. 2022 Apr 23;43(7):4107–4124. doi: 10.1007/s10072-022-06068-x

Table 1.

Characteristics of the included studies

Study
Banning et al. [36] USA	Objective Study design Sample Outcomes Assessment Results	To assess depression over a 5-year follow-up period and to relate its trajectories to AD biomarkers Retrospective longitudinal study 3030 Pt with AD; gender: n.a.; age: nd.; dementia severity: prodromal AD criteria: DSM-IV-TR, NIA-AA, and NINCDS-ADRDA Cognitive ability assessment: MMSE Depression Assessment: NPI and NPI-Q Association between increasing probability of depression over time and AD pathology, i.e., lower CSF Aβ42 and higher t-tau and p-tau levels. Association between AD pathology and de novo or (initially) rising symptoms of depression
Banning et al. [35] USA	Objectives Study design Sample Outcomes Assessment Results	To study (inter)relations of AD biomarkers and neuropsychiatric symptoms in AD dementia and the impact of the cognitive functioning Retrospective cross-sectional study 626 Pt with AD; M: 299; F: 327; age: 73.9; dementia severity: mild level AD criteria: NINCDS-ADRDA and DSM-IV Cognitive abilities assessment: MMSE Anxiety and depression assessment: NPI, NPI-Q Association between the presence of anxiety and lower CSF levels of Ab42 and higher levels of CSF t-tau and p-tau, mediated by MMSE. No association between depression and Ab42 values, t-tau, p-tau, and reduced hippocampal volume (HCV) and between anxiety and HCV → Association of anxiety with AD pathology, due to impaired cognitive functioning, as initial compensating behaviour. Depression more related to psychosocial (i.e., awareness and psychological reaction to AD) or environmental (i.e., relationship with caregivers) or other biological factors (i.e., HPA axis or chronic inflammation)
Rouch et al. [51] France	Objective Study design Sample Outcomes Assessment Results	To evaluate the association between cognitive functioning and the occurrence of behavioural and psychological symptoms of dementia Prospective study. Pt were assessed at 6-, 12-, and 18-month follow-up 237 Pt with prodromal or mild AD; M: 100; F: 137; age: 79.5; age at onset: n.a.; dementia severity: mild level AD criteria: NINCDS-ADRDA Cognitive ability assessment: MMSE Anxiety and depression assessment: NPI Association between lower inhibition performance on Stroop test and subsequent higher risk of anxiety and depression → Stroop test involves anterior cingulate cortex that is involved in depression
Wu et al. [53] China	Objective Study design Sample Outcomes Assessment Results	To explore the probable neuroanatomical substrate of depressive symptoms of AD patients Cross-sectional study with control group 20 Pt with AD; M: 11; F: 9; age: 67.15; dementia severity: CDR 0.5–2 normal to moderate AD criteria: NINCDS-ADRDA Cognitive ability assessment: MMSE, ADL Anxiety and depression assessment: HAMA and HDRS Negative association between depression and insular and inferior frontal lobe grey matter volume, controlling for MMSE → Atrophy of the insula and the inferior frontal lobe more severe for depressed patients. Due to insular degeneration, depressive symptoms in AD could be related to abnormal somatic sensations; affective symptoms tend to reduce as AD progresses
Baillon et al. [49] England	Objective Study design Sample Outcomes Assessment Results	To compare neuropsychiatric symptoms (NPS) in people with early-onset Alzheimer’s disease (EOAD) and late-onset AD (LOAD) Retrospective 24 Pt with EOAD (< 65 years), M: 11; F: 13; 56 patients with LOAD (> 65 years), M: 20; F: 36; mean age: 59.3 EOAD, 82.3 LOAD. Duration of illness (months): 50.3 (41.8) EOAD, 26.9 (22.7) LOAD. Dementia severity: mild level AD criteria: NINCDS-ADRDA Cognitive ability assessment: MMSE, Bristol Activities of Daily Living Scale (BADLS) Anxiety and depression assessment: NPI Anxiety and depression higher in patients with EOAD compared to patients with LOAD → Diagnosis and AD-related changes in lifestyles, roles, and responsibility are greater in EOAD patients. Depression and anxiety occurring throughout the AD course both due to brain damage and psychosocial factors
Barca et al. [54] Norway	Objective Study design Sample Outcomes Assessment Results	To investigate the different trajectories of depressive symptoms among patients with AD and the relationship between the progression of AD and different trajectories Longitudinal observational study 282 Pt (177 with dementia due to AD and 105 with prodromal AD); M: 130; F:152; age: 73.2; AD duration: n.a.; dementia severity: mild level AD criteria: ICD-10; NINCDS-ADRDA Cognitive ability assessment: MMSE Depression assessment: Cornell Scale for Depression in Dementia and Clinical Dementia Rating Scale (CDR) Identified three distinct trajectories of depressive symptoms: stable low-average; high and decreasing; moderate and increasing. Association between the trajectories and AD progression: more depression in faster dementia → Faster progression leads to organic depression due to brain damages. Depression could also occur as a psychological reaction to greater impairments and can cause cognitive impairment
Tanaka et al. [43] Japan	Objective Study design Sample Outcomes Assessment Results	To investigate the relationship between dementia severity and behavioural and psychological symptoms in early-onset AD patients Cross-sectional 92 Pt with early-onset AD; M: 31; F: 61; age: 59.0; AD duration (years): 5.6; dementia severity: mild to severe AD criteria: NINCDS-ADRDA Cognitive ability assessment: MMSE Depression and anxiety assessment: Neuropsychiatric Inventory No differences in depression and anxiety among the three AD severity groups → Early-onset AD can lead to a poor social adjustment in society and family. Depression and anxiety are influenced by both psychosocial factors and advancing brain damage
Kaiser et al. [34] USA	Objective Study design Sample Outcomes Assessment Results	To evaluate anxiety in early-onset AD (EOAD) versus late-onset AD (LOAD) Cross-sectional 45 Pt (23 with EOAD, age: 57.68; 22 with LOAD, age: 80.32); M: 31; F: 14; AD duration (years): 3.09 (EOAD), 3.91 (LOAD); dementia severity: mild to moderate AD criteria: NINCDS-ADRDA Cognitive ability assessment: MMSE Anxiety assessment: NPI Higher anxiety in early-onset AD pts than in late-onset AD pts. Association between anxiety, gender, MMSE, and separation from caregivers in early-onset AD pts. Association between anxiety and psychotic and activating psychiatric symptoms related to dementia progression in late-onset AD pts → Men with early-onset AD are in midlife and have many roles and responsibilities. Thus, early-onset AD has higher impact on the individual than late-onset AD
Lebedeva et al. [44] Sweden	Objective Study design Sample Outcomes Assessment Results	To examine the association between depressive symptoms and neuroanatomical changes, brain structure and cerebrospinal fluid AD biomarkers Cohort observational study 189 AD Pt with and without depression; M: 94; F: 95; age: 71,1; AD duration (years): n.a.; dementia severity: n.a AD criteria: NINCDS-ADRDA and DSM-IV/ICD-10 Cognitive ability assessment: MMSE Depression assessment: Cornell Scale for Depression in Dementia and Geriatric Depression Scale Association between depression and changes in the temporal and parietal regions, including supramarginal, superior and inferior temporal and fusiform gyri, right posterior cingulate, and precuneus. Correlation between cortical thickness and t-τ was greater in depressed pts. in precuneus and parahippocampal cortex → More neurodegeneration on limbic structures in depressed AD patients. Disruptions of limbic neural networks can explain depression
Panegyres et al. [20] Australia	Objective Study design Sample Outcomes Assessment Results	Exploring clinical differences between early-onset AD patients and late-onset AD patients Cross-sectional study 3747 AD Pt with anxiety or depression (614 with early-onset AD; 3133 with late-onset AD); M: 1686; F: 2061; age: 59.3 (early-onset AD) 76.2 (late-onset AD); AD duration: n.a.; dementia severity: n.a AD criteria: McKhann criteria Cognitive ability assessment: n/a Anxiety and depression assessment: NPI, EQ-5D-3L, and GDS Early-onset AD pts were more likely to have anxiety or depression than late-onset pts. → They might be related to dementia severity and more rapid progression
Tagai et al. [42] Japan	Objective Study design Sample Outcomes Assessment Results	To investigate how anxiety in AD is related to the structure and function of the brain Retrospective study 26 Pt with probable AD; M: 6; F: 20; age: 74.95; AD duration: 27 months; dementia severity: mild level AD criteria: NINCDS-ADRDA; MRI; SPECT Cognitive function assessment: MMSE; CDR-SB; FAB Anxiety assessment: Behave-AD Association between anxiety, atrophy in the right precuneus (Pcs) and inferior parietal lobule (IPL), and hyperperfusion of the bilateral anterior cingulate cortex ACC → Pcs, IPL, and ACC belong to the fear neurocircuitry and are involved in anxiety disorders. In AD, their degeneration could explain anxiety
Zahodne et al. [33] USA	Objective Study design Sample Outcomes Assessment Results	To investigate longitudinal associations between functional abilities, cognitive status, and depressive symptoms in AD. Longitudinal study. Pt were assessed prospectively at 6-month intervals for up to 16 years, with an average of 5.5 years 517 Pt with probable AD; M: 222; F: 295; age: 74.19; AD duration: n.a.; dementia severity: mild level AD criteria: NINCDS-ADRDA Cognitive ability assessment: mMMSE; BDRS Depression assessment: CUSPAD Not worsening of depressive symptoms over AD course. Depressive symptoms predicted functional decline and vice versa → Depression may be reactive to the loss of functional ability, but it is not only a reaction to cognitive decline
Spalletta et al. [52] Italy	Objective Study design Sample Outcomes Assessment Results	To investigate cognitive progression of AD patients with or without major depressive episode Longitudinal study 119 newly diagnosed probable AD patients. M: 52; F: 67; age: 74.7; AD duration: 2.4 years; dementia severity: mild severity AD criteria: NINCDS-ADRDA Cognitive ability assessment: Mental Deterioration Battery, MMSE Depression assessment: a structured interview following modified DSM-IV diagnostic criteria for major depressive episode in AD More MMSE decline in pts with persistent depression, with incident depression over follow-up and in never depressed pts than in pts with recovered depression. → Depression in AD can be linked to additional cognitive impairment in AD, i.e., frontal planning impairments, that disappear or improve with remission of depression
van Vliet et al. [40] Holland	Objective Study design Sample Outcomes Assessment Results	To assess neuropsychiatric symptoms in young-onset AD (YO-AD)* and late-onset AD (LO-AD) Prospective cohort study Pt were assessed every 6 months for 2 years 221 Pt: 98 with YO-AD (age of onset before 65), 123 with LO-AD; M: 99; F: 122; age: 70; AD duration (years): 5.8 (YO-AD) 2.9 (LO-AD); dementia severity: moderate level AD criteria: 4th edition of the Diagnostic and Statistical Manual of Mental Disorders, Text Revision (2000) and the Dutch Consensus guidelines Cognitive ability assessment: MMSE Depression and anxiety assessment: Neuropsychiatric Inventory Depression and anxiety prevalence is lower in young-onset AD than in late-onset AD Depression is the most prevalent symptom in late-onset AD, and it decreases over time. Depression is less persistent in young-onset AD than in late-onset AD → Non-memory phenotype is associated with less atrophy of the medial temporal lobe, so with less symptoms. In oldest patients, contextual factors, i.e., death of a loved one or physical disability, and cerebrovascular diseases may increase depression
Meynen et al. [39] Netherlands	Objective Study design Sample Outcomes Assessment Results	To investigate the relationship between depressive state and neuropathological hallmarks of AD Prospective longitudinal study. Pt were evaluated every 6 months during the last years of their lives 43 Pt with possible or probable AD; M: 10; F: 33; age: 82.8; AD onset: 73.7 years; AD duration: 9.1 years; age of death: 82.8; dementia severity: severe level AD criteria: NINCDS-ADRDA; DSM-III-R; Braak stage for tangles Cognitive function assessment: MMSE at baseline; GDS and FAST at 6-month intervals Depression Assessment: CSDD Association between depression and the density of neuritic plaques in the entire cortex, and stronger in the temporal cortex, independently from clinical dementia and AD duration → Decreased cortical metabolism could determine both neuritic plaques and depression. The presence of neuritic plaques in the cortex might contribute, possibly through a toxicity of Aβ-amyloid, to the occurrence of depression. The neuronal damage in the temporal cortex could lead to disinhibition of the HPA-axis that contributes to depression. Vice versa, depression, associated to HPA hyperactivity and cardiovascular disease, may contribute to AD progress
Wilson et al. [32] USA	Objective Study design Sample Outcomes Assessment Results	To characterize change in depressive symptoms before and after the onset of dementia in AD Longitudinal study 1. Subgroup was evaluated every 3 years for a mean of 8 to 9 years 2. Subgroup: annual evaluation, for a mean of 3 years 1. Group: 357 Pt who developed AD during the study; M: 141; F: 216; age: 82.5 years; dementia severity: mild level 2. Group: 340 Pt (107 with AD, 81 with MCI, 152 with no cognitive impairment); M: 140; F: 200; age: 81.27 years AD criteria: NINCDS-ADRDA Cognitive function assessment: MMSE Depression assessment: (1) group: CES-D (self-report) v (2) group: HDRS (informant report) No change in depression during 2 to 3 years of observation after the diagnosis except for a slight decrease in positive affect → AD has little systematic effect on depression; since AD develops, impaired memory and executive control seem to stop the continuity of the depressive state
Amieva et al. [50] France	Objective Study design Sample Outcomes Assessment Results	To examine the emergence of the first clinical symptoms over a 14-year period of follow-up before the dementia phase of AD Longitudinal study. Subjects were evaluated at home at the initial visit and at 1, 3, 5, 8, 10, 13, and 15 years 350 AD Pt.; M: 243; F: 107; age: 86.2; AD duration: n.a.; dementia severity: n.a AD criteria: NINCDS-ADRDA Cognitive ability assessment: a battery of tests including MMSE Depression assessment: Center for Epidemiologic Studies-Depression scale (CESD) Association between global deficits and depressive symptoms. → Depression could be an early reaction to perceived cognitive decline
Wilson et al. [31] USA	Objective Study design Sample Outcomes Assessment Results	To test the hypothesis that depressive symptoms increase during the prodromal phase of AD Prospective cohort study 190 Pt with incident AD, M: 54; F: 136; age: 80.0; AD duration (years): 3.9; dementia severity: n.a AD criteria: NINCDS-ADRDA Cognitive ability assessment: MMSE Depression assessment: CES-D No significant changes in depressive symptoms after the AD diagnosis, although symptoms tended to decrease in women relative to men and in those with a higher premorbid level of openness and a lower premorbid level of agreeableness. Not increasing in depression as mild cognitive impairment developed → Depressive symptoms might influence the relation of the AD pathologic changes to cognition. Depression was associated with sex and personality, and some people experience a depressive reaction to AD
Tsang et al. [41] Singapore	Objective Study design Sample Outcomes Assessment Results	To correlate several glutamatergic measures with chronic anxiety in AD Prospective longitudinal study 21 Pt with AD (10 with low anxiety—LA; 11 with high anxiety—HA); M: 6; F:15; age: 77.4; age at onset: 70.45; age at death: 79.85; AD duration: 9.4 years Dementia severity: severe cognitive impairment AD criteria: CERAD scale Cognitive function assessment: MMSE; ADL Anxiety/depression assessment: NPI Higher binding affinity to glycine recognition sites (GlyRS) in pt with higher anxiety. Association between higher GlyRS affinity, selective reduction of N-methyl-d-aspartate NMDA receptor NR2A density, and elevated anxiety → The development of anxiety in AD can have a neurochemical basis. Changes in the NMDA receptor complex can lead to GlyRS hyperfunction that lead to anxiety
Hashimoto et al. [30] USA	Objective Study design Sample Outcomes Assessment Results	To investigate the association between anxiety and regional glucose metabolism in AD Observational, cross-sectional 41 Pt: M: 35, F: 6; age: 75.5 years; AD: 2.8 years AD criteria: NINCDS-ADRDA Cognitive ability assessment: MMSE Anxiety and depression assessment: NPI Higher anxiety associated with lower resting metabolism in the bilateral entorhinal cortex, anterior parahippocampal gyrus, and left anterior superior temporal gyrus and insula → Reduced functional activity in the bilateral anterior inferomedial temporal cortex may contribute to anxiety in AD, independently from cognitive decline
Cannon-Spoor et al. [28] USA	Objective Study design Sample Outcomes Assessment Results	To examine the effect of history of major depressive disorder (MDD) on cognitive performance in AD patients Multi-site prospective study 43 Pt with AD (22 AD + MDD; 21 AD − MDD); M: 16; F: 27. Age: 69; age at onset of AD: 66.5; AD duration: 3.35 years Dementia severity: mild-to-moderate cognitive impairment AD criteria: NINCDS-ADRDA; CDR Cognitive function assessment: test battery consisting of MMSE, WAIS-R, Mattis Initiation/Perseveration subscale, Buschke SRT, Fluency task Depression Assessment: CADD A history of depression in AD Pt was associated with more severe cognitive deficits → MDD and AD may share some underlying genetic diathesis or may share risk factors. The experience of MDD, particularly if long-lasting or repeated, may result in an insult that increases the risk for AD or increases the severity of cognitive symptoms
Holtzer et al. [29] USA	Objective Study design Sample Outcomes Assessment Results	To examine the temporal relationship between depressive symptoms, function, and cognitive status in Pt with probable AD Multicentre cohort study Pt were followed for up to 14 years and evaluated every 6 months 536 Pt with probable AD (210 with AD and depression) M: 220; F: 316; age: 74; AD duration: 4.06 years Dementia severity: mild level of cognitive and functional impairments AD criteria: NINCDS-ADRDA; DSM-III-R Cognitive and functional ability assessment: 3MS; BDRS Depression assessment: CUSPAD Depression was associated with functional impairment but not with cognitive impairment. Decline in function, indeed, preceded the first episode of depressive symptoms → Lower functional activity may be a risk factor for the onset of depressive symptoms in AD
Milwain et al. [48] UK	Objective Study design Sample Outcomes Assessment Results	To investigate whether depression may influence the clinical expression of AD, analysing the relationship between cognition, the neuropathological stages of AD, and depressive symptoms Longitudinal study Pt with cognitive impairment were evaluated every 6 months, annually for those without 89 Pt with AD (48 with depression) M: 39; F: 50; age: 79.4 Dementia severity: 14.24% Pt in the pre-clinical stage of AD, 21.36% in the intermediate stages of AD, 43.61% in the final stages of AD AD criteria: Braak stage Cognitive function assessment: CAMCOG Depression assessment: CAMDEX Depression was associated with a more severe cognitive impairment, but only in intermediate stages of AD. Indeed, depressive symptoms had no impact during the early and advanced stages of AD → Depressive symptoms may contribute to the cognitive decline of AD Pt. The low prevalence of depression in the final stages of AD may be due to the fact that demented Pt are not able to express the depressive disorder
Gilley et al. [27] USA	Objective Study design Sample Outcomes Assessment Results	To evaluate factors related to the development of depressive symptoms in Pt with AD Longitudinal study. Pt were evaluated at baseline and at up to 4 annual follow-up examinations 410 Pt with AD, M: 136; F: 274; age: 75.5; age duration: n.a Dementia severity: moderate level at the study onset and a severe level at the last evaluation AD criteria: McKhann criteria Cognitive function assessment: MMSE Depression assessment: HRS-D + quantitative structured interviews with family members Premorbid neuroticism personality was associated with an increased rate of depressive symptoms in AD Pt Cognitive impairment was associated with a small reduction in mood symptoms and a modest increase in somatic symptoms → Decline in mood symptoms with increasing severity of cognitive impairment in Pt with AD can be explained as the result of the degradation of the ability to experience or express emotion as severity of AD increases
Wilson et al. [25] USA	Objective Study design Sample Outcomes Assessment Results	To study the relationship between depressive symptoms, clinical AD, and cognitive impairment Longitudinal study 130 elder participants, of whom 51 with probable AD AD criteria: NINCDS-ADRDA Cognitive ability assessment: 19 cognitive function tests Depression assessment: Center for Epidemiologic Studies Depression Scale (CES-D) Association of depressive symptoms with clinical AD and cognitive impairment seems to be independent of cortical plaques and tangles. → Depression-related glucocorticoid effects on neuronal function can contribute to risk of dementia. Depressive symptoms can also contribute to cognitive decline and clinical AD through some psychological mechanism
Zubenko et al. [26] USA	Objective Study design Sample Outcomes Assessment Results	To describe the prevalence and clinical features of the major depressive syndrome of AD, comparing Pt with AD to elderly Pt without AD Comparative study 243 Pt with probable AD. M: 100; F: 143. Age: 78.4; age at onset of AD: 69.0; dementia severity: moderate level 151 No-AD Pt. M: 70; F: 81; age: 70.9 AD criteria: NINCDS-ADRDA Cognitive function assessment: MMSE; CDR Depression assessment: HAM-D; CADD Higher lifetime prevalence of major depression among AD Pt and higher prevalence of MD in AD Pt with severe cognitive impairment → Premorbid major depressive episodes might increase the risk of developing AD, while prevalence of depressive episodes that occurred in the context of AD may be related to neurodegenerative events that contribute to the aetiology of major depression among AD Pt
Heun et al. [38] Germany	Objective Study design Sample Outcomes Assessment Results	To clarify the relationship between the age at onset of depression in relation to the onset of dementia Longitudinal study 57 Pt with AD and MD. M: 18; F: 39. Age: 74.2; age at onset of AD: 71.7; AD duration: n.a AD criteria: ICD-10 Cognitive function assessment: MMSE, SIDAM Depression assessment: CIDI Partial correlation between the onset of cognitive impairment and the onset of depression → Depression in AD might not be a symptom of psychological distress, but a symptom of the neurodegenerative process of AD that causes cognitive dysfunction as well
Chemerinski et al. [46] Argentina	Objective Study design Sample Outcomes Assessment Results	To examine the prevalence and correlates of generalized anxiety disorder (GAD) in AD Cross-sectional study 54 Pt with probable AD (18 with GAD compared with 36 Pt without anxiety disorder). M: 45%; F: 55%; age: 73.9; AD duration: 3.15 Dementia severity: mild (AD GAD ꞊ 39%; AD control ꞊ 72%), moderate (AD GAD ꞊ 44%; AD control ꞊ 22%), severe (AD GAD ꞊ 17%; AD control ꞊ 6%) AD criteria: NINCDS-ADRDA Cognitive function assessment: MMSE; CDR Anxiety assessment: DSM-III-R; SCID; SCID-II; HAM-D; HAM-A; Apathy Scale; Bech Mania Scale; PLACS GAD in AD was not associated with more severe cognitive impairment → GAD in AD may indicate a subsyndromal depressive state
Haupt, et al. [37] Germany	Objective Study design Sample Outcomes Assessment Results	To study the association between depression and severity of cognitive impairment in AD Longitudinal study. Pt were followed over 2 years with annual evaluations 78 Pt with AD. M: 21; F: 57. Age: 74.3; AD duration: 4.9 years; age at onset: 69.4; dementia severity: mild-to-moderate level AD criteria: NINCDS-ADRA; ICD-10 Cognitive function assessment: CAMDEX; CAMCOG; MMSE; GDS; DS; DBS Depression assessment: DMAS Depressive symptoms in AD Pt are in part associated with a greater severity of cognitive impairment → However, depressive symptoms are not prognostically relevant with respect to a lower or higher rate of symptom progression
Migliorelli et al. [45] Argentina	Objective Study design Sample Outcomes Assessment Results	To examine the prevalence, risk factors, and correlates of depression among patients with AD Cross-sectional study 103 Pt with probable AD, divided into three groups: major depression (N = 24), dysthymia (N = 29), and no depression (N = 50) M: 27; F: 76. Age: 73.2; AD duration: 4.3 years; age at onset: 68.9; dementia severity: mild (44.29%), moderate (47.38%), severe (14.42%) AD criteria: NINCDS-ADRDA Cognitive function assessment: MMS; WAB; TMT; WCST; BNT; TT; Digit Span Depression assessment: DSM-III-R; SCID; SCID-II; PSE; FH-RDC; HAM-D; HAM-A; FIM; STC High frequency of depression among Pt with probable AD. Specifically, dysthymia was primarily in the early stages of AD, and major depression was distributed across the different stages of the illness. No significant between-group differences in the severity of cognitive deficits → Dysthymia may be an emotional reaction to the progressive cognitive decline, while major depression may be related to biological factors
Förstl et al. [47] UK	Objective Study design Sample Outcomes Assessment Results	To examine the changes in the locus coeruleus (LC), substantia nigra (SN), basal nucleus of Meynert of AD Pt with and without depression and relate this to clinical features Prospective study 52 Pt with AD (14 with depression compared with 38 without depression) M: 12; F: 40; age: 83.2 AD duration: 8.2 (AD + D group) 7.5 (AD group without depression); dementia severity: severe cognitive impairment AD criteria: NINCDS-ADRDA Cognitive and functional ability assessment: MMSE, CAMCOG Depression assessment: GMSS, CAMDEX In AD Pt with depression, a lower neuronal count in the locus coeruleus and a higher in the basal nucleus of Meynert than AD Pt without depression were observed. There were no differences of the neuron numbers in the SN Pt with depression showed less cognitive impairment and their verbal skills were better preserved → The observed disproportionate loss of noradrenergic and cholinergic neurons in the LC and basal nucleus of Meynert may represent an important organic substrate of depression in AD
Lopez et al. [23] USA	Objective Study design Sample Outcomes Assessment Results	To evaluate the cognitive functions of patients (Pt) with probable AD and major depression in comparison with Pt with AD and no depression Longitudinal study. Two evaluations: at baseline and 1-year follow-up 10 Pt with AD and depression (developed after the onset of symptoms of dementia) compared with 10 nondepressed Pt with AD; M: 4; F: 16. Age (years): 67.45; AD duration (years): 3.2; dementia severity: mild level AD criteria: NINCDS-ADRA Cognitive function assessment: MMSE Depression assessment: DSM-III-R; HAM-D No association between depression and cognitive impairment. Pt with AD and depression did not manifest more severe neuropsychological impairments than Pt with AD without depression → Depression does not modify the neuropsychological features and the rate of progression of AD
Pearlson et al. [24] USA	Objective Study design Sample Outcomes Assessment Results	To study family history of affective disorder in AD Pt with first-episode depression Cross-sectional study 112 AD Pt (41 with depression) M: 34; F: 78; age: 68.9; AD duration: n.a.; dementia severity: severe cognitive impairment AD criteria: NINCDS-ADRDA Cognitive function assessment: MMSE Depression assessment: DSM-III; FH-RDC (in first and second-degree relatives) → The depressed patients had significantly more first- and second-degree relatives with depression than did control subjects Alzheimer’s disease as it evolves may interact with an existing genetic vulnerability to affective disorder, which is not expressed until the degenerative changes of Alzheimer’s disease unfold
Zweig et al. [22] USA	Objective Study design Sample Outcomes Assessment Results	To evaluate the pathological involvement of the locus coeruleus (LC), the dorsal raphe nucleus (DR), and the central superior (raphe) nucleus (CSN) in a series of aged control subjects and AD patients with or without depression Longitudinal study 22 AD Pt (8 with depression), AD duration: 7.75; + 12 aged control subjects; Age: 70.7; M: 16; F: 18 Dementia severity: moderate-to-severe cognitive impairment AD criteria: post-mortem histological evaluation Cognitive function assessment: MMSE Depression assessment: DSM-III Compared with control subjects, AD Pt showed higher levels of neuronal loss and higher counts of NFTs, particularly within the LC. Patients with AD complicated by major depression had fewer neurons at the mid-level of the LC and at the rostral level of the CSN in comparison with nondepressed patients → These findings demonstrate histological changes in the brain related to the presence of depression

Study

Banning et al. [36]

USA

Objective

Study design

Sample

Outcomes

Assessment

Results

To assess depression over a 5-year follow-up period and to relate its trajectories to AD biomarkers

Retrospective longitudinal study

3030 Pt with AD; gender: n.a.; age: nd.; dementia severity: prodromal

AD criteria: DSM-IV-TR, NIA-AA, and NINCDS-ADRDA

Cognitive ability assessment: MMSE

Depression Assessment: NPI and NPI-Q

Association between increasing probability of depression over time and AD pathology, i.e., lower CSF Aβ42 and higher t-tau and p-tau levels. Association between AD pathology and de novo or (initially) rising symptoms of depression

Banning et al. [35]

USA

Objectives

Study design

Sample

Outcomes

Assessment

Results

To study (inter)relations of AD biomarkers and neuropsychiatric symptoms in AD dementia and the impact of the cognitive functioning

Retrospective cross-sectional study

626 Pt with AD; M: 299; F: 327; age: 73.9; dementia severity: mild level

AD criteria: NINCDS-ADRDA and DSM-IV

Cognitive abilities assessment: MMSE

Anxiety and depression assessment: NPI, NPI-Q

Association between the presence of anxiety and lower CSF levels of Ab42 and higher levels of CSF t-tau and p-tau, mediated by MMSE. No association between depression and Ab42 values, t-tau, p-tau, and reduced hippocampal volume (HCV) and between anxiety and HCV

→ Association of anxiety with AD pathology, due to impaired cognitive functioning, as initial compensating behaviour. Depression more related to psychosocial (i.e., awareness and psychological reaction to AD) or environmental (i.e., relationship with caregivers) or other biological factors (i.e., HPA axis or chronic inflammation)

Rouch et al. [51]

France

Objective

Study design

Sample

Outcomes

Assessment

Results

To evaluate the association between cognitive functioning and the occurrence of behavioural and psychological symptoms of dementia

Prospective study. Pt were assessed at 6-, 12-, and 18-month follow-up

237 Pt with prodromal or mild AD; M: 100; F: 137; age: 79.5; age at onset: n.a.; dementia severity: mild level

AD criteria: NINCDS-ADRDA

Cognitive ability assessment: MMSE

Anxiety and depression assessment: NPI

Association between lower inhibition performance on Stroop test and subsequent higher risk of anxiety and depression

→ Stroop test involves anterior cingulate cortex that is involved in depression

Wu et al. [53]

China

Objective

Study design

Sample

Outcomes

Assessment

Results

To explore the probable neuroanatomical substrate of depressive symptoms of AD patients

Cross-sectional study with control group

20 Pt with AD; M: 11; F: 9; age: 67.15; dementia severity: CDR 0.5–2 normal to moderate

AD criteria: NINCDS-ADRDA

Cognitive ability assessment: MMSE, ADL

Anxiety and depression assessment: HAMA and HDRS

Negative association between depression and insular and inferior frontal lobe grey matter volume, controlling for MMSE

→ Atrophy of the insula and the inferior frontal lobe more severe for depressed patients. Due to insular degeneration, depressive symptoms in AD could be related to abnormal somatic sensations; affective symptoms tend to reduce as AD progresses

Baillon et al. [49]

England

Objective

Study design

Sample

Outcomes

Assessment

Results

To compare neuropsychiatric symptoms (NPS) in people with early-onset Alzheimer’s disease (EOAD) and late-onset AD (LOAD)

Retrospective

24 Pt with EOAD (< 65 years), M: 11; F: 13; 56 patients with LOAD (> 65 years), M: 20; F: 36; mean age: 59.3 EOAD, 82.3 LOAD. Duration of illness (months): 50.3 (41.8) EOAD, 26.9 (22.7) LOAD. Dementia severity: mild level

AD criteria: NINCDS-ADRDA

Cognitive ability assessment: MMSE, Bristol Activities of Daily Living Scale (BADLS)

Anxiety and depression assessment: NPI

Anxiety and depression higher in patients with EOAD compared to patients with LOAD

→ Diagnosis and AD-related changes in lifestyles, roles, and responsibility are greater in EOAD patients. Depression and anxiety occurring throughout the AD course both due to brain damage and psychosocial factors

Barca et al. [54]

Norway

Objective

Study design

Sample

Outcomes

Assessment

Results

To investigate the different trajectories of depressive symptoms among patients with AD and the relationship between the progression of AD and different trajectories

Longitudinal observational study

282 Pt (177 with dementia due to AD and 105 with prodromal AD); M: 130; F:152; age: 73.2; AD duration: n.a.; dementia severity: mild level

AD criteria: ICD-10; NINCDS-ADRDA

Cognitive ability assessment: MMSE

Depression assessment: Cornell Scale for Depression in Dementia and Clinical Dementia Rating Scale (CDR)

Identified three distinct trajectories of depressive symptoms: stable low-average; high and decreasing; moderate and increasing. Association between the trajectories and AD progression: more depression in faster dementia

→ Faster progression leads to organic depression due to brain damages. Depression could also occur as a psychological reaction to greater impairments and can cause cognitive impairment

Tanaka et al. [43]

Japan

Objective

Study design

Sample

Outcomes

Assessment

Results

To investigate the relationship between dementia severity and behavioural and psychological symptoms in early-onset AD patients

Cross-sectional

92 Pt with early-onset AD; M: 31; F: 61; age: 59.0; AD duration (years): 5.6; dementia severity: mild to severe

AD criteria: NINCDS-ADRDA

Cognitive ability assessment: MMSE

Depression and anxiety assessment: Neuropsychiatric Inventory

No differences in depression and anxiety among the three AD severity groups

→ Early-onset AD can lead to a poor social adjustment in society and family. Depression and anxiety are influenced by both psychosocial factors and advancing brain damage

Kaiser et al. [34]

USA

Objective

Study design

Sample

Outcomes

Assessment

Results

To evaluate anxiety in early-onset AD (EOAD) versus late-onset AD (LOAD)

Cross-sectional

45 Pt (23 with EOAD, age: 57.68; 22 with LOAD, age: 80.32); M: 31; F: 14; AD duration (years): 3.09 (EOAD), 3.91 (LOAD); dementia severity: mild to moderate

AD criteria: NINCDS-ADRDA

Cognitive ability assessment: MMSE

Anxiety assessment: NPI

Higher anxiety in early-onset AD pts than in late-onset AD pts. Association between anxiety, gender, MMSE, and separation from caregivers in early-onset AD pts. Association between anxiety and psychotic and activating psychiatric symptoms related to dementia progression in late-onset AD pts

→ Men with early-onset AD are in midlife and have many roles and responsibilities. Thus, early-onset AD has higher impact on the individual than late-onset AD

Lebedeva et al. [44]

Sweden

Objective

Study design

Sample

Outcomes

Assessment

Results

To examine the association between depressive symptoms and neuroanatomical changes, brain structure and cerebrospinal fluid AD biomarkers

Cohort observational study

189 AD Pt with and without depression; M: 94; F: 95; age: 71,1; AD duration (years): n.a.; dementia severity: n.a

AD criteria: NINCDS-ADRDA and DSM-IV/ICD-10

Cognitive ability assessment: MMSE

Depression assessment: Cornell Scale for Depression in Dementia and Geriatric Depression Scale

Association between depression and changes in the temporal and parietal regions, including supramarginal, superior and inferior temporal and fusiform gyri, right posterior cingulate, and precuneus. Correlation between cortical thickness and t-τ was greater in depressed pts. in precuneus and parahippocampal cortex

→ More neurodegeneration on limbic structures in depressed AD patients. Disruptions of limbic neural networks can explain depression

Panegyres et al. [20]

Australia

Objective

Study design

Sample

Outcomes

Assessment

Results

Exploring clinical differences between early-onset AD patients and late-onset AD patients

Cross-sectional study

3747 AD Pt with anxiety or depression (614 with early-onset AD; 3133 with late-onset AD); M: 1686; F: 2061; age: 59.3 (early-onset AD) 76.2 (late-onset AD); AD duration: n.a.; dementia severity: n.a

AD criteria: McKhann criteria

Cognitive ability assessment: n/a

Anxiety and depression assessment: NPI, EQ-5D-3L, and GDS

Early-onset AD pts were more likely to have anxiety or depression than late-onset pts. → They might be related to dementia severity and more rapid progression

Tagai et al. [42]

Japan

Objective

Study design

Sample

Outcomes

Assessment

Results

To investigate how anxiety in AD is related to the structure and function of the brain

Retrospective study

26 Pt with probable AD; M: 6; F: 20; age: 74.95; AD duration: 27 months; dementia severity: mild level

AD criteria: NINCDS-ADRDA; MRI; SPECT

Cognitive function assessment: MMSE; CDR-SB; FAB

Anxiety assessment: Behave-AD

Association between anxiety, atrophy in the right precuneus (Pcs) and inferior parietal lobule (IPL), and hyperperfusion of the bilateral anterior cingulate cortex ACC

→ Pcs, IPL, and ACC belong to the fear neurocircuitry and are involved in anxiety disorders. In AD, their degeneration could explain anxiety

Zahodne et al. [33]

USA

Objective

Study design

Sample

Outcomes

Assessment

Results

To investigate longitudinal associations between functional abilities, cognitive status, and depressive symptoms in AD. Longitudinal study. Pt were assessed prospectively at 6-month intervals for up to 16 years, with an average of 5.5 years

517 Pt with probable AD; M: 222; F: 295; age: 74.19; AD duration: n.a.; dementia severity: mild level

AD criteria: NINCDS-ADRDA

Cognitive ability assessment: mMMSE; BDRS

Depression assessment: CUSPAD

Not worsening of depressive symptoms over AD course. Depressive symptoms predicted functional decline and vice versa

→ Depression may be reactive to the loss of functional ability, but it is not only a reaction to cognitive decline

Spalletta et al. [52]

Italy

Objective

Study design

Sample

Outcomes

Assessment

Results

To investigate cognitive progression of AD patients with or without major depressive episode

Longitudinal study

119 newly diagnosed probable AD patients. M: 52; F: 67; age: 74.7; AD duration: 2.4 years; dementia severity: mild severity

AD criteria: NINCDS-ADRDA

Cognitive ability assessment: Mental Deterioration Battery, MMSE

Depression assessment: a structured interview following modified DSM-IV diagnostic criteria for major depressive episode in AD

More MMSE decline in pts with persistent depression, with incident depression over follow-up and in never depressed pts than in pts with recovered depression. → Depression in AD can be linked to additional cognitive impairment in AD, i.e., frontal planning impairments, that disappear or improve with remission of depression

van Vliet et al. [40]

Holland

Objective

Study design

Sample

Outcomes

Assessment

Results

To assess neuropsychiatric symptoms in young-onset AD (YO-AD)* and late-onset AD (LO-AD)

Prospective cohort study

Pt were assessed every 6 months for 2 years

221 Pt: 98 with YO-AD (age of onset before 65), 123 with LO-AD; M: 99; F: 122; age: 70; AD duration (years): 5.8 (YO-AD) 2.9 (LO-AD); dementia severity: moderate level

AD criteria: 4th edition of the Diagnostic and Statistical Manual of Mental Disorders, Text Revision (2000) and the Dutch

Consensus guidelines

Cognitive ability assessment: MMSE

Depression and anxiety assessment: Neuropsychiatric Inventory

Depression and anxiety prevalence is lower in young-onset AD than in late-onset AD

Depression is the most prevalent symptom in late-onset AD, and it decreases over time. Depression is less persistent in young-onset AD than in late-onset AD

→ Non-memory phenotype is associated with less atrophy of the medial temporal lobe, so with less symptoms. In oldest patients, contextual factors, i.e., death of a loved one or physical disability, and cerebrovascular diseases may increase depression

Meynen et al. [39]

Netherlands

Objective

Study design

Sample

Outcomes

Assessment

Results

To investigate the relationship between depressive state and neuropathological hallmarks of AD

Prospective longitudinal study. Pt were evaluated every 6 months during the last years of their lives

43 Pt with possible or probable AD; M: 10; F: 33; age: 82.8; AD onset: 73.7 years; AD duration: 9.1 years; age of death: 82.8; dementia severity: severe level

AD criteria: NINCDS-ADRDA; DSM-III-R; Braak stage for tangles

Cognitive function assessment: MMSE at baseline; GDS and FAST at 6-month intervals

Depression Assessment: CSDD

Association between depression and the density of neuritic plaques in the entire cortex, and stronger in the temporal cortex, independently from clinical dementia and AD duration

→ Decreased cortical metabolism could determine both neuritic plaques and depression. The presence of neuritic plaques in the cortex might contribute, possibly through a toxicity of Aβ-amyloid, to the occurrence of depression. The neuronal damage in the temporal cortex could lead to disinhibition of the HPA-axis that contributes to depression. Vice versa, depression, associated to HPA hyperactivity and cardiovascular disease, may contribute to AD progress

Wilson et al. [32]

USA

Objective

Study design

Sample

Outcomes

Assessment

Results

To characterize change in depressive symptoms before and after the onset of dementia in AD

Longitudinal study

1. Subgroup was evaluated every 3 years for a mean of 8 to 9 years

2. Subgroup: annual evaluation, for a mean of 3 years

1. Group: 357 Pt who developed AD during the study; M: 141; F: 216; age: 82.5 years; dementia severity: mild level

2. Group: 340 Pt (107 with AD, 81 with MCI, 152 with no cognitive impairment); M: 140; F: 200; age: 81.27 years

AD criteria: NINCDS-ADRDA

Cognitive function assessment: MMSE

Depression assessment: (1) group: CES-D (self-report) v (2) group: HDRS (informant report)

No change in depression during 2 to 3 years of observation after the diagnosis except for a slight decrease in positive affect

→ AD has little systematic effect on depression; since AD develops, impaired memory and executive control seem to stop the continuity of the depressive state

Amieva et al. [50]

France

Objective

Study design

Sample

Outcomes

Assessment

Results

To examine the emergence of the first clinical symptoms over a 14-year period of follow-up before the dementia phase of AD

Longitudinal study. Subjects were evaluated at home at the initial visit and at 1, 3, 5, 8, 10, 13, and 15 years

350 AD Pt.; M: 243; F: 107; age: 86.2; AD duration: n.a.; dementia severity: n.a

AD criteria: NINCDS-ADRDA

Cognitive ability assessment: a battery of tests including MMSE

Depression assessment: Center for Epidemiologic Studies-Depression scale (CESD)

Association between global deficits and depressive symptoms. → Depression could be an early reaction to perceived cognitive decline

Wilson et al. [31]

USA

Objective

Study design

Sample

Outcomes

Assessment

Results

To test the hypothesis that depressive symptoms increase during the prodromal phase of AD

Prospective cohort study

190 Pt with incident AD, M: 54; F: 136; age: 80.0; AD duration (years): 3.9; dementia severity: n.a

AD criteria: NINCDS-ADRDA

Cognitive ability assessment: MMSE

Depression assessment: CES-D

No significant changes in depressive symptoms after the AD diagnosis, although symptoms tended to decrease in women relative to men and in those with a higher premorbid level of openness and a lower premorbid level of agreeableness. Not increasing in depression as mild cognitive impairment developed

→ Depressive symptoms might influence the relation of the AD pathologic changes to cognition. Depression was associated with sex and personality, and some people experience a depressive reaction to AD

Tsang et al. [41]

Singapore

Objective

Study design

Sample

Outcomes

Assessment

Results

To correlate several glutamatergic measures with chronic anxiety in AD

Prospective longitudinal study

21 Pt with AD (10 with low anxiety—LA; 11 with high anxiety—HA); M: 6; F:15; age: 77.4; age at onset: 70.45; age at death: 79.85; AD duration: 9.4 years

Dementia severity: severe cognitive impairment

AD criteria: CERAD scale

Cognitive function assessment: MMSE; ADL

Anxiety/depression assessment: NPI

Higher binding affinity to glycine recognition sites (GlyRS) in pt with higher anxiety. Association between higher GlyRS affinity, selective reduction of N-methyl-d-aspartate NMDA receptor NR2A density, and elevated anxiety

→ The development of anxiety in AD can have a neurochemical basis. Changes in the NMDA receptor complex can lead to GlyRS hyperfunction that lead to anxiety

Hashimoto et al. [30]

USA

Objective

Study design

Sample

Outcomes

Assessment

Results

To investigate the association between anxiety and regional glucose metabolism in AD

Observational, cross-sectional

41 Pt: M: 35, F: 6; age: 75.5 years; AD: 2.8 years

AD criteria: NINCDS-ADRDA

Cognitive ability assessment: MMSE

Anxiety and depression assessment: NPI

Higher anxiety associated with lower resting metabolism in the bilateral entorhinal cortex, anterior parahippocampal gyrus, and left anterior superior temporal gyrus and insula

→ Reduced functional activity in the bilateral anterior inferomedial temporal cortex may contribute to anxiety in AD, independently from cognitive decline

Cannon-Spoor et al. [28]

USA

Objective

Study design

Sample

Outcomes

Assessment

Results

To examine the effect of history of major depressive disorder (MDD) on cognitive performance in AD patients

Multi-site prospective study

43 Pt with AD (22 AD + MDD; 21 AD − MDD); M: 16; F: 27. Age: 69; age at onset of AD: 66.5; AD duration: 3.35 years

Dementia severity: mild-to-moderate cognitive impairment

AD criteria: NINCDS-ADRDA; CDR

Cognitive function assessment: test battery consisting of MMSE, WAIS-R, Mattis Initiation/Perseveration subscale, Buschke SRT, Fluency task

Depression Assessment: CADD

A history of depression in AD Pt was associated with more severe cognitive deficits

→ MDD and AD may share some underlying genetic diathesis or may share risk factors. The experience of MDD, particularly if long-lasting or repeated, may result in an insult that increases the risk for AD or increases the severity of cognitive symptoms

Holtzer et al. [29]

USA

Objective

Study design

Sample

Outcomes

Assessment

Results

To examine the temporal relationship between depressive symptoms, function, and cognitive status in Pt with probable AD

Multicentre cohort study

Pt were followed for up to 14 years and evaluated every 6 months

536 Pt with probable AD (210 with AD and depression) M: 220; F: 316; age: 74; AD duration: 4.06 years

Dementia severity: mild level of cognitive and functional impairments

AD criteria: NINCDS-ADRDA; DSM-III-R

Cognitive and functional ability assessment: 3MS; BDRS

Depression assessment: CUSPAD

Depression was associated with functional impairment but not with cognitive impairment. Decline in function, indeed, preceded the first episode of depressive symptoms

→ Lower functional activity may be a risk factor for the onset of depressive symptoms in AD

Milwain et al. [48]

Objective

Study design

Sample

Outcomes

Assessment

Results

To investigate whether depression may influence the clinical expression of AD, analysing the relationship between cognition, the neuropathological stages of AD, and depressive symptoms

Longitudinal study

Pt with cognitive impairment were evaluated every 6 months, annually for those without

89 Pt with AD (48 with depression) M: 39; F: 50; age: 79.4

Dementia severity: 14.24% Pt in the pre-clinical stage of AD, 21.36% in the intermediate stages of AD, 43.61% in the final stages of AD

AD criteria: Braak stage

Cognitive function assessment: CAMCOG

Depression assessment: CAMDEX

Depression was associated with a more severe cognitive impairment, but only in intermediate stages of AD. Indeed, depressive symptoms had no impact during the early and advanced stages of AD

→ Depressive symptoms may contribute to the cognitive decline of AD Pt. The low prevalence of depression in the final stages of AD may be due to the fact that demented Pt are not able to express the depressive disorder

Gilley et al. [27]

USA

Objective

Study design

Sample

Outcomes

Assessment

Results

To evaluate factors related to the development of depressive symptoms in Pt with AD

Longitudinal study. Pt were evaluated at baseline and at up to 4 annual follow-up examinations

410 Pt with AD, M: 136; F: 274; age: 75.5; age duration: n.a

Dementia severity: moderate level at the study onset and a severe level at the last evaluation

AD criteria: McKhann criteria

Cognitive function assessment: MMSE

Depression assessment: HRS-D + quantitative structured interviews with family members

Premorbid neuroticism personality was associated with an increased rate of depressive symptoms in AD Pt

Cognitive impairment was associated with a small reduction in mood symptoms and a modest increase in somatic symptoms

→ Decline in mood symptoms with increasing severity of cognitive impairment in Pt with AD can be explained as the result of the degradation of the ability to experience or express emotion as severity of AD increases

Wilson et al. [25]

USA

Objective

Study design

Sample

Outcomes

Assessment

Results

To study the relationship between depressive symptoms, clinical AD, and cognitive impairment

Longitudinal study

130 elder participants, of whom 51 with probable AD

AD criteria: NINCDS-ADRDA

Cognitive ability assessment: 19 cognitive function tests

Depression assessment: Center for Epidemiologic Studies Depression Scale (CES-D)

Association of depressive symptoms with clinical AD and cognitive impairment seems to be independent of cortical plaques and tangles. → Depression-related glucocorticoid effects on neuronal function can contribute to risk of dementia. Depressive symptoms can also contribute to cognitive decline and clinical AD through some psychological mechanism

Zubenko et al. [26]

USA

Objective

Study design

Sample

Outcomes

Assessment

Results

To describe the prevalence and clinical features of the major depressive syndrome of AD, comparing Pt with AD to elderly Pt without AD

Comparative study

243 Pt with probable AD. M: 100; F: 143. Age: 78.4; age at onset of AD: 69.0; dementia severity: moderate level

151 No-AD Pt. M: 70; F: 81; age: 70.9

AD criteria: NINCDS-ADRDA

Cognitive function assessment: MMSE; CDR

Depression assessment: HAM-D; CADD

Higher lifetime prevalence of major depression among AD Pt and higher prevalence of MD in AD Pt with severe cognitive impairment

→ Premorbid major depressive episodes might increase the risk of developing AD, while prevalence of depressive episodes that occurred in the context of AD may be related to neurodegenerative events that contribute to the aetiology of major depression among AD Pt

Heun et al. [38]

Germany

Objective

Study design

Sample

Outcomes

Assessment

Results

To clarify the relationship between the age at onset of depression in relation to the onset of dementia

Longitudinal study

57 Pt with AD and MD. M: 18; F: 39. Age: 74.2; age at onset of AD: 71.7; AD duration: n.a

AD criteria: ICD-10

Cognitive function assessment: MMSE, SIDAM

Depression assessment: CIDI

Partial correlation between the onset of cognitive impairment and the onset of depression

→ Depression in AD might not be a symptom of psychological distress, but a symptom of the neurodegenerative process of AD that causes cognitive dysfunction as well

Chemerinski et al. [46]

Argentina

Objective

Study design

Sample

Outcomes

Assessment

Results

To examine the prevalence and correlates of generalized anxiety disorder (GAD) in AD

Cross-sectional study

54 Pt with probable AD (18 with GAD compared with 36 Pt without anxiety disorder). M: 45%; F: 55%; age: 73.9; AD duration: 3.15

Dementia severity: mild (AD GAD ꞊ 39%; AD control ꞊ 72%), moderate (AD GAD ꞊ 44%; AD control ꞊ 22%), severe (AD GAD ꞊ 17%; AD control ꞊ 6%)

AD criteria: NINCDS-ADRDA

Cognitive function assessment: MMSE; CDR

Anxiety assessment: DSM-III-R; SCID; SCID-II; HAM-D; HAM-A; Apathy Scale; Bech Mania Scale; PLACS

GAD in AD was not associated with more severe cognitive impairment

→ GAD in AD may indicate a subsyndromal depressive state

Haupt, et al. [37]

Germany

Objective

Study design

Sample

Outcomes

Assessment

Results

To study the association between depression and severity of cognitive impairment in AD

Longitudinal study. Pt were followed over 2 years with annual evaluations

78 Pt with AD. M: 21; F: 57. Age: 74.3; AD duration: 4.9 years; age at onset: 69.4; dementia severity: mild-to-moderate level

AD criteria: NINCDS-ADRA; ICD-10

Cognitive function assessment: CAMDEX; CAMCOG; MMSE; GDS; DS; DBS

Depression assessment: DMAS

Depressive symptoms in AD Pt are in part associated with a greater severity of cognitive impairment

→ However, depressive symptoms are not prognostically relevant with respect to a lower or higher rate of symptom progression

Migliorelli et al. [45]

Argentina

Objective

Study design

Sample

Outcomes

Assessment

Results

To examine the prevalence, risk factors, and correlates of depression among patients with AD

Cross-sectional study

103 Pt with probable AD, divided into three groups: major depression (N = 24), dysthymia (N = 29), and no depression (N = 50)

M: 27; F: 76. Age: 73.2; AD duration: 4.3 years; age at onset: 68.9; dementia severity: mild (44.29%), moderate (47.38%), severe (14.42%)

AD criteria: NINCDS-ADRDA

Cognitive function assessment: MMS; WAB; TMT; WCST; BNT; TT;

Digit Span

Depression assessment: DSM-III-R; SCID; SCID-II; PSE; FH-RDC; HAM-D; HAM-A; FIM; STC

High frequency of depression among Pt with probable AD. Specifically, dysthymia was primarily in the early stages of AD, and major depression was distributed across the different stages of the illness. No significant between-group differences in the severity of cognitive deficits

→ Dysthymia may be an emotional reaction to the progressive cognitive decline, while major depression may be related to biological factors

Förstl et al. [47]

Objective

Study design

Sample

Outcomes

Assessment

Results

To examine the changes in the locus coeruleus (LC), substantia nigra (SN), basal nucleus of Meynert of AD Pt with and without depression and relate this to clinical features

Prospective study

52 Pt with AD (14 with depression compared with 38 without depression) M: 12; F: 40; age: 83.2

AD duration: 8.2 (AD + D group) 7.5 (AD group without depression); dementia severity: severe cognitive impairment

AD criteria: NINCDS-ADRDA

Cognitive and functional ability assessment: MMSE, CAMCOG

Depression assessment: GMSS, CAMDEX

In AD Pt with depression, a lower neuronal count in the locus coeruleus and a higher in the basal nucleus of Meynert than AD Pt without depression were observed. There were no differences of the neuron numbers in the SN

Pt with depression showed less cognitive impairment and their verbal skills were better preserved

→ The observed disproportionate loss of noradrenergic and cholinergic neurons in the LC and basal nucleus of Meynert may represent an important organic substrate of depression in AD

Lopez et al. [23]

USA

Objective

Study design

Sample

Outcomes

Assessment

Results

To evaluate the cognitive functions of patients (Pt) with probable AD and major depression in comparison with Pt with AD and no depression

Longitudinal study. Two evaluations: at baseline and 1-year follow-up

10 Pt with AD and depression (developed after the onset of symptoms of dementia) compared with 10 nondepressed Pt with AD; M: 4; F: 16. Age (years): 67.45; AD duration (years): 3.2; dementia severity: mild level

AD criteria: NINCDS-ADRA

Cognitive function assessment: MMSE

Depression assessment: DSM-III-R; HAM-D

No association between depression and cognitive impairment. Pt with AD and depression did not manifest more severe neuropsychological impairments than Pt with AD without depression

→ Depression does not modify the neuropsychological features and the rate of progression of AD

Pearlson et al. [24]

USA

Objective

Study design

Sample

Outcomes

Assessment

Results

To study family history of affective disorder in AD Pt with first-episode depression

Cross-sectional study

112 AD Pt (41 with depression) M: 34; F: 78; age: 68.9; AD duration: n.a.; dementia severity: severe cognitive impairment

AD criteria: NINCDS-ADRDA

Cognitive function assessment: MMSE

Depression assessment: DSM-III; FH-RDC (in first and second-degree relatives)

→ The depressed patients had significantly more first- and second-degree relatives with depression than did control subjects

Alzheimer’s disease as it evolves may interact with an existing genetic vulnerability to affective disorder, which is not expressed until the degenerative changes of Alzheimer’s disease unfold

Zweig et al. [22]

USA

Objective

Study design

Sample

Outcomes

Assessment

Results

To evaluate the pathological involvement of the locus coeruleus (LC), the dorsal raphe nucleus (DR), and the central superior (raphe) nucleus (CSN) in a series of aged control subjects and AD patients with or without depression

Longitudinal study

22 AD Pt (8 with depression), AD duration: 7.75; + 12 aged control subjects;

Age: 70.7; M: 16; F: 18

Dementia severity: moderate-to-severe cognitive impairment

AD criteria: post-mortem histological evaluation

Cognitive function assessment: MMSE

Depression assessment: DSM-III

Compared with control subjects, AD Pt showed higher levels of neuronal loss and higher counts of NFTs, particularly within the LC. Patients with AD complicated by major depression had fewer neurons at the mid-level of the LC and at the rostral level of the CSN in comparison with nondepressed patients

→ These findings demonstrate histological changes in the brain related to the presence of depression

Notes: *Young-onset AD is synonymous with early-onset AD and they both indicate AD onset before age 65. 3MS, Modified version of the Mini-Mental State Examination; ACC, anterior cingulate cortex; ACE-R, Addenbrooke’s Cognitive Examination Revised; ADL, activities of daily living; BDRS, Blessed Dementia Rating Scale; BPSD, Behavioral and Psychological Symptoms of Dementia; BEHAVE-AD, Behavioural Abnormalities in AD Rating scale; BMS, Bech Mania Scale; BNT, Boston Naming Test; Buschke SRT, Buschke Selective Reminding Task; CADD, Clinical Assessment of Depression in Dementia; CAMCOG, Cambridge Cognition Examination; CAMDEX, Cambridge Examination for Mental Disorders of the Elderly; CIDI, Composite International Diagnostic Interview; CDR, Clinical Dementia Rating; CDR-SB, Clinical Dementia Rating scale sum of boxes; CERAD, Consortium to Establish a Registry for AD; CES-D, Center for Epidemiologic Studies Depression Scale; CSDD, Cornell Scale for Depression in Dementia; CSF, cerebrospinal fluid; CUSPAD, Columbia University Scale for Psychopathology in Alzheimer’s Disease; DBS, Dementia Behaviour Scale; DMAS, Dementia Mood Assessment Scale; DS, Blessed Dementia Scale; EOAD, early-onset Alzheimer’s disease; FAB, Frontal Assessment Battery; FAS, Verbal Fluency; FAST, Functional Assessment Staging scale; FH-RDC, Family History Research Diagnostic Criteria; FIM, Functional Independence Measure; GAD, general anxiety disorder; GDS, Geriatric Depression Scale; GDS, Global Deterioration Scale; GlyRS, Glycyl-tRNA synthetase; HADS-A, Hospital Anxiety and Depression Scale-Anxiety subscale; HAM-A, Hamilton Anxiety Rating Scale; HAM-D, Hamilton Depression Rating Scale; HDRS, Hamilton Depression Rating Scale; HRS-D, Hamilton Rating Scale for Depression; iADL, instrumental activity of daily living; ICD-10, International Classification of Diseases Tenth Revision; IPL, inferior parietal lobule; MD, major depression; MDRS, Mattis Dementia Rating Scale; LOAD, late-onset Alzheimer’s disease; MMSE, Mini Mental State Examination; mMMSE, Modified Mini-Mental State Exam; MRI, magnetic resonance imaging; NIAA, National Institute on Aging-Alzheimer’s Association criteria; NINCDS-ADRDA, National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association criteria; NMDA, N-methyl-d-aspartate; NPI, Neuropsychiatric Inventory; NPI-Q, Neuropsychiatric Inventory Questionnaire; Pcs, precuneus; PDC-Dad, Provisional Diagnostic Criteria for Depression of Alzheimer’s disease; PLACS, Pathological Laughing and Crying Scale; PSE, Present State Examination; SCID, Structured Clinical Interview for DSM; SCID-II, Structured Clinical Interview for DSM-III-R-Personality Disorders; SPECT, single-photon emission computed tomography; SIDAM, Structured Interview for the Diagnosis of Dementia of the Alzheimer’s type, multi-infarct dementia, and dementias of other etiologies; SRT, Buschke selective reminding test; STC, Social Ties Checklist; TMT, Trail Making Test; TT, Token Test; WAB, Western Aphasia Battery; WAIS-R, Wechsler Adult Intelligence Scale; WCST, Wisconsin Card Sorting Test