Review

Journal of Geriatric Psychiatry

and Neurology
Apathy as a Predictor for Conversion From 2023, Vol. 36(1) 3–17
© The Author(s) 2022
Mild Cognitive Impairment to Dementia:
Article reuse guidelines:
A Systematic Review and Meta-Analysis of sagepub.com/journals-permissions
DOI: 10.1177/08919887221093361
Longitudinal Studies journals.sagepub.com/home/jgp

David Fresnais, MD1,2, Mats B. Humble, MD, PhD1 , Susanne Bejerot, MD, PhD1 ,
Adrian D. Meehan, MD, PhD1,3, and Brynjar Fure, MD, PhD1,2 

Abstract
Background: Apathy is one of the most prevalent neurobehavioral manifestations in mild cognitive impairment (MCI)
and is included among the behavioral and psychological symptoms of dementia (BPSD). Studies suggest that the presence
of apathy could be associated with increased dementia risk. The role of apathy in conversion from MCI to dementia, and
whether apathy could be a relevant predictor for dementia progression, are still matters of investigation. Aim: To study
the relationship between apathy and progression to dementia in individuals with MCI. Methods: A systematic literature
search in Medline, Embase, Cochrane Library, Epistemonikos, PsychINFO, and CINAHL was performed according to the
Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The search included longitudinal studies
reporting on the association between apathy and dementia. Results: The main outcome was pooled unadjusted hazard
ratios (HR) of apathy in dementia conversion and included 11 studies with 9504 individuals. There was a significant
association between apathy and dementia conversion, HR = 1.54; 95% CI, 1.29, 1.84. Subgroup analysis showed a
significant association between apathy and progression to AD. Conclusion: Apathy was associated with an increased
risk of conversion to AD and all-cause dementia in patients with MCI. The role of apathy as a marker for incident
dementia needs to be investigated in large, high-quality studies.

Keywords
behavioral disturbance, cognitive impairment, dementia, elderly, apathy

Introduction In addition to memory loss and other cognitive im-

pairments, neuropsychiatric symptoms are common in both
Mild cognitive impairment (MCI) is a condition charac- MCI5 and dementia.6 These behavioral and psychological
terized by objective evidence of cognitive impairment, symptoms of dementia (BPSD) are, in the absence of
sometimes defined as < 1.5 standard deviations (SD) on prominent cognitive impairments, also referred to as
any cognitive test according to the Petersen criteria, mild behavioral impairment (MBI).7 The Neuropsychi-
without impairment of activities of daily living.1 The Jak & atric inventory-questionnaire (NPI-Q) is one of several
Bondi criteria for MCI require two or more impaired test
scores at least one SD below age-normative data.2 Indi- 1
School of Medical Sciences, Örebro University, Örebro, Sweden
viduals with MCI are at increased risk for progressing to 2
Department of Internal Medicine, Central Hospital Karlstad, Region
dementia, although some remain stable or return to normal Värmland, Sweden
cognition.3,4 Identifying clinical predictive factors for 3
Department of Geriatrics, Faculty of Medicine and Health, Örebro
dementia progression in individuals with MCI is therefore University, Örebro, Sweden
an important clinical concern. Hypothetically, if such
Corresponding Author:
clinical predictive factors can be modified by treatment, it Brynjar Fure, School of Medical Sciences, Örebro University,
could even be explored whether such treatment may delay Fakultetsgatan 1, Örebro 702 81, Sweden.
or prevent conversion to dementia. Email: Brynjar.Fure@oru.se
4 Journal of Geriatric Psychiatry and Neurology 36(1)

instruments used to identify BPSD and MBI. NPI-Q is a The search was performed with the help of a trained in-
validated, informant-based interview that assesses symp- formation specialist and was limited to English or Scan-
toms in the following 12 domains: agitation, irritability, dinavian language studies. The full search strategy is
disinhibition, elation, motor disturbance, depression, shown in Supplementary Material 1.
anxiety, apathy, sleep, appetite, delusions, and hallucina-
tions.8 One of the most prevalent behavioral symptoms in
Selection Criteria
MCI and dementia is apathy,9,10 which can be defined as a
loss of motivation in conjunction with reduced goal- The present systematic review followed the Preferred
directed behavior, cognitive activity and emotions.11 Reporting Items for Systematic Reviews and Meta-
Apathy and apathy symptoms, in both clinical practice analyses (PRISMA). Two investigators applied eligibil-
and research settings, can be assessed and defined using ity criteria and independently screened titles and abstracts
different criteria and instruments. In addition to the NPI-Q, for inclusion after the removal of duplicated literature.
apathy can be assessed using the Apathy Evaluation Scale Full-text records were then assessed according to the pre-
(AES)12 or a subscale of the Geriatric Depression Scale specified selection criteria. Included studies had to report
(GDS),13 among others. Apathy has been shown to increase on the association between apathy and dementia diagnoses
the risk of dementia progression in individuals with in individuals with MCI. Studies focusing on patients
MCI.14-16 Apathy has also been correlated with higher levels selected for specific medical conditions such as stroke or
of neurofibrillary tangles in individuals with dementia.17 A other neurological conditions were excluded. One addi-
previous meta-analysis including studies published before tional study was identified from hand searching reference
October 2017 showed that apathy almost doubled the risk of lists in previous reviews regarding the association between
progression from MCI to dementia in memory clinic pa- apathy and incident dementia.
tients18 and, since then, several studies on this topic have
been published. Apathy has therefore been proposed as a
potential prognostic factor for impending dementia.
Data Extraction and Analysis
The role of apathy in predicting progression from MCI Two investigators independently extracted data from the
to dementia has been further explored in recent longitu- included studies. HRs and ORs for conversion from MCI
dinal studies which present diverging results,19-21 with to dementia in patients with symptoms of apathy were
varying incidence of dementia conversion possibly due to obtained, as well as measurements of apathy, ascertain-
differences in follow-up time, cognitive instruments used ment of MCI and dementia diagnoses, criteria for con-
and sex distribution among studies, and is still a matter of version to dementia, and subtype of dementia. Since
investigation. The present meta-analysis was performed to different studies had adjusted HRs and ORs for different
evaluate the evidence from longitudinal cohort studies for variables, we chose to use unadjusted HRs and ORs in our
the potential association between apathy in individuals meta-analyses to avoid introducing more heterogeneity in
with MCI and risk of incident dementia. our results. Information on the general characteristics of
the included studies was obtained according to a data
extraction form, including: first author of the study,
Methods publication year, country and setting of research, study
design, number of patients included, and patient demo-
Search Strategy
graphics including age, sex distribution, and educational
Searches. The predefined review protocol for this system- level of included patients. Study investigators were not
atic review and meta-analysis was registered in the Inter- contacted for unreported data or additional details. If data
national Prospective Register of Systematic Reviews on different subtypes of dementia was available, all-cause
(PROSPERO) (CRD42021274742). Medline, EMBASE, dementia was used. A subgroup analysis using AD as the
Cochrane Library, PsycINFO, CINAHL, and Epis- preferred outcome was carried out.
temonikos were systematically searched from 2000 to 2021
to identify longitudinal cohort studies assessing apathy and
Statistical Methods
subsequent incident dementia. The search strategy included
the following pre-specified criteria: (1) individuals with MCI; The risk of conversion from MCI to dementia in patients
(2) assessment of BPSD including apathy; (3) clearly defined with symptoms of apathy was explored using HRs and
dementia diagnosis; (4) longitudinal studies. Search terms ORs in logarithmic scales. Weights were automatically
included “cognitive dysfunction,” “mild cognitive impair- assigned according to the algorithm in RevMan 5.4.1.22
ment,” “dementia,” “Alzheimer’s disease,” “behavioral and Differences in the proportion of individuals with apathy
psychological symptoms of dementia,” “conversion,” “pro- among converters to dementia compared to non-converters
gression,” “prospective studies,” and “longitudinal studies.” were also analyzed. Additionally, mean apathy scores
Fresnais et al. 5

according to the NPI were compared between converters commonly used instrument, defining apathy as either mild
and non-converters. Random-effects models were used (score = 1), moderate (score = 2), or severe (score = 3).
due to the heterogenous study characteristics. P-values
were 2-sided.
Meta-Analysis of Results
Statistical analyses were performed using RevMan
5.4.1.22 The association between apathy and conversion from MCI
to dementia was assessed by analyzing unadjusted HRs of
apathy, if available. Additional analyses of ORs for apathy
Quality Assessment and Risk of Bias in conversion to dementia, mean NPI scores and the
The quality of the included studies, including risk of bias in proportion of individuals with apathy between converters
each study, was assessed independently by two investi- and non-converters were performed. Moreover, a subgroup
gators using the Critical Appraisals Skills Programme analysis of HRs of apathy in conversion from MCI to AD
(CASP)23 checklist designed for cohort studies. The was performed.
Grading of Recommendations, Assessment, Development
and Evaluations (GRADE)24 tool was used to evaluate the HRs of Apathy in Conversion from MCI to AD and All-Cause
overall confidence in the effect estimates across studies for Dementia. Eleven out of 18 studies included in the meta-
each pooled outcome. analyses were used in the main analysis of HRs for apathy
in conversion to dementia, and involved 9504
individuals.14,19,20,26–29,32–35 Sample sizes of included
Disagreements Between Individual Judgments studies ranged from 8331 to 4932.19 Meta-analysis of
Any disagreements in study selection, data extraction or pooled HRs for apathy in dementia conversion showed a
quality assessment of studies were resolved by consensus. statistically significant association between apathy and
dementia conversion, HR = 1.54; 95% CI, 1.29, 1.84; P <
.001, see Figure 2. In addition, analysis of HRs for apathy
Results in conversion to AD revealed a significant association,
HR = 1.31; 95% CI, 1.15, 1.49; P < .001, see Figure 3.
Literature Search
A total of 18 relevant studies were identified from the literature Additional Analyses; Proportion of Individuals with Apathy,
search after removal of duplicated and irrelevant literature and Mean NPI-Scores, ORs of Apathy. There was a significant
screening titles and abstracts.14,19-21,25-38 In all, 59 articles were difference in mean NPI apathy scores between converters
read in full text for eligibility, and of these, 17 studies fulfilled and non-converters with mean difference (MD) = .34; 95%
the pre-specified inclusion criteria. One additional article was confidence interval, .11, .56; P = .003, but not for the
identified from a previously published meta-analysis.29 The proportion of individuals with apathy in converters
process of finding relevant articles is demonstrated in Figure 1; compared to non-converters, OR = 1.91; 95% CI, .64,
Supplementary Material 2 shows the reasons for the exclusion 5.66; P = .25, see Figure 4 and Figure 5, respectively.
of 42 articles after full-text reading. Meta-analysis of ORs for apathy in dementia conversion
showed no significant association, OR = 2.79; 95% CI, .45,
17.21; P = .27, see Figure 6.
Study Characteristics
Table 1 shows the general characteristics of included
studies, ascertainment of MCI, and measurement and
Assessment of Quality of the Included Studies
proportion of individuals with apathy. Dementia subtype Table 3 shows the evaluation of included studies according
and diagnostic criteria, conversion rates from MCI to de- to the CASP checklist for cohort studies.
mentia, duration of follow-up, and the reported association GRADE was used for the assessment of confidence in
between apathy and dementia conversion are shown in the pooled estimates, which was estimated as low to very
Table 2. All studies were prospective cohort studies and low, meaning that there is a significant possibility that
published between 2009 and 2020. Conversion rates from further studies will affect the results; see Table 4.
MCI to dementia ranged from 15.214 to 41.9%.37 The
proportion of individuals presenting with apathy was be-
tween 9.2 and 65.0%. Mean follow-up time was 3.1 years.
Discussion
The most frequently used diagnostic criteria for MCI and This systematic review and meta-analysis was conducted
dementia were the Petersen criteria1 and NINCDS- in order to investigate the role of apathy in conversion from
ADRDA39 followed by DSM-IV.40 Measurements of ap- MCI to dementia. Analyses of HRs of incident dementia
athy varied across studies and NPI-Q8 was the most revealed a significant relationship between apathy and
6 Journal of Geriatric Psychiatry and Neurology 36(1)

Figure 1. PRISMA 2020 flow chart showing process of identification of studies. PRISMA = Preferred Reporting Items for Systematic
Reviews and Meta-analyses, n = number.

dementia conversion. The association with apathy was standard diagnostic criteria for MCI and dementia al-
statistically significant for both all-cause dementia and AD, though diagnostic criteria varied between studies. The
although confidence in our pooled estimates is “low” mean follow-up time was 3.1 years. Since the annual
according to GRADE. Further analyses of NPI-apathy progression from MCI to dementia is approximately 10%
scores and the proportion of individuals with apathy in in clinical settings,42 a longer follow-up time would have
converters versus non-converters to dementia supported this allowed for the identification of subjects who progressed
association, with higher scores and presence of symptoms, to dementia at a later stage.
respectively, in converters compared to non-converters. On A number of studies have explored the relationship
the other hand, when performing analyses of ORs extracted between apathy and dementia conversion in individuals
from the included studies, this association disappeared. with MCI, most of them reporting apathy to be associated
Results appear generalizable to memory clinic patients with incident dementia.14,19,26,28,29,33 However some
but may not be directly applicable to older community- studies did not find apathy to be a risk factor for dementia
dwelling individuals, since most studies were performed conversion.20,27,32,35 Disparities in results may be a con-
in a memory clinic setting. The number of patients sequence of differences in study design, as well as defi-
presenting with apathy symptoms at baseline and the nitions of apathy, MCI, and dementia. MCI was most
conversion rates from MCI to dementia are in line with commonly diagnosed using the Petersen criteria1 or
what is reported in the literature.41 Most studies used modified versions of these criteria, and the most frequently
Table 1. General characteristics of included studies and ascertainment of cognitive impairment and apathy.

Tool used for

Fresnais et al.

measurement of
Author and year of Education, apathy; and cases, N
publication Country Setting Sample and diagnostic criteria for MCI N Age, N (SD) Female, N, (%) mean (SD), y (%)

Yang,20 2020 China Population- MCI, ≥ 60 years; compound memory score 465 With NPS 76.3 With NPS NPS 3.8 (3.2); Chinese version of
based ≤1.5 SD compared to NCI (6.6) years; (72.8); no no NPS 2.6 the NPI-Q
no NPS 75.3 NPS (66.1) (3.1) (CNPI-Q); 59
(7.4) (12.7)
Mallo,24 2020 Spain Health MCI/NCI; Petersen criteria 128 67.3 (8.0) 74 (57.8) NR NPI-Q, NR
centers
Dietlin,19 2019 France Memory clinic MCI; MMSE ≥24 96 78.7 (5.6) 57 (59.4) 8.4 (3.9) NPI-Q, NR
Goukasian,25 2019 USA Database of MCI, SMC, NCI, AD; ADNI criteria 1077; 559 71.9 (7.4) 24043 16.1 (2.7) NPI, NPI-Q; 170
memory MCI (30.4)
clinics
Ruthirakuhan,18 Canada Database of MCI; NR 4932 73.2 (9.2) 2450 (49.6) Apathy 15.4 NPI-Q; 8% apathy
2019 memory (3.2); no only, 14% apathy
clinics apathy 15.3 and depression
(3.3)
Yokoi,26 2019 Japan Database of MCI; (i) memory disturbance confirmed by 234 72.8 (5.9) 118 (50.4) 13.0 (2.8) NPI-Q (translated
memory study partner; (ii) and validated in
clinics MMSE score >23; (iii) CDR score of .5; and Japanese); 43
(iv) logical memory on WMS-R (18.5)
Guercio,27 2015 United Memory clinic MCI/NCI; no dementia, preserved ADL, 75; 57 MCI 74.7 (8.0) 31 (41.3) 16.8 (2.6) AES; NR
States Logical memory IIa on WMS-R, CDR
score of .5, MMSE >23
Pink,28 2015 United Population- MCI; revised Mayo Clinic criteria for MCI 322 82.1 (IQR 77.7, 151 (45.5) 12 (IQR 12, 15) NPI-Q; 55 (16.6)
States based 85.0)
Brodaty,29 2014 Australia Memory MCI; Petersen criteria 185 Dementia 75.3 Dementia 29 Dementia NPI; 59 (31.9)
clinics (6.7); no (55.8); no (46.2%); no
dementia dementia 56 dementia
76.0 (7.0) (42.1) (50.0%)
Sobów,30 2014 Poland Memory clinic MCI; NIA-AA, CDR score of 0.5 83 75.0 (1.9) 33 (56.9) 9 NPI; 20 (24.1)
Peters,31 2013 United Population- CIND; 1.5 SD < normative mean, CDR 230 81.9 (5.1) 115 (50.0) 13.4 (3.1) NPI; 21 (9.2)
States based score of .5
Rosenberg,32 2013 United Database of MCI; clinical diagnosis 1821 75.3 (9.3) 920 (50.5) 15.2 (6.2) NPI-Q, GDS; 304
States memory (16.7)
clinics

(continued)
7
 8

Table 1. (continued)

Tool used for

measurement of
Author and year of Education, apathy; and cases, N
publication Country Setting Sample and diagnostic criteria for MCI N Age, N (SD) Female, N, (%) mean (SD), y (%)

Somme,33 2013 Spain Outpatient a-MCI; adapted operational criteria for 132 69.8 (8.7) 62 (46.9) 10.6 (4.4) Spanish 12-item
memory amnestic MCI version of the
unit NPI; 69 (52.2)
Richard,34 2012 Netherlands Database of MCI; WMS-R, MMSE >23, and CDR >0.5 397 74.8 (7.5) 141 (35.5) 15.7 (3.0) GDS-3A; 178 (44.8)
memory
clinics
Gallassi,35 2010 Italy Memory clinic MCI/NCI; Neuropsychological tests with 92;54 68.9 (8.9) 33 (61.1) 8.7 (4.7) NPI; NR
1.5-SD cutoff derived by the same included
normative data in
analyses
Palmer,13 2010 Italy Memory clinic a-MCI; Petersen criteria 131 70.8 (6.5) 54 (41.2) High education NPI, clinical,
80 (61.1%) Starkenstein
criteria; 14 (10.7)
Ramakers36, 2009 Netherlands Memory clinic MCI; Petersen criteria 263 66.9 (7.7) 11644 Low, middle, HAMD; 171 (65.0)
high (%): 23/
46/31
Vicini Chilovi,37 Italy Memory clinic MCI; (i) presence of a cognitive complaint; 124 71.3 (7.7) 84 (68) 7.4 (3.5) AES; 36 (29.0)
2009 (ii) absence of dementia; (iii) change
from normal functioning; (iv) decline in
any area of cognitive functioning; (v)
preserved overall functioning
NR = not reported; SD = standard deviation; SMC = subjective memory complaint; MCI = mild cognitive impairment; a- MCI = amnestic-mild cognitive impairment; n = number; y = years; NCI = no cognitive
impairment; NPI = Neuropsychiatric Inventory; NPI-Q = Neuropsychiatric Inventory-Questionnaire; MMSE = Mini-Mental State Examination; ADNI = Alzheimer’s Disease Neuroimaging Initiative; CDR =
Clinical Dementia Rating; WMS-r = Wechsler Memory Scale-revised; ADL = Activities of Daily Living; AES = Apathy Evaluation Scale; IQR = Interquartile range; NIA-AA = the National Institute of Aging and
Alzheimer’s Association; CIND = Cognitive Impairment No Dementia; GDS = Geriatric Depression Scale; HAMD = Hamilton Depression Rating Scale.
Journal of Geriatric Psychiatry and Neurology 36(1)
Fresnais et al. 9

Table 2. Association between apathy and dementia, follow-up, and dementia incidence.

Reported association
Conversion to between apathy and
dementia dementia conversion (95%
Dementia CI), unadjusted
Author and year Dementia diagnostic Follow-up time, mean (SD), Overall, N Apathy,
of publication subtype criteria y (%) N (%)

Yang,20 2020 AD DSM-IV-TR 3 78 (16.8) 5 (7.9) OR: .44 (.08–2.42)

criteria
Mallo,24 2020 All-cause DMS-4-TR 6* 30 (23.4) NR NR
Dietlin,19 2019 AD CDR 3.5 (IQR: 2.9-4) 42 (43.8) NR HR: 1.54 (.78–3.04)
Goukasian,25 AD NINCDS- 3.6 (2.1) NR NR HR: 3.02 (2.17–4.20)
2019 ADRDA
Ruthirakuhan,18 AD NINCDS- 1.9 1713 (34.7) NR HR: 1.24 (1.05–1.46)
2019 ADRDA,
NIA-AA
Yokoi,26 2019 AD NINCDS- 3.5 (.8) 101 (43.2) 24 (23.8) HR: 1.57 (.99–2.49)
ADRDA
Guercio,27 2015 AD CDR MCI: 1.4 (1.2) NCI: .7 (.7) 11 (28.2) NR HR: 1.19 (1.09–1.3)
Pink,28 2015 All-cause DSM-IV 3.0 (IQR: 2.5–5.3) 117 (35.2) 25 (45.5) HR: 1.62 (1.03–2.55)
Brodaty,29 2014 All-cause DSM-IV 3 52 (28.1) NR NR
Sobów,30 2014 All-cause Change in CDR 2 27 (32.5) 18 (90.0) OR: 70.7 (5.70–876.9)
score from .5
to 1 (or
more)
Peters,31 2013 All-cause NINCDS- 3.3 85 (37.0) 7 (33.3) HR: .93 (.43–2.01)
ADRDA;
NINDS-
AIREN
Rosenberg,32 All-cause, CDR, clinical 1.2 (.3) NR NR HR: 1.38 (1.2–1.56)
2013 AD diagnosis
Somme,33 2013 AD, all- DSM-IV criteria 3.5 (2.9) 38 (28.8) 21 (30.4) HR: 2.2 (1.00–4.82)
cause for dementia
and
NINCDS-
ADRDA
criteria for
AD
Richard,34 2012 All-cause Clinical 2.7 (1.0) 166 (41.8) 82 (46.1) HR: 1.43 (.86–2.38)
Gallassi,35 2010 All-cause DSM-IV 4 10 (18.5) NR NR
Palmer,13 2010 AD NINCDS- 1.4 (8.4) 15 (15.2) 650 HR: 4.6 (1.70–12.45)
ADRDA
Ramakers,36 2009 AD, all- NINCDS- 5.4 90 (41.9) 50 (37.0) OR: .67 (.4–1.12)
cause ADRDA and
DSM-IV
Vicini Chilovi,37 All-cause NINCDS- 2.0 (.2) 28 (22.6) 13 (36.1) 7.07 (1.99–25.12)
2009 ADRDA,
NINDS-
AIREN
SD = Standard deviation; y = years; CI = confidence interval; n = number; DSM-IV = Diagnostic and Statistic Manual of Mental Disorders fourth edition;
DSM-IV-TR = Diagnostic and Statistic Manual of Mental Disorders fourth edition-text revision; OR = odds ratio; HR = hazard ratio; CDR = Clinical
Dementia Rating; AD = Alzheimer’s disease; IQR = interquartile range; NINCDS-ADRA = National Institute of Neurological and Communicative
Diseases and Stroke/Alzheimer’s Disease and Related Disorders Association; NIA-AA = the National Institute of Aging and Alzheimer’s Association;
NINDS-AIREN = ; National Institute of Neurological Disorders and Stroke and the Association Internationale pour l’Enseignement en Neurosciences.
“up to 6 years follow-up”.
10 Journal of Geriatric Psychiatry and Neurology 36(1)

Figure 2. Forest plot showing HR of apathy in conversion from MCI to all-cause dementia; MCI = Mild Cognitive Impairment; CI =
Confidence Interval; IV = Inverse Variance.

Figure 3. Forest plot showing HR of apathy in conversion from MCI to AD; AD = Alzheimer’s Disease; MCI = Mild Cognitive
Impairment; CI = Confidence Interval, IV = Inverse Variance.

Figure 4. Forest plot showing mean difference in NPI apathy scores between converters from MCI to dementia versus non-
converters; MCI = Mild Cognitive Impairment; NPI = Neuropsychiatric Inventory; CI = Confidence Interval, IV = Inverse Variance.

used diagnostic criteria for dementia were DSM-IV40 and apathy.18 This meta-analysis included studies until 2017
NINCDS-ADRDA.39 While apathy was assessed using and since then several new publications on the subject
NPI-Q8 in the majority of studies, the cut-off values for have appeared. Among the more recent publications
diagnosis of apathy varied in some studies. It is possible (published 2019 or later), Ruthirakuhan et al.19 and
that the NPI was used since it is convenient for detecting Goukasian et al,26 found a significant association for de-
other neuropsychiatric symptoms in addition to apathy. mentia conversion while Dietlin et al.20 and Yokoi et al.27
There are currently very few other available apathy in- did not, although a non-significant trend towards dementia
struments in clinical practice. In the study by Brodaty et al., conversion was observed.
the NPI-Q cut-off for apathy was at least 1 point,30 while Subgroup analyses revealed that apathy was associated
the cut-off was at least 2 points in the study by Palmer with higher risk of conversion from MCI to AD, in addition
et al.14 In addition, some studies looked at specific to all-cause dementia. This was expected since mixed pa-
symptoms of apathy instead of using NPI-Q. The meta- thologies of vascular disturbances and neurodegeneration
analysis by van Dalen et al.18 from 2018 found a two-fold are common in AD, especially in elderly individuals.43
increased risk for incident dementia in MCI patients with Indeed, Palmer 2010 found that apathy was associated
Fresnais et al. 11

Figure 5. Forest plot showing the proportion of individuals with apathy symptoms in converters from MCI to dementia versus non-
converters; MCI = Mild Cognitive Impairment; CI = Confidence Interval, IV = Inverse Variance.

Figure 6. Forest plot showing OR of apathy in conversion from MCI to all-cause dementia; MCI = Mild Cognitive Impairment; CI =
Confidence Interval, IV = Inverse Variance.

with a sevenfold increased risk of incident AD in patients neurodegenerative and vascular pathology, as seen in
with amnestic MCI.14 dementia, has led to the concept of “Mild Behavioral
The biological mechanisms by which apathy and other Impairment,” which is a term for individuals presenting
neurobehavioral manifestations may contribute to incident with neuropsychiatric symptoms without evidence of
dementia in MCI is currently a matter of investigation, and concurrent cognitive impairment, used to identify indi-
it is not clear whether apathy is merely prodromal to viduals at higher risk for dementia.49
dementia or a causal risk factor. One study found that However, a statistically significant association between
elderly individuals with symptoms of apathy had reduced apathy and incident dementia does not necessarily confer a
brain volumes compared to those without apathy,44 and it clinical significance, and the potential use of apathy in
is therefore plausible that apathy could indicate changes predicting conversion to dementia in MCI patients is
and disease processes associated with cognitive disor- limited by the lack of validated and adapted tools for
ders. It is well known that apathy can be a symptom of measuring apathy in MCI. In addition, apathy is a non-
depression.12 Several of the included studies excluded specific symptom occurring in numerous other disease
individuals with a diagnosis of major depressive disorder. processes affecting the brain, such as in multiple
One study, which compared the contribution of apathy sclerosis,50 Parkinson’s disease,51 post stroke,52,53
and depression to dementia conversion, found that apathy psychosis,54,55 and depression,12 and in hormonal dis-
alone, but not depression alone, significantly increased turbances such as hypothyroidism56 and hyperparathy-
the risk of conversion from MCI to dementia,19 indicating roidism,57 all of which occur increasingly with age.
that apathy could be linked to neuropathological pro- Apathy is also common in elderly individuals without
cesses in the brain distinct from those of depression. cognitive impairment,58 and increases with age in other-
Apathy in individuals with MCI could increase the risk of wise healthy community-dwelling individuals.30
dementia conversion through neurodegenerative pathol- The analysis of mean NPI apathy scores revealed a
ogy. Indeed, the presence of apathy has been indepen- significant mean difference of .34 points, which is a very
dently associated with AD pathology,45 brain hypo- modest difference in a clinical setting. Still, previous studies
metabolism,46 and alterations in neurotransmitter systems report that even mild symptoms of apathy and other neu-
in patients with cognitive impairment.47 In individuals ropsychiatric symptoms increase the risk of progression
with MCI, apathy could indicate an underlying neuro- from MCI to dementia, with potential importance in clinical
pathology, and that these patients are at increased risk of practice. Palmer et al.14 demonstrated that milder symptoms
incident dementia.48 The fact that apathy and other of apathy measured with NPI could predict progression to
neuropsychiatric symptoms can represent underlying AD, even without a concurrent apathy diagnosis.
 12

Table 3. Assessment according to CASP (Q 1-5, 9-11 for cohort studies) checklists for included studies.

Did the Was the Was the Was the Have the Have they taken Was the
study cohort exposure outcome authors account of the Was the follow-up Can the Do the
address a recruited in accurately accurately identified all confounding follow-up of Do you results be results fit
Author and clearly an measured to measured to important factors in the of subjects subjects believe applied to with other
year of focused acceptable minimize minimize confounding design and/or complete long the the local available Overall
publication issue? way? bias? bias? factors? analysis? enough? enough? results? population? evidence? appraisal

Yang, 2020 + ? + + + + + + + + + ?
Mallo, 2020 + ? + + — — ? + + + + —
Dietlin, 2019 + + + + + — + + + + + —
Ruthirakuhan, + + + + + + ? ? + + + ?
2019
Goukasian + + + + + + + + + + + +
2019
Yokoi 2019 + ? + + + + + + + + + +
Guercio, 2015 + + + + + + + + + + + +
Pink, 2015 + + + + + + + + + + + +
Brodaty, 2014 + + + + + + - + + + + —
Sobów, 2014 + + + + + + ? + + + + ?
Peters, 2013 + ? + + + + + + + + + ?
Rosenberg, + ? + ? + + - + + + + —
2013
Somme, 2013 + + + + + + + + + + + +
Richard, 2012 + ? + ? + + ? + + + + ?
Gallassi, 2010 + ? + + + + — + + + + —
Palmer, 2010 + ++ + + + + + + + + + +
Ramakers, + ? + + + + + + + + + ?
2009
Vicini Chilovi, + ? + ? + — ? + + + + —
2009
CASP = Critical Appraisals Skills Programme; +, yes; -, no; ?, cannot tell; Q = question (s).
Journal of Geriatric Psychiatry and Neurology 36(1)
Table 4. GRADE evidence table with assessments of our confidence in the estimates.

Certainty assessment № of patients Effect

Fresnais et al.

№ of Risk of Other No Relative(95% Absolute (95%

studies Study design bias Inconsistency Indirectness Imprecision considerations Apathy apathy CI) CI) Certainty Importance

HR of apathy in conversion from MCI to all-cause dementia

11 observational seriousa,b,c not serious not serious not serious strong — 1.54 HR higher ⨁⨁ss IMPORTANT
studies association (1.29 higher Low
to 1.84
higher)
HR of apathy in conversion from MCI to AD
6 observational seriousa,b,c not serious not serious not serious strong — HR 1.31 higher ⨁⨁ss IMPORTANT
studies association (1.15 higher Low
to 1.49
higher)
Mean difference in NPI apathy score between converters from MCI to dementia versus non-converters
4 observational serious not serious not serious serious d,e none - MD .34 NPI ⨁sssVery IMPORTANT
studies a,b,c points higher low
(.11 higher
to .56
higher)
Proportion of individuals with apathy symptoms in converters from MCI to dementia versus non-converters
5 observational serious serious d,f not serious serious d,e none — OR 1.38 higher ⨁sss IMPORTANT
studies a,b,c (.47 higher Very low
to 4.07
higher)
OR of apathy in conversion of MCI to all-cause dementia
4 observational seriousa,b,c seriousd,f not serious seriousd,e none — OR 2.78 higher ⨁sss IMPORTANT
studies (.45 higher Very low
to 17.08
higher)
CI: Confidence interval; MD: Mean difference; HR = Hazard Ratio; OR = Odds Ratio; AD = Alzheimers’s Disease; MCI = Mild Cognitive Impairment; NPI = Neuropsychiatric Index GRADE = Grading of
Recommendations, Assessment, Development and Evaluations.
a
Unclear attrition bias.
b
Inclusion of participants
c
Unclear if confounders were considered in analyses
d
Wide CI
e
Few participants in some studies
f
Crosses line of no effect.
13
14 Journal of Geriatric Psychiatry and Neurology 36(1)

Studies included in the current meta-analysis used overlooked. (2) Since apathy and progression to dementia
different tools to assess apathy, most frequently NPI. are associated with study dropout, there is risk of attrition
Guercio et al.28 found that apathy scores reported by bias and attenuation of results. (3) HRs were not available
clinicians were more useful in predicting conversion to for all studies. (4) Analyses were not always adjusted for
dementia than scores reported by informants or subjects. It symptoms of depression. (5) The confidence in our pooled
has been shown that it is challenging for individuals with estimates according to GRADE are “low” or “very low”
MCI accurately to report cognitive and behavioral due to methodological weaknesses which included, most
symptoms, most likely due to anosognosia or reduced frequently, missing information on inclusion criteria, small
memory. This is supported by the study by Sugarman et al. sample sizes in some studies, unclear attrition bias and
reporting significant associations for symptoms measured wide CIs; (6) some of the analyses included relatively few
with NPI-Q, which is informant based, but not for GDS-15, studies; (7) ORs used in two of our meta-analyses might
when used as a self-reported scale.48 Therefore, apathy have been more prone to attrition bias than HRs. Never-
assessed by clinicians might be more useful in predicting theless, this systematic review and meta-analysis presents a
conversion from MCI to dementia. In clinical situations, transparent methodology of sorting, including and as-
instruments for apathy diagnosis such as AES12 could be sessing studies, and accuracy of the literature search was
considered in the investigation of dementia as well as ensured by a trained information specialist.
depression in elderly patients. This would allow for close In conclusion, the results from the current meta-analysis
follow-up of individuals with combined apathy and cog- suggest that apathy is associated with an increased risk of
nitive impairment who are at excess risk of disease pro- conversion from MCI to all-cause dementia as well as to
gression. In addition, these patients may profit from AD. However, no firm conclusion regarding the role of
potential new apathy treatment options. Indeed, a recently apathy in dementia progression can be established due to
published RCT found positive effects of methylphenidate the methodological weaknesses in many of the included
up to 6 months compared to placebo for the treatment of studies that affect our confidence in the results. The role of
apathy symptoms in patients with AD.59 apathy in predicting incident dementia, alone or in com-
There are some limitations in the current review and bination with other neuropsychiatric symptoms and clin-
meta-analysis: (1) We did not include conference abstracts ical parameters, needs to be investigated in larger, high-
in the article selection process or contact authors in cases of quality studies. Further studies should also preferably
missing data, and therefore some literature may have been include the concept of MBI.

HR(s) Hazard Ratio(s);

Appendix
IV Inverse Variance;
Abbreviations MBI Mild Behavioral Impairment;
MCI Mild Cognitive Impairment;
AD Alzheimer’s disease;
NCI No Cognitive Impairment;
AES Apathy Evaluation Scale
MD Mean Difference;
BPSD Behavioral and Psychological NIA-AA National Institute on Aging and
Symptoms of Dementia; Alzheimer’s Association;
CASP Critical Appraisals Skills NPI Neuropsychiatric Inventory;
Programme; NPI-Q Neuropsychiatric Inventory
CDR Clinical Dementia Rating; Questionnaire;
CI Confidence Interval; NINCDS-ADRDA National Institute of Neurological
CIND Cognitive Impairment No Dementia; and Communicative Diseases and
DSM-IV Diagnostic and Statistical Manual of Stroke/Alzheimer’s Disease and
Mental Disorders 4th edition; Related Disorders Association;
DSM-4-TR Diagnostic and Statistical Manual of NINDS-AIREN National Institute of Neurological
Mental Disorders 4th edition, text Disorders and Stroke and
revised; Association Internationale pour la
GDS Geriatric Depression Scale; Recherché et l’Enseignement en
GRADE The Grading of Recommendations, Neurosciences;
Assessment, Development, and OR(s) Odds Ratio(s);
Evaluations; PRISMA Preferred Reporting Items for
HAM-D The Hamilton Depression Rating Systematic Reviews and Meta-
Scale; analyses;
Fresnais et al. 15

PROSPERO International Prospective Register References

of Systematic Reviews; 1. Petersen RC. Mild cognitive impairment as a diagnostic
SD Standard Deviation; entity. J Intern Med. 2004;256(3):183-194
WMR Wechsler Memory Scale-Revised. 2. Bondi MW, Edmonds EC, Jak AJ, Clark LR, Delano-Wood
L, McDonald CR, et al. Neuropsychological criteria for mild
Acknowledgments cognitive impairment improves diagnostic precision, bio-
The authors would like to thank information specialist Marika marker associations, and progression rates. J Alzheimers
Svalstedt at the Hospital Library, Central Hospital Karlstad for Dis. 2014;42(1):275-289
assisting in performing the literature search and for excellent 3. Koepsell TD, Monsell SE. Reversion from mild cognitive
support and assistance with the present systematic review and impairment to normal or near-normal cognition: Risk factors
meta-analysis. and prognosis. Neurology. 2012;79(15):1591-1598
4. Marcos G, Santabárbara J, Lopez-Anton R, De-la-Cámara C,
Author Contributions Gracia-Garcı́a P, Lobo E, et al. Conversion to dementia in mild
DF and BF conceived and designed the study. DF and BF per- cognitive impairment diagnosed with DSM-5 criteria and with
formed the data extraction, quality assessment of studies and Petersen’s criteria. Acta Psychiatr Scand. 2016;133(5):378-385
meta-analyses. DF wrote the first draft of the manuscript and 5. Martin E, Velayudhan L. Neuropsychiatric Symptoms in
revisions of drafts. BF reviewed and contributed to revision mild cognitive impairment: A literature review. Dement
of all the drafts. All authors, including MH, SB, and AM, Geriatr Cogn Disord. 2020;49(2):146-155
revised the manuscript critically for important intellectual 6. Zhao Q-F, Tan L, Wang H-F, Jiang T, Tan M-S, Tan L, et al.
content. The prevalence of neuropsychiatric symptoms in Alz-
heimer’s disease: Systematic review and meta-analysis. J
Declaration of Conflicting Interests Affect Disord. 2016;190:264-271
The author(s) declared no potential conflicts of interest with respect 7. Taragano FE, Allegri RF, Lyketsos C. Mild behavioral
to the research, authorship, and/or publication of this article. impairment: A prodromal stage of dementia. Dement
Neuropsychol. 2008;2(4):256-260
Funding 8. Kaufer DI, Cummings JL, Ketchel P, Smith V, MacMillan A,
Shelley T, et al. Validation of the NPI-Q, a brief clinical form
The author(s) disclosed receipt of the following financial support of the neuropsychiatric inventory. J Neuropsychiatry Clin
for the research, authorship, and/or publication of this article: The Neurosci. 2000;12(2):233-239.
study was funded by Örebro University, School of Medical 9. Siafarikas N, Selbaek G, Fladby T, Šaltytė Benth J, Auning
Sciences, Örebro, Sweden, and Karlstad Central Hospital, E, Aarsland D. Frequency and subgroups of neuropsychi-
Karlstad, Sweden. atric symptoms in mild cognitive impairment and different
stages of dementia in Alzheimer’s disease. Int Psychoger-
Data Availability Statement iatr. 2018;30(1):103-113
All data generated or analyzed during this study are included in 10. Lyketsos CG, Lopez O, Jones B, Fitzpatrick AL, Breitner J,
this article and its supplementary material files. Further inquiries DeKosky S. Prevalence of neuropsychiatric symptoms in
can be directed to the corresponding author. dementia and mild cognitive impairment: Results from the
cardiovascular health study. JAMA. 2002;288(12):1475-1483
Ethical Approval 11. Robert P, Onyike CU, Leentjens AFG, Dujardin K, Aalten P,
An ethics statement is not applicable because this study is based Starkstein S, et al. Proposed diagnostic criteria for apathy in
exclusively on published literature. This systematic review and Alzheimer’s disease and other neuropsychiatric disorders.
meta-analysis was performed in accordance with Swedish Law Eur Psychiatry. 2009;24(2):98-104
and guidelines of the Ethical Committee of Uppsala Univer- 12. Marin RS, Biedrzycki RC, Firinciogullari S. Reliability and
sity, Sweden. validity of the apathy evaluation scale. Psychiatry Res. 1991;
38(2):143-162
ORCID iDs 13. Brink TL, Yesavage JA, Lum O, Heersema PH, Adey M,
Rose TL. Screening tests for geriatric depression. Clin
Mats B. Humble  https://orcid.org/0000-0002-3587-6075 Gerontol. 1982;1(1):37-43
Susanne Bejerot  https://orcid.org/0000-0001-6726-7787 14. Palmer K, Di Iulio F, Varsi AE, Gianni W, Sancesario G,
Brynjar Fure  https://orcid.org/0000-0001-6888-7101 Caltagirone C, et al. Neuropsychiatric predictors of pro-
gression from amnestic-mild cognitive impairment to Alz-
Supplemental Material heimer’s disease: the role of depression and apathy. J
Supplemental material for this article is available online. Alzheimers Dis. 2010;20(1):175-183
16 Journal of Geriatric Psychiatry and Neurology 36(1)

15. Teng E, Lu PH, Cummings JL. Neuropsychiatric symptoms impairment category on dementia conversion or cognitive
are associated with progression from mild cognitive im- decline in patients with mild cognitive impairment. Psy-
pairment to Alzheimer’s disease. Dement Geriatr Cogn chogeriatrics. 2019;19(6):591-600
Disord. 2007;24(4):253-259 28. Guercio BJ, Donovan NJ, Munro CE, Aghjayan SL,
16. Robert PH, Berr C, Volteau M, Bertogliati C, Benoit M, Wigman SE, Locascio JJ, et al. The apathy evaluation scale:
Sarazin M, et al. Apathy in patients with mild cognitive A comparison of subject, informant, and clinician report in
impairment and the risk of developing dementia of Alz- cognitively normal elderly and mild cognitive impairment. J
heimer’s disease: a one-year follow-up study. Clin Neurol Alzheim Dis. 2015;47(2):421-432
Neurosurg. 2006;108(8):733-736 29. Pink A, Stokin GB, Bartley MM, Roberts RO, Sochor O,
17. Skogseth R, Mulugeta E, Jones E, Ballard C, Rongve A, Machulda MM, et al. Neuropsychiatric symptoms, APOE
Nore S, et al. Neuropsychiatric correlates of cerebrospinal ε4, and the risk of incident dementia: A population-based
fluid biomarkers in Alzheimer’s disease. Dement Geriatr study. Neurology. 2015;84(9):935-943
Cogn Disord. 2008;25(6):559-563 30. Brodaty H, Connors MH, Ames D, Woodward M. on behalf
18. van Dalen JW, van Wanrooij LL, Moll van Charante EP, of the PRIME study group. Progression from mild cognitive
Brayne C, van Gool WA, Richard E. Association of impairment to dementia: A 3-year longitudinal study. Aust N
apathy with risk of incident dementia: A systematic re- Z J Psychiatry. 2014;48(12):1137-1142
view and meta-analysis. JAMA Psychiatr. 2018;75(10): 31. Sobów T, Fendler W, Magierski R. Body mass index and
1012 mild cognitive impairment-to-dementia progression in 24
19. Ruthirakuhan M, Herrmann N, Vieira D, Gallagher D, months: A prospective study. Eur J Clin Nutr. 2014;68(11):
Lanctôt KL. The roles of apathy and depression in predicting 1216-1219
alzheimer disease: A longitudinal analysis in older adults 32. Peters ME, Rosenberg PB, Steinberg M, Norton MC, Welsh-
with mild cognitive impairment. Am J Geriatr Psychiatry. Bohmer KA, Hayden KM, et al. Neuropsychiatric symptoms
2019;27(8):873-882 as risk factors for progression from CIND to dementia: The
20. Dietlin S, Soto M, Kiyasova V, Pueyo M, de Mauleon A, cache county study. Am J Geriatr Psychiatr. 2013;21(11):
Delrieu J, et al. Neuropsychiatric symptoms and risk of 1116-1124
progression to Alzheimer’s disease among mild cognitive 33. Rosenberg PB, Mielke MM, Appleby BS, Oh ES, Geda YE,
impairment subjects. J Alzheimers Dis. 2019;70(1):25-34 Lyketsos CG. The association of neuropsychiatric symptoms
21. Yang A-N, Wang X-L, Rui H-R, Luo H, Pang M, Dou X-M. in MCI with incident dementia and Alzheimer disease. Am J
Neuropsychiatric symptoms and risk factors in mild cog- Geriatr Psychiatr. 2013;21(7):685-695
nitive impairment: A cohort investigation of elderly patients. 34. Somme J, Fernández-Martı́nez M, Molano A, Zarranz JJ.
J Nutr Health Aging. 2020;24(2):237-241 Neuropsychiatric symptoms in amnestic mild cognitive
22. Review Manager (RevMan) [Computer Program]. Version impairment: Increased risk and faster progression to de-
5.4. The Cochrane Collaboration.; 2020 mentia. Curr Alzheimer Res. 2013;10(1):86-94
23. Critical Appraisal Skills Programme (2018). CASP Co- 35. Richard E, Schmand B, Eikelenboom P, Yang SC, Ligthart
hort Study Checklist. [online] Available at: https://casp- SA, Moll van Charante EP, et al. Symptoms of apathy are
uk.b-cdn.net/wp-content/uploads/2018/03/CASP-Cohort- associated with progression from mild cognitive impairment
Study-Checklist-2018_fillable_form.pdf. Accessed: 01/ to Alzheimer’s disease in non-depressed subjects. Dement
10/2021 Geriatr Cogn Disord. 2012;33(2–3):204-209
24. Schünemann H, Brożek J, Guyatt G, Oxman A, (eds). 36. Gallassi R, Oppi F, Poda R, Scortichini S, Stanzani Maserati
GRADE handbook for grading quality of evidence and M, Marano G, et al. Are subjective cognitive complaints a
strength of recommendations. The GRADE Working Group; risk factor for dementia? Neurol Sci. 2010;31(3):327-336
2013. Available from: guidelinedevelopment.org/handbook 37. Ramakers IHGB, Visser PJ, Aalten P, Kester A, Jolles J,
25. Mallo SC, Valladares-Rodriguez S, Facal D, Lojo-Seoane C, Verhey FRJ. Affective symptoms as predictors of Alz-
Fernández-Iglesias MJ, Pereiro AX. Neuropsychiatric heimer’s disease in subjects with mild cognitive im-
symptoms as predictors of conversion from MCI to de- pairment: A 10-year follow-up study. Psychol Med. 2010;
mentia: A machine learning approach. Int Psychogeriatr. 40(7):1193-1201
2020;32(3):381-392 38. Vicini Chilovi B, Conti M, Zanetti M, Mazzù I, Rozzini L,
26. Goukasian N, Hwang KS, Romero T, Grotts J, Do TM, Groh Padovani A. Differential impact of apathy and depression
JR, et al. Association of brain amyloidosis with the incidence in the development of dementia in mild cognitive im-
and frequency of neuropsychiatric symptoms in ADNI: A pairment patients. Dement Geriatr Cogn Disord. 2009;
multisite observational cohort study. BMJ Open. 2019;9(12): 27(4):390-398
e031947 39. McKhann G, Drachman D, Folstein M, Katzman R, Price D,
27. Yokoi Y, Takano H, Sakata M, Maruo K, Nakagome K, Stadlan EM. Clinical diagnosis of Alzheimer’s disease:
Matsuda H. Discrete effect of each mild behavioural Report of the NINCDS-ADRDA Work Group* under the
Fresnais et al. 17

auspices of department of health and human services task study of the apathy evaluation scale. J Neurol Sci. 2014;
force on Alzheimer’s disease. Neurology. 1984;34(7):939 347(1–2):295-300
40. Bell CC. DSM-IV: Diagnostic and statistical manual of 51. Pedersen KF, Larsen JP, Alves G, Aarsland D. Prevalence
mental disorders. JAMA. 1994;272(10):828 and clinical correlates of apathy in Parkinson’s disease: A
41. Mitchell AJ, Shiri-Feshki M. Rate of progression of mild community-based study. Parkinsonism Relat Disord. 2009;
cognitive impairment to dementia-meta-analysis of 41 ro- 15(4):295-299.
bust inception cohort studies. Acta Psychiatr Scand. 2009; 52. Kennedy JM, Granato DA, Goldfine AM. Natural history of
119(4):252-265. poststroke apathy during acute rehabilitation. J Neuropsy-
42. Bruscoli M, Lovestone S. Is MCI really just early dementia? chiatry Clin Neurosci. 2015;27(4):333-338
A systematic review of conversion studies. Int Psychoger- 53. Vlachos G, Ihle-Hansen H, Bruun Wyller T, Brækhus A,
iatr. 2004;16(2):129-140 Mangset M, Hamre C, et al. Cognitive and emotional
43. Schneider JA, Arvanitakis Z, Leurgans SE, Bennett DA. The symptoms in patients with first-ever mild stroke: The syn-
neuropathology of probable Alzheimer disease and mild drome of hidden impairments. J Rehabil Med. 2021;53(1):
cognitive impairment. Ann Neurol. 2009;66(2):200-208 jrm00135
44. Grool AM, Geerlings MI, Sigurdsson S, Eiriksdottir G, 54. Konstantakopoulos G, Ploumpidis D, Oulis P, Patrikelis P,
Jonsson PV, Garcia ME, et al. Structural MRI correlates of Soumani A, Papadimitriou GN, et al. Apathy, cognitive
apathy symptoms in older persons without dementia: AGES- deficits and functional impairment in schizophrenia.
Reykjavik Study. Neurology. 2014;82(18):1628-1635 Schizophr Res. 2011;133(1–3):193-198
45. Mori T, Shimada H, Shinotoh H, Hirano S, Eguchi Y, 55. Faerden A, Friis S, Agartz I, Barrett EA, Nesvåg R, Finset A,
Yamada M, et al. Apathy correlates with prefrontal amyloid et al. Apathy and functioning in first-episode psychosis.
β deposition in Alzheimer’s disease. J Neurol Neurosurg Psychiatr Serv. 2009;60(11):1495-1503
Psychiatry. 2014;85(4):449-455 56. Demartini B, Masu A, Scarone S, Pontiroli AE, Gambini O.
46. Delrieu J, Desmidt T, Camus V, Sourdet S, Boutoleau- Prevalence of depression in patients affected by sub-
Bretonnière C, Mullin E, et al. Apathy as a feature of clinical hypothyroidism. Panminerva Med. 2010;52(4):
prodromal Alzheimer’s disease: An FDG-PET ADNI study. 277-282
Int J Geriatr Psychiatry. 2015;30(5):470-477 57. Joborn C, Hetta J, Palm ér M, Akerstr öm G, Ljunghall S.
47. Udo N, Hashimoto N, Toyonaga T, Isoyama T, Oyanagi Y, Psychiatric symptomatology in patients with primary
Narita H, et al. Apathy in Alzheimer’s disease correlates hyperparathyroidism. Ups J Med Sci. 1986;91(1):
with the dopamine transporter level in the caudate nuclei. 77-87
Dement Geriatr Cogn Disord Extra. 2020;10(2):86-93 58. Groeneweg-Koolhoven I, Comijs HC, Naarding P, de Waal
48. Sugarman MA, Alosco ML, Tripodis Y, Steinberg EG, Stern MWM, van der Mast RC. Presence and correlates of apathy
RA. Neuropsychiatric Symptoms and the diagnostic stability in non-demented depressed and non-depressed older per-
of mild cognitive impairment. JAD. 2018;62(4):1841-1855 sons. Eur J Psychiat. 2015;29(2):119-130
49. Ismail Z, Agüera-Ortiz L, Brodaty H, Cieslak A, Cummings J, 59. Mintzer J, Lanctôt KL, Scherer RW, Rosenberg PB,
Fischer CE, et al. The mild behavioral impairment checklist Herrmann N, Van Dyck CH, et al. Effect of methylphenidate
(MBI-C): A rating scale for neuropsychiatric symptoms in pre- on apathy in patients with Alzheimer disease: The ADMET 2
dementia populations. J Alzheimers Dis. 2017;56(3):929-938 randomized clinical trial. JAMA Neurol. 2021;78(11):
50. Raimo S, Trojano L, Spitaleri D, Petretta V, Grossi D, 1324-1332. Available from: https://jamanetwork.com/journals/
Santangelo G. Apathy in multiple sclerosis: A validation jamaneurology/fullarticle/2784538