15 item are shown in Table 4 for each CDR group. The three most common symptoms were “dropped many activities and interest” (no. 2), “more problems with memory than others” (no. 10), and “full of energy” (no. 13), for all CDR groups, although the order of frequencies and scores varied somewhat between groups. The frequency of symptoms related to “memory problem” (no. 10) paradoxically decreased as CDR increased: 74.9% in the CDR 0.5 group, 62.8% in the CDR 1 group, and 43.6% in the CDR 2 group (p < 0.001). The prevalence of three Factor 2 depressive symptoms (“unhappiness and dissatisfaction”) was significantly different between groups, with the lowest values reported in the CDR 2 group (Table 4): “satisfied with life” (no. 1) (p = 0.048), “in good spirits most of time” (no. 5) (p = 0.049), and “wonderful to be alive” (no. 11) (p = 0.036). The results of mean scores on these three symptoms also showed the same pattern (Table 4).

Relationship between depression and disease severity

Results from the logistic regression models are presented in Table 5. Odds ratio (ORs) and 95% confidence interval (95% CIs) from the models were used to determine whether each depressive symptom was associated with EOAD severity. Compared to very mild EOAD (CR 0.5), mild disease (CR 1) was associated with an approximately twofold higher likelihood of at least one of two specificFactor 1 depressive symptoms (Table 5): “feel pretty worthless” (no. 12) (OR, 2.04; 95% CI, 1.19–3.50; p = 0.010) and “situation is hopeless” (no. 14) (OR, 1.84; 95% CI, 1.07–3.16; p = 0.028). Compared to mild stage EOAD (CR 1), moderate stage disease (CR 2) was associated with an approximately twofold times higher likelihood of at least one of two specific Factor 2 symptoms: “prefer to stay at home” (no. 9) (OR, 2.69; 95% CI, 1.08–6.71; p = 0.033) and “full of energy” (no. 13) (OR, 2.12; 95% CI, 1.02–4.40; P = 0.043).

DISCUSSION

In this study, we confirmed that depressive symptoms of GDS-15 can be categorized into three factors in Korean patients with EOAD, and that the frequency and pattern of depressive symptoms changes according to disease severity. The main findings of this study were as follows: 1) depression symptoms decreased in moderate EOAD; 2) patients with EOAD were paradoxically less likely to report subjective memory problems as the severity of dementia increased; 3) depressive symptoms related to “unhappiness and dissatisfaction” (Factor 2) were significantly less frequent in moderate EOAD than in very mild and mild EOAD; and 4) depressive symptoms related to “hopelessness and ominousness” (Factor 1) have greater risk to appear when EOAD progresses from very mild to mild, while depressive symptoms related to “unhappiness and dissatisfaction” (Factor 2) have greater risk to appear from mild to moderate.

Many researchers have explored the potential mechanisms of depression in AD in many ways, but the mechanisms remain unclear. From a neuroanatomical viewpoint, the link between depression and AD is related to neurodegeneration in the frontal-limbic circuits or frontal-subcortical circuits. In particular, the dorsolateral prefrontal area is significantly involved in the pathogenesis of depressive symptoms in AD [43]. Moreover, the neuropathological changes induce subsequent hypothalamus-pituitary-adrenal (HPA) axis dysfunction, inflammatory processes, and neurotrophin deficiency, which have potential roles in depression and AD [44]. In terms of neuroinflammatory theory, chronic inflammatory changes induce overexpression of proinflammatory cytokines, which promote further amyloid production, deposition, and plaque evolution that are correlated with depression in AD [45]. From a neurobiological perspective, alterations of glutamate and the glutamatergic signaling pathway in depression and AD (influenced by HPA axis dysfunction, excitotoxicity, and neuroinflammation) are considered overlapping features that relate the twodiseases [46].

Our results revealed significant differences in depression according to disease stage. Our findingthat depression decreased in moderate EOAD contrasts with the previous finding that depression becomes more severe in the moderate stage of LOAD [47]. As described in the paper of Tanaka et al. [25], because many EOAD patients have an important role in society or family at the time of disease onset, they are more likely to experience poor social adjustment, which could lead to a higher frequency of depression as EOAD progresses from a very mild to mild stage. Therefore, depression is likely influenced by both psychosocial factors and advancing brain damage in EOAD [25]. Another possible explanation might be that depression becomes less apparent in later stages of dementia as the cognitive abilities that are necessary to recognize and sustain depressive conditions deteriorate and the ability to verbalize symptoms also declines. Moreover, the discrepancy between stages was primarily observed in depressive symptoms related to “unhappiness and dissatisfaction” (Factor 2), which decreased as dementia progressed from mild to moderate. This might be because easy forgetting or cognitive disability leads patients to feel less stressful and less unhappy. Similarly, the paradoxically fewer complaints about memory as dementia progresses might reflect deficits in insight about memory problems [48].

As the pattern of depressive symptoms tends to vary depending on disease stage, this suggests that these symptoms reflect a continuum of psychological changes that have occurred since the patients first noticed problems. As Houde et al. reported that depression with melancholic features are particularly predictive of further evolution to AD [49], it would be desirable to focus on specific depressive symptoms, not just total scores, at each stage because of evidence suggesting that some depressive patterns are determinants of dementia or predementia syndromes. When assessing depression, focusing on symptoms related to “hopelessness and ominousness” (Factor 1) would be valuable in EOAD patients progressing from very mild to mild stage disease, whereas symptoms related to “unhappiness and dissatisfaction” would be more useful in patients progressing from mild to moderate EOAD.

The present study contains several limitations, however. First, this was a cross-sectional and hospital-based study, which raises the possibility of a bias in patient selection and limits the generalizability of our findings. Therefore, a longitudinal study is required. Second, we did not collect detailed information about the current use of antidepressants, as well as the types of or compliance with antidementia drugs. Previously, donepezil was found to be associated with an improvement of neuropsychiatric symptoms, including depression, in AD patients [34 , 51]. This was postulated to reflect improved cholinergic neurotransmission with donepezil [50, 51].In addition, while a meta-analysis by Sepehryet al. [52] reported that current evidence does not support the efficacy of selective serotonin reuptake inhibitor/serotonin-noradrenaline reuptake inhibitor therapy for symptoms of comorbid depression in AD, and a systematic review concluded that the literature offered only weak support for the effectiveness of antidepressants for patients with depression and dementia [53], another review summarizing current data on the use of antidepressants in the treatment of neuropsychiatric symptoms of dementia indicated that antidepressants can be effective in treating neuropsychiatric symptoms, including depression [54]. Despite these conflicting publications, not only antidepressants but also cholinesterase inhibitors could affect GDS-15 scores; thus, we should have considered the impact of these medications on depression. Third, we did not directly compare LOAD and EOAD, which would have provided more information. Notwithstanding these limitations, the present study has improved our understanding of the depressive symptoms in EOAD.

In conclusion, our results suggest that the patterns of depressive symptoms differ by EOAD severity. Therefore, future studies assessing the relationship between depression and dementia should consider not only the total depression score but also each depressive symptom. Our results may help clinicians focus on the most appropriate approach to dealing with depressive symptoms at each stage of EOAD.

Footnotes

ACKNOWLEDGMENTS

This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health, Welfare, and Family Affairs, Republic of Korea (HI10C2020) and the Original Technology Research Program for Brain Science through the National Research Foundation of Korea (KRF) funded by the Korean government (MSIP) (No. 2014M3C7A1064752).

Authors’ disclosures available online ().

References

Verdelho

, Madureira

, Moleiro

, Ferro

, O’Brien

, Poggesi

, Pantoni

, Fazekas

, Scheltens

, Waldemar

, Wallin

, Erkinjuntti

, Inzitari

(2013) Depressive symptoms predict cognitive decline and dementia in older people independently of cerebral white matter changes: The LADIS study. J Neurol Neurosurg Psychiatry 84, 1250–1254.

Olazaran

, Trincado

, Bermejo-Pareja

(2013) Cumulative effect of depression on dementia risk. Int J Alzheimers Dis 2013, 457175–.

Kohler

, Allardyce

, Verhey

, McKeith

, Matthews

, Brayne

, Savva

(2013) Cognitive decline and dementia risk in older adults with psychotic symptoms: A prospective cohort study. Am J Geriatr Psychiatry 21, 119–128.

Kohler

, van Boxtel

, Jolles

, Verhey

(2011) Depressive symptoms and risk for dementia: A 9-year follow-up of the Maastricht Aging Study. Am J Geriatr Psychiatry 19, 902–905.

Weisenbach

, Boore

, Kales

(2012) Depression and cognitive impairment in older adults. Curr Psychiatry Rep 14, 280–288.

Richard

, Reitz

, Honig

, Schupf

, Tang

, Manly

, Mayeux

, Devanand

, Luchsinger

(2013) Late-life depression, mild cognitive impairment, and dementia. JAMA Neurol 70, 374–382.

Diniz

, Butters

, Albert

, Dew

, Reynolds

(2013) Late-life depression and risk of vascular dementia and Alzheimer’s disease: Systematic review and meta-analysis of community-based cohort studies. Br J Psychiatry 202, 329–335.

Barnes

, Yaffe

, Byers

, McCormick

, Schaefer

, Whitmer

(2012) Midlife vs late-life depressive symptoms and risk of dementia: Differential effects for Alzheimer disease and vascular dementia. Arch Gen Psychiatry 69, 493–498.

Gracia-Garcia

, de-la-Camara

, Santabarbara

, Lopez-Anton

, Quintanilla

, Ventura

, Marcos

, Campayo

, Saz

, Lyketsos

, Lobo

(2015) Depression and incident Alzheimer disease: The impact of disease severity. Am J Geriatr Psychiatry 23, 119–129.

10.

Hsiao

, Teng

(2013) Depressive symptoms in clinical and incipient Alzheimer’s disease. Neurodegener Dis Manag 3, 147–155.

11.

Palmer

, Di Iulio

, Varsi

, Gianni

, Sancesario

, Caltagirone

, Spalletta

(2010) Neuropsychiatric predictors of progression from amnestic-mild cognitive impairment to Alzheimer’s disease: The role of depression and apathy. J Alzheimers Dis 20, 175–183.

12.

Van der Mussele

, Fransen

, Struyfs

, Luyckx

, Marien

, Saerens

, Somers

, Goeman

, De Deyn

, Engelborghs

(2014) Depression in mild cognitive impairment is associated with progression to Alzheimer’s disease: A longitudinal study. J Alzheimers Dis 42, 1239–1250.

13.

Spalletta

, Caltagirone

, Girardi

, Gianni

, Casini

, Palmer

(2012) The role of persistent and incident major depression on rate of cognitive deterioration in newly diagnosed Alzheimer’s disease patients. Psychiatry Res 198, 263–268.

14.

Panza

, Frisardi

, Capurso

, D’Introno

, Colacicco

, Imbimbo

, Santamato

, Vendemiale

, Seripa

, Pilotto

, Capurso

, Solfrizzi

(2010) Late-life depression, mild cognitive impairment, and dementia: Possible continuum?. Am J Geriatr Psychiatry 18, 98–116.

15.

Di Iulio

, Palmer

, Blundo

, Casini

, Gianni

, Caltagirone

, Spalletta

(2010) Occurrence of neuropsychiatric symptoms and psychiatric disorders in mild Alzheimer’s disease and mild cognitive impairment subtypes. IntPsychogeriatr 22, 629–640.

16.

Aalten

, de Vugt

, Jaspers

, Jolles

, Verhey

(2005) The course of neuropsychiatric symptoms in dementia. Part I: Findings from the two-year longitudinal Maasbed study. Int J Geriatr Psychiatry 20, 523–530.

17.

Selbaek

, Kirkevold

, Engedal

(2008) The course of psychiatric and behavioral symptoms and the use of psychotropic medication in patients with dementia in Norwegian nursing homes–a 12-month follow-up study. Am J Geriatr Psychiatry 16, 528–536.

18.

Wetzels

, Zuidema

, de Jonghe

, Verhey

, Koopmans

(2010) Course of neuropsychiatric symptoms in residents with dementia in nursing homes over 2-year period. Am J Geriatr Psychiatry 18, 1054–1065.

19.

Bergh

, Engedal

, Roen

, Selbaek

(2011) The course of neuropsychiatric symptoms in patients with dementia in Norwegian nursing homes. Int Psychogeriatr 23, 1231–1239.

20.

Serra

, Perri

, Fadda

, Padovani

, Lorusso

, Pettenati

, Caltagirone

, Carlesimo

(2010) Relationship between cognitive impairment and behavioural disturbances in Alzheimer’s disease patients. Behav Neurol 23, 123–130.

21.

Park

, Choi

, Park

, Kim

, Lee

, Han

, Kim

, Han

, Moon

, Yang

, Park

, Yoon

, Seo

, Na

, Lee

(2015) Cognitive profiles and neuropsychiatric symptoms in Korean early-onset Alzheimer’s disease patients: A CREDOS study. J Alzheimers Dis 44, 661–673.

22.

, Pinto

, Cunha

, Lemos

, Letra

, Simoes

, Santana

(2012) Differences between early and late-onset Alzheimer’s disease in neuropsychological tests. FrontNeurol 3, 81–.

23.

Toyota

, Ikeda

, Shinagawa

, Matsumoto

, Hokoishi

, Fukuhara

, Ishikawa

, Mori

, Adachi

, Komori

, Tanabe

(2007) Comparison of behavioral and psychological symptoms in early-onset and late-onset Alzheimer’s disease. Int J Geriatr Psychiatry 22, 896–901.

24.

Shinagawa

, Ikeda

, Toyota

, Matsumoto

, Mori

, Ishikawa

, Fukuhara

, Komori

, Hokoishi

, Tanabe

(2007) Frequency and clinical characteristics of early-onset dementia in consecutive patients in a memory clinic. Dement Geriatr Cogn Disord 24, 42–47.

25.

Tanaka

, Hashimoto

, Fukuhara

, Ishikawa

, Yatabe

, Kaneda

, Yuuki

, Honda

, Matsuzaki

, Tsuyuguchi

, Hatada

, Ikeda

(2015) Relationship between dementia severity and behavioural and psychological symptoms in early-onset Alzheimer’s disease. Psychogeriatrics 3, 12108.

26.

Panegyres

, Chen

(2014) Early-onset Alzheimer’s disease: A global cross-sectional analysis. Eur J Neurol 21, 1149–1154. e64–65

27.

Marshall

, Fairbanks

, Tekin

, Vinters

, Cummings

(2007) Early-onset Alzheimer’s disease is associated with greater pathologic burden. J Geriatr Psychiatry Neurol 20, 29–33.

28.

Gour

, Felician

, Didic

, Koric

, Gueriot

, Chanoine

, Confort Gouny

, Guye

, Ceccaldi

, Ranjeva

(2014) Functional connectivity changes differ in early and late-onset Alzheimer’s disease. Hum Brain Mapp 35, 2978–2994.

29.

Cho

, Seo

, Kim

, Ye

, Kim

, Noh

, Kim

, Yoon

, Seong

, Kim

, Kang

, Chin

, Kim

, Lee

, Na

(2013) Changes in subcortical structures in early- versus late-onset Alzheimer’s disease. Neurobiol Aging 34, 1740–1747.

30.

Cho

, Jeon

, Kang

, Lee

, Kim

, Shin

, Kim

, Noh

, Im

, Kim

, Chin

, Seo

, Na

(2013) Longitudinal changes of cortical thickness in early- versus late-onset Alzheimer’s disease. Neurobiol Aging 34, 1921.e9–1921.e15.

31.

Cavedo

, Pievani

, Boccardi

, Galluzzi

, Bocchetta

, Bonetti

, Thompson

, Frisoni

(2014) Medial temporal atrophy in early and late-onset Alzheimer’s disease. Neurobiol Aging 35, 2004–2012.

32.

Bigio

, Hynan

, Sontag

, Satumtira

, White

(2002) Synapse loss is greater in presenile than senile onset Alzheimer disease: Implications for the cognitive reserve hypothesis. Neuropathol Appl Neurobiol 28, 218–227.

33.

Reitz

, Brayne

, Mayeux

(2011) Epidemiology of Alzheimer disease. Nat Rev Neurol 7, 137–152.

34.

Spalletta

, Caltagirone

, Padovani

, Sorbi

, Attar

, Colombo

, Cravello

, EVOLUTION study Working Group (2014) Cognitive and affective changes in mild to moderate Alzheimer’s disease patients undergoing switch of cholinesterase inhibitors: A 6-month observational study. PLoS One 9, e89216.

35.

McKhann

, Drachman

, Folstein

, Katzman

, Price

, Stadlan

(1984) Clinical diagnosis of Alzheimer’sdisease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34, 939–944.

36.

Park

, Na

, Han

, Kim

, Cheong

, Kim

, Hong

, Kim

, Ku

, Moon

, Lee

, Shim

, Youn

, Kim

, Park

, Cha

, Seo

, Lee

(2011) Clinical characteristics of a nationwide hospital-based registry of mild-to-moderate Alzheimer’s disease patients in Korea: A CREDOS(Clinical Research Center for Dementia of South Korea) study. J Korean Med Sci 26, 1219–1226.

37.

Morris

(1993) The Clinical Dementia Rating (CDR): Current version and scoring rules. Neurology 43, 2412–2414.

38.

Yesavage

, Brink

, Rose

, Lum

, Huang

, Adey

, Leirer

(1982) Development and validation of a geriatric depression screening scale: A preliminary report. J Psychiatr Res 17, 37–49.

39.

Kim

, Park

, Lee

, Huh

, Lee

, Han

, Choi

, Lee

, Kim

, Woo

(2008) Standardization of the Korean version of the geriatric depression scale: Reliability, validity, and factor structure. Psychiatry Investig 5, 232–238.

40.

Cho

, Bae

, Suh

(1999) Validation of geriatric depression scale, Korean version (GDS) in the assessment of DSM-III-R major depression. J Korean Neuropsychiatr Assoc 38, 48–63.

41.

Sheikh

, Yesavage

, Brooks

, Friedman

, Gratzinger

, Hill

, Zadeik

, Crook

(1991) Proposed factor structure of the Geriatric Depression Scale. Int Psychogeriatr 3, 23–28.

42.

Bae

, Cho

(2004) Development of the Korean version of the Geriatric Depression Scale and its short form among elderly psychiatric patients. J Psychosom Res 57, 297–305.

43.

Terada

, Oshima

, Sato

, Ikeda

, Nagao

, Hayashi

, Hayashibara

, Yokota

, Uchitomi

(2014) Depressive symptoms and regional cerebral blood flow in Alzheimer’s disease. Psychiatry Res 221, 86–91.

44.

Chi

, Yu

, Tan

(2014) Depression in Alzheimer’s disease: Epidemiology, mechanisms, and management. J Alzheimers Dis 42, 739–755.

45.

Hermida

, McDonald

, Steenland

, Levey

(2012) The association between late-life depression, mild cognitive impairment and dementia: Is inflammation the missing link?. Expert Rev Neurother 12, 1339–1350.

46.

Khundakar

, Thomas

(2015) Neuropathology of depression in Alzheimer’s disease: Current knowledge and the potential for new treatments. J Alzheimers Dis 44, 27–41.

47.

Caputo

, Monastero

, Mariani

, Santucci

, Mangialasche

, Camarda

, Senin

, Mecocci

(2008) Neuropsychiatric symptoms in 921 elderly subjects with dementia: A comparison between vascular and neurodegenerative types. Acta Psychiatr Scand 117, 455–464.

48.

Orfei

, Varsi

, Blundo

, Celia

, Casini

, Caltagirone

, Spalletta

(2010) Anosognosia in mild cognitive impairment and mild Alzheimer’s disease: Frequency and neuropsychological correlates. Am J Geriatr Psychiatry 18, 1133–1140.

49.

Houde

, Bergman

, Whitehead

, Chertkow

(2008) A predictive depression pattern in mild cognitive impairment. Int J Geriatr Psychiatry 23, 1028–1033.

50.

Gauthier

, Feldman

, Hecker

, Vellas

, Ames

, Subbiah

, Whalen

, Emir

(2002) Efficacy of donepezil on behavioral symptoms in patients with moderate to severe Alzheimer’s disease. Int Psychogeriatr 14, 389–404.

51.

Cummings

, McRae

, Zhang

(2006) Effects of donepezil on neuropsychiatric symptoms in patients with dementia and severe behavioral disorders. Am J Geriatr Psychiatry 14, 605–612.

52.

Sepehry

, Lee

, Hsiung

, Beattie

, Jacova

(2012) Effect of selective serotonin reuptake inhibitors in Alzheimer’s disease with comorbid depression: A meta-analysis of depression and cognitive outcomes. Drugs Aging 29, 793–806.

53.

Nelson

, Devanand

(2011) A systematic review and meta-analysis of placebo-controlled antidepressant studies in people with depression and dementia. J Am Geriatr Soc 59, 577–585.

54.

Henry

, Williamson

, Tampi

(2011) Efficacy and tolerability of antidepressants in the treatment of behavioral and psychological symptoms of dementia, a literature review of evidence. Am J Alzheimers Dis Other Demen 26, 169–183.