In e na ional Jou nal o
En i onmen al Resea ch
and Public Heal h
A icle
Anhedonia as a Po en ial Risk Fac o o Alzheime ’s Disease in
a Communi y-Dwelling Elde ly Sample: Resul s om he
ZARADEMP P ojec
Da id Vaque o-Puyuelo 1,2,† , Concepción De-la-Cáma a 1,2,3,4,†, Bea iz Olaya 4,5 ,
Pa icia G acia-Ga cía2,3,4,6,*, An onio Lobo 2,3,4, Raúl López-An ón3,4,7 and Ja ie San abá ba a 3,4,8


Ci a ion: Vaque o-Puyuelo, D.;
De-la-Cáma a, C.; Olaya, B.;
G acia-Ga cía, P.; Lobo, A.;
López-An ón, R.; San abá ba a, J.
Anhedonia as a Po en ial Risk Fac o
o Alzheime ’s Disease in a
Communi y-Dwelling Elde ly
Sample: Resul s om he
ZARADEMP P ojec . In . J. En i on.
Res. Public Heal h 2021,18, 1370.
h ps://doi.o g/10.3390/ije ph18041370
Academic Edi o : Ma yam Vase i
Recei ed: 18 Decembe 2020
Accep ed: 30 Janua y 2021
Published: 3 Feb ua y 2021
Publishe ’s No e: MDPI s ays neu al
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Copy igh : © 2021 by he au ho s.
Licensee MDPI, Basel, Swi ze land.
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A ibu ion (CC BY) license (h ps://
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1Psychia y Se ice, Hospi al Clínico Uni e si a io Lozano Blesa, 50009 Za agoza, Spain;
648724@uniza .es (D.V.-P.); edelacam@uniza .es (C.D.-l.-C.)
2Depa men o Medicine, Psychia y and De ma ology, Uni e sidad de Za agoza, 50009 Za agoza, Spain;
alobo@uniza .es
3Ins i u o de In es igación Sani a ia de A agón (IIS A agón), 50009 Za agoza, Spain;
lan on@uniza .es (R.L.-A.); jsan aba ba a@uniza .es (J.S.)
4
Cen o de In es igación Biomédica en Red de Salud Men al (CIBERSAM), Minis y o Science and Inno a ion,
28029 Mad id, Spain; [email p o ec ed]
5Resea ch, Inno a ion and Teaching Uni , Pa c Sani a i San Joan de Déu, Uni e si a de Ba celona,
08007 Ba celona, Spain
6Psychia y Se ice, Hospi al Uni e si a io Miguel Se e , 50009 Za agoza, Spain
7Depa men o Psychology and Sociology, Uni e sidad de Za agoza, 50009 Za agoza, Spain
8Depa men o Mic obiology, Pedia ics, Radiology and Public Heal h, Uni e sidad de Za agoza,
50009 Za agoza, Spain
*Co espondence: 461766@uniza .es; Tel.: +34-976-761-715
† Bo h au ho s con ibu ed equally.
Abs ac :
(1) In oduc ion: Demen ia is a majo public heal h p oblem, and Alzheime ’s disease (AD)
is he mos equen sub ype. Cla i ying he po en ial isk ac o s is necessa y in o de o imp o e
demen ia-p e en ion s a egies and quali y o li e. He e, ou pu pose was o in es iga e he ole o
he absence o hedonic one; anhedonia, unde s ood as he educ ion on p e ious enjoyable daily
ac i i ies, which occasionally is unde de ec ed and unde diagnosed; and he isk o de eloping AD
in a cogni i ely unimpai ed and non-dep essed popula ion sample. (2) Me hod: We used da a om
he Za agoza Demen ia and Dep ession (ZARADEMP) p ojec , a longi udinal epidemiological s udy
on demen ia and dep ession. A e excluding subjec s wi h demen ia, a sample o 2830 dwelle s aged
≥
65 yea s was ollowed o 4.5 yea s. The ge ia ic men al s a e examina ion was used o iden i y
cases o anhedonia. AD was diagnosed by a panel o esea ch psychia is s acco ding o Diagnos ic
and S a is ical Manual o Men al Diso de s, Fou h Edi ion (DSM-IV) c i e ia. A mul i a ia e su i al
analysis and Cox p opo ional haza ds eg ession model we e pe o med, and he analysis was
con olled by an analysis o he p esence o clinically signi ican dep ession. (3) Resul s: We ound a
signi ican associa ion be ween anhedonia cases and AD isk in he uni a ia e analysis (haza d a io
(HR): 2.37; 95% CI: 1.04–5.40). This associa ion pe sis ed mo e s ongly in he ully adjus ed model.
(4) Conclusions: Iden i ying cogni i ely in ac indi iduals wi h anhedonia is a p io i y o implemen
p e en i e s a egies ha could delay he p og ession o cogni i e and unc ional impai men in
subjec s a isk o AD.
Keywo ds:
anhedonia; Alzheime ’s disease; psychopa hology; isk ac o ; neu opsychia y;
communi y s udy
1. In oduc ion
Demen ia cons i u es a se ious public heal h challenge wo ldwide. By 2030, 82 million
people a e expec ed o de elop demen ia, and ha numbe is expec ed o each o e
152 million in 2050 [
1
,
2
]. Cogni i e impai men is a co e symp om, along wi h he p esence
In . J. En i on. Res. Public Heal h 2021,18, 1370. h ps://doi.o g/10.3390/ije ph18041370 h ps://www.mdpi.com/jou nal/ije ph
In . J. En i on. Res. Public Heal h 2021,18, 1370 2 o 12
o unc ional impai men in he con ex o a g adual and p og essi e clinical e olu ion [
3
].
In his con ex , Alzheime ’s disease is he mos equen sub ype o demen ia, and i has
a huge impac no only on he pa ien (ins i u ionaliza ion, isk o mo ali y, e c.) and
he ca egi e s (such as psychia ic complica ions) [
4
,
5
], bu also on he socioeconomic
dimension [
1
,
2
]. The lack o an e ec i e ea men highligh s he need o he iden i ica ion
o po en ial psychopa hological isk ac o s, and he imp o emen o p e en ion s a egies
o dec ease i s incidence and imp o e quali y o li e. Ne e heless, longe pe iods o
obse a ion a e needed, wi h a su icien ame o ime o educe he isk o AD, so u he
in es iga ions a e undamen al.
The associa ion be ween clinically signi ican dep ession and demen ia is well
known [6,7]
. This is speci ically ue o se e e and majo episodes [
8
], wi h se e e cases o
dep ession being ou imes a g ea e isk o Alzheime ’s disease (AD) compa ed wi h
subjec s wi hou dep ession [
9
]. The e a e wo main clinical mani es a ions o diagnose a
majo dep essi e diso de : hypo hymia and/o anhedonia [
3
]. Hypo hymia is unde s ood
as a dec ease in he baseline holo hymic s a e, which includes he a ec i e one and
emo ional eac i i y. Anhedonia is concep ualized as he p esence o a educ ion o lack o
in e es o enjoymen in p e iously pleasu able p ojec s, which could be unde s ood as a
ype o nega i e non-cogni i e symp om [10] o a mood- ela ed one.
P e ious s udies [
11
–
16
] sugges ha anhedonia could be ei he a po en ial p eclinical
sign o cogni i e decline o a psychopa hological isk ac o o demen ia. Howe e , he
po en ial associa ion o dep ession-spec um symp oms and Alzheime ’s disease is s ill
unknown. Fu he mo e, he he e ogenei y o he de ini ion o anhedonia ac oss di e en
s udies has led o mixed esul s.
In he Za agoza Demen ia and Dep ession (ZARADEMP) p ojec , a longi udinal
epidemiological s udy o demen ia and dep ession conduc ed in communi y-dwelling
olde adul s, he au ho s ound ha anhedonia was equen ly obse ed among cases o
Alzheime ’s disease (46.8% s. 2.5% in non-demen ed pa icipan s) [
10
,
11
]. O he epidemi-
ological s udies sugges ha he p esence o anhedonia implies a wo- imes g ea e isk
o mild cogni i e impai men and, ema kably, his symp om inc eases he p obabili y o
demen ia by a ac o o i e [
15
], pa icula ly Alzheime ’s disease [
16
]. These esul s may be
suppo ed by s udies showing a link be ween apa hy and amyloid bu den in mild cogni i e
impai men [
12
], and by hose epo ing an associa ion o “apa hy-anhedonia” symp oms
and hypome abolism in ce ain b ain egions and hippocampal olume educ ions [
13
],
wi h a p obable p oin lamma o y ole o he mic oglia [14].
Al hough a link be ween anhedonia and he isk o demen ia is s ongly
sugges ed [15,16]
,
u he epidemiological s udies wi h ep esen a i e samples o cogni i ely in ac people
a e needed. Thus, ou pu pose was o in es iga e he ela ionship be ween anhedonia and
he isk o Alzheime ’s disease in cogni i ely in ac communi y-dwelling elde ly people
wi hou dep ession.
2. Ma e ials and Me hods
2.1. Sample
We used da a om he ZARADEMP p ojec [17,18], a longi udinal popula ion-based
s udy conduc ed in Za agoza, Spain. The main objec i e was o es ima e he incidence
and isk ac o s o demen ia and dep ession in adul s aged 55 yea s o olde . Fu he
in o ma ion abou objec i es and design has been published p e iously [18].
B ie ly, a andom sample o communi y-dwelling olde people was d awn om he
Spanish o icial census lis o 1991, which included ins i u ionalized indi iduals and was
s a i ied wi h p opo ional alloca ion by age and gende . The e usal a e was 20.5%;
4803 indi iduals pa icipa ed a baseline (Wa e I s a ed in 1994). Indi iduals wi h all-
cause demen ia we e excluded om he wo ollow-up wa es (second wa e in 1997 and
hi d wa e in 1999) because we we e in e es ed in cogni i ely in ac indi iduals, so ha
s ingen c i e ia we e applied. Addi ionally, subjec s wi h “subsynd omal” demen ia a
In . J. En i on. Res. Public Heal h 2021,18, 1370 3 o 12
baseline, acco ding o he Ge ia ic Men al S a e (GMS) Au oma ed Ge ia ic Examina ion
o Compu e Assis ed Taxonomy package (AGECAT) c i e ia [19], we e also excluded.
Fo ease o compa ison wi h he exis ing li e a u e, we ocused on pa icipan s aged
65 yea s and olde . Addi ionally, we ocused on hose pa icipan s who pa icipa ed bo h
a baseline and in he second wa e, esul ing in a inal sample o 1642 pa icipan s o
s a is ical analysis [20].
2.2. P ocedu e
In phase I, he ZARADEMP in e iew was conduc ed by well- ained and egula ly
supe ised lay-in e iewe s a each pa icipan ’s esidence, o in hospi al i his op ion
was p e e ed.
This in e iew inco po a ed s anda dized and alida ed Spanish e sions o he
ollowing in e na ional ins umen s: Mini-Men al S a e Examina ion (MMSE) [
21
], Ge i-
a ic Men al S a e (GMS) [
19
], and His o y and Ae iology Schedule ( o asses psychia ic
his o y) [
22
], and he Ka z Index [
23
] and Law on and B ody Scale [
24
] ( o assess basic
and ins umen al ac i i ies o daily li ing (ADLs), espec i ely). The Eu opean S ud-
ies o Demen ia (EURODEM) Risk Fac o s Ques ionnai e [
19
,
25
] was used o conside
medical his o y.
In phase II, a ained esea ch psychia is eassessed pa icipan s o con i m he
suspec ed clinical diagnosis o demen ia and/o dep ession. The alidi y o his app oach
has been es ablished [
26
]. A simila p ocedu e was implemen ed in he second and hi d
(2.5 and 4.5 yea s la e , espec i ely), in which in e iewe s we e no awa e o he esul s o
he baseline in e iew desc ibed be o ehand. A mo e de ailed accoun o he me hods has
been published elsewhe e [17].
2.3. E hics
The E hics Commi ee o Resea ch o A agón (CEICA) app o ed he p ojec in acco -
dance wi h Spanish law. The Decla a ion o Helsinki p inciples [
27
] o w i en in o med
consen , con iden iali y, and p i acy we e main ained h oughou he p ojec .
2.4. Clinical Measu emen s
2.4.1. Alzheime ’s Disease Assessmen and Diagnosis
A he end o he baseline assessmen , iden i ied “cases” o demen ia and “subcases”
o demen ia (acco ding o GMS-c i e ia) we e excluded om he ollow-up wa es. Pa ici-
pan s we e conside ed “p obable cases” on he basis o a GMS h eshold “global” sco e
(1/2) and/o MMSE (23/24) s anda d cu o poin s.
A panel o ou esea ch psychia is s made he inal diagnoses o cases o demen-
ia. The alidi y o his diagnos ic p ocess has also been p o en [
26
]. Va iables in he
ZARADEMP in e iew we e ope a ionalized o con o m o he Diagnos ic and S a is ical
Manual o Men al Diso de s, Fou h Edi ion (DSM-IV) [
3
] c i e ia, used o diagnose cases.
Ag eemen by a leas h ee ou o he ou psychia is s was necessa y o a diagnosis o
“inciden ” demen ia and “ ype o demen ia” (e.g., AD o ascula demen ia).
To documen he accu acy o he panel o psychia is s, de ec ed cases we e in i ed
o a hospi al diagnos ic wo k-up, which included a neu ological examina ion and neu-
oimaging. Fo he pu poses o his pape , we ocused on AD cases. Nacional Ins i u e o
Neu ological and Communica i e Diso de s and S oke-Alzheime
´
s Disease and Rela ed
Diso de s Associa ion (NINCDS-ADRDA) c i e ia we e applied o diagnose AD.
2.4.2. Anhedonia Assessmen and Diagnosis
Ge ia ic Men al S a e (GMS) is a semi-s uc u ed s anda dized clinical in e iew o
assessing he men al s a e o elde ly people [
19
]. I includes melancholic i ems, such as he
symp om o anhedonia, and a compu e ized diagnos ic p og am, namely AGECAT. This
consis s o a se o compu e algo i hms o analyze he GMS da a, which was applied o
In . J. En i on. Res. Public Heal h 2021,18, 1370 4 o 12
each he psychia ic diagnosis [
19
,
28
]. The eliabili y and alidi y o he Spanish e sion
o he GMS-AGECAT p ocedu e has been epo ed elsewhe e [28].
Fo he pu pose o his s udy, he symp om o anhedonia, which appea s in he
DSM-IV and in he In e na ional Classi ica ion o Diseases (ICD-10) as a melancholic o a
nega i e-non-cogni i e clinical mani es a ion, was ope a ionalized using he in o ma ion
om he GMS h ough he ollowing ques ions: Do you ake pleasu e in any hing? Wha do
you like doing la ely? Has he e been any change? We ollowed s anda d GMS p ocedu es
o use bina y a iables h oughou he calcula ion p ocess. To his end, we eco ded
“0” (when he symp om was absen ), and sco es “1” (symp om p esen , bu mild o no
equen ) and “2” (symp om equen and/o se e e) we e collapsed.
2.5. Co a ia es
The po en ial con ounde s assessed a baseline included sociodemog aphic cha ac e -
is ics (age, gende [
29
], educa ional le el, ma i al s a us [
30
–
32
], and li ing alone), medical
isk ac o s based on he medical his o y ob ained using he EURODEM Risk Fac o s Ques-
ionnai e [
33
] ( ascula disease [
34
], hype ension, and diabe es), cogni i e s a e (MMSE
sco e), unc ional disabili y (ADL [
35
]), body mass index (BMI), and clinically signi ican
dep ession [9,36,37].
2.6. S a is ical Analysis
Di e ences be ween baseline cha ac e is ics acco ding o anhedonia s a us we e as-
sessed using wo- ailed chi-squa e es s on ca ego ical da a, and di e ences in a iables
wi h app oxima ely no mal dis ibu ions we e assessed using a wo- ailed - es . S anda d
p ocedu es we e used o calcula e he incidence a e and incidence a e a io (IRR).
The ollow-up pe iod ended in he second ollow-up examina ion ( hi d wa e) o
he cogni i ely in ac indi iduals, a he da e o in i a ion o e usals, a he da e o
mo ing away o dea h (based on ac ual da a om he Ci il Regis y, Pad ón Municipal de
Habi an es de Za agoza), o a he ime o onse o demen ia o cases. The ime o onse o
demen ia was es ima ed o be he ime om baseline o he midpoin be ween diagnosis
and he p e ious examina ion.
We buil Kaplan–Meie su i al cu es acco ding o he anhedonia s a us. The p oba-
bili y o AD- ee su i al ac oss g oups was assessed by means o he Ta one-Wa e es .
We used he Cox p opo ional haza ds eg ession model o calcula e he isk o
pa icipan s who had he psychopa hological symp om o anhedonia (cases), compa ed
wi h hose wi hou his clinical mani es a ion (no cases), o expe iencing AD, and wi h age
as imescale wi h delayed en y [
38
]. To explo e he mechanisms explaining he associa ion
be ween anhedonia and he isk o de eloping AD, we used a se ies o models in which
we g adually con olled o he po en ial modi ie s p e iously men ioned. We con i med
he assump ion o p opo ional haza ds by means o he The neau and G ambsch es [
39
].
S a is ical analyses we e conduc ed using R so wa e (h p://www. -p ojec .o g)
(R Founda ion o S a is ical Compu ing, Vienna, Aus ia), wi h he epiR package o
analyze epidemiologic da a, and he su i al and su mine packages o he su i al
analyses.
3. Resul s
Ou inal sample included 2830 olde adul s ee o demen ia a baseline (median
4.4 yea s; in e qua ile ange: 2.8–4.9 yea s). Du ing he ollow-up pe iod (4.5 yea s),
1565 (55.3%) we e non-inciden AD cases, 77 (2.7%) we e inciden AD cases, 44 (1.5%) we e
inciden cases o o he demen ias, 605 (21.4%) died, and 539 (19%) we e los (by e usal
o ake pa , changing esidence, o being impossible o con ac ; Figu e 1). Those los o
dead du ing ollow-up we e olde (p< 0.001) and mo e likely o be illi e a e han hose
e-e alua ed; he MMSE sco es we e also lowe among hose los o dead (p< 0.001; da a
no shown).
In . J. En i on. Res. Public Heal h 2021,18, 1370 5 o 12
In . J. En i on. Res. Public Heal h 2021, 18, x FOR PEER REVIEW 5 o 13
du ing ollow-up we e olde (p < 0.001) and mo e likely o be illi e a e han hose e-e al-
ua ed; he MMSE sco es we e also lowe among hose los o dead (p < 0.001; da a no
shown).
Figu e 1. Za agoza Demen ia and Dep ession (ZARADEMP) p ojec s udy low cha . No es:
AD—Alzheime ’s disease.
Table 1 shows he sociodemog aphic cha ac e is ics a baseline acco ding o he AD
incidence s a us. Pa icipan s wi h inciden AD we e signi ican ly olde , we e mo e likely
o be emale, o me ly ma ied, o o ha e a lowe educa ional le el, and we e mo e likely
o ha e dep ession, o pe o m wo se cogni i ely, o ha e anhedonia, and o ha e mo e
unc ional disabili ies han pa icipan s wi hou AD.
Figu e 1. Za agoza Demen ia and Dep ession (ZARADEMP) p ojec s udy low cha . No es: AD—Alzheime ’s disease.
Table 1shows he sociodemog aphic cha ac e is ics a baseline acco ding o he AD
incidence s a us. Pa icipan s wi h inciden AD we e signi ican ly olde , we e mo e likely
o be emale, o me ly ma ied, o o ha e a lowe educa ional le el, and we e mo e likely
o ha e dep ession, o pe o m wo se cogni i ely, o ha e anhedonia, and o ha e mo e
unc ional disabili ies han pa icipan s wi hou AD.
The c ude compa ison o he su i al cu es acco ding o anhedonia s a us (
Figu e 2
)
e ealed a mo e a o able su i al p obabili y in he no case g oup (Ta one-Wa e es ;
p= 0.003). In ac , he age su i al median was 96.3 yea s (95% CI: 94.2–100) o no
case pa icipan s, signi ican ly highe han 91.1 yea s (95% CI: 89.5–100) o he cases
o anhedonia.
Table 2shows a signi ican associa ion be ween “anhedonia cases” a baseline and AD
isk. Compa ed wi h no cases, he p opo ion o inciden cases and he incidence a e o
AD we e highe among anhedonia cases (IRR = 2.5; p- alue = 0.021). Table 2also shows he
esul s o he Cox eg ession analysis o he isk o AD associa ed wi h anhedonia s a us.
The isk o AD was almos 2.5- old highe in anhedonia cases compa ed wi h no cases
when he socio-demog aphics ac o s we e con olled o (haza d a io (HR): 2.37; 95% CI:
1.04–5.40). This associa ion pe sis ed o was sligh ly highe in he ully adjus ed model.

In . J. En i on. Res. Public Heal h 2021,18, 1370 6 o 12
Table 1. Baseline cha ac e is ics acco ding o inciden AD s a us.
Follow-Up AD S a us
Va iables Non-Inciden AD
(N = 1565)
Inciden AD
(N = 77) p-Value
Socio-demog aphic cha ac e is ics
Age (yea s) 73.4 (6.5) 84.1 (6.6) <0.001
Female sex 874 (55.8%) 55 (71.4%) 0.010
Educa ion (yea s) 7.6 (3.9) 5.7 (3.5) <0.001
Ma i al s a us
( e . single) <0.001
Ma ied/in couple 1001 (63.9%) 23 (29.9%)
Fo me ly ma ied 409 (26.1%) 53 (68.8%)
Psychopa hological isk ac o s
Dep ession 110 (7%) 10 (13%) 0.082
Anhedonia 48 (3%) 7 (9%) 0.011
Beha iou al isk ac o s
BMI 27.1 (6.3) 26.1 (5.1) <0.001
Vascula isk ac o s
Diabe es 192 (12.2%) 8 (10.4%) 0.770
Hype ension 1116 (71.3%) 49 (63.6%) 0.181
P e ious ascula disease
110 (7%) 5 (6.5%) 0.304
Func ional and cogni i e s a us
Basic ADLs 69 (4.4%) 13 (16.9%) <0.001
Ins umen al ADLs 131 (8.4%) 32 (41.6%) <0.001
MMSE sco e 30.8 (2.8) 27.4 (2.9) <0.001
No es: AD (Alzheime Disease); ADLs: Ac i i ies o Daily Li ing; BMI: Body Mass Index. Da a a e gi en as mean
(s anda d de ia ion) o equency (%).
Table 2. Anhedonia s a us a baseline and isk o AD.
UNIVARIATE MODEL MULTIVARIATE
MODEL
ANHEDONIA
STATUS AT
BASELINE
No. (%) o AD
Inciden Cases
Pe son-
Yea s
IR
(pe 1000
Pe son-Yea s)
(95% CI)
IRR
(95% CI)
HR
(95% CI) p-Value HR
(95% CI) p-Value
No case
(n = 1587) 70 (4.4%) 10,529 6.6
(5.2–8.4) 1 1 1
Case
(n = 55) 7 (12.7%) 424 16.5
(6.6–34.0)
2.48
(1.14–5.40)
2.37
(1.04–5.40) 0.039 2.95
(1.03–8.47) 0.043
No es: AD—Alzheime ’s disease; IR—incidence a e; IRR—incidence a e a io; HR—haza d a io. Repo ed HR o AD is ela ed o no
cases. CIs and p- alues ela ed o HR we e om a “no mal app oxima ion” o Wald’s
χ
2 es wi h 1 d . Model 1: included anhedonia
plus e ms o socio-demog aphic cha ac e is ics (sex, yea s o educa ion, and ma i al s a us). Model 2: included addi ional e ms o
ascula isk ac o s (body mass index, p e ious ascula disease, hype ension, and diabe es), dep ession, disabili y, and cogni i e s a us
a baseline (MMSE).
In . J. En i on. Res. Public Heal h 2021,18, 1370 7 o 12
In . J. En i on. Res. Public Heal h 2021, 18, x FOR PEER REVIEW 7 o 13
Figu e 2. Su i al cu es o inciden AD acco ding o he Anhedonia s a us a baseline. No es: S a a: Anhedonia g oup. Su i al
median (age o su i al p obabili y = 0.50 in each anhedonia g oup) is ep esen ed by a dashed black line. n.censo is he numbe
o censo ed da a (pa icipan s who died o we e los du ing ollow-up).
Table 2 shows a signi ican associa ion be ween “anhedonia cases” a baseline and
AD isk. Compa ed wi h no cases, he p opo ion o inciden cases and he incidence a e
o AD we e highe among anhedonia cases (IRR = 2.5; p- alue = 0.021). Table 2 also shows
he esul s o he Cox eg ession analysis o he isk o AD associa ed wi h anhedonia
s a us. The isk o AD was almos 2.5- old highe in anhedonia cases compa ed wi h no
cases when he socio-demog aphics ac o s we e con olled o (haza d a io (HR): 2.37;
95% CI: 1.04–5.40). This associa ion pe sis ed o was sligh ly highe in he ully adjus ed
model.
Figu e 2.
Su i al cu es o inciden AD acco ding o he Anhedonia s a us a baseline. No es: S a a: Anhedonia g oup.
Su i al median (age o su i al p obabili y = 0.50 in each anhedonia g oup) is ep esen ed by a dashed black line. n.censo
is he numbe o censo ed da a (pa icipan s who died o we e los du ing ollow-up).
4. Discussion
Ou obse a ions sugges ha he appea ance o anhedonia in cogni i ely in ac and
non-dep essed olde people inc eases he isk o de eloping AD by 2.5 imes, compa ed
wi h hose wi hou anhedonia and a e con olling o he e ec o sociodemog aphic
ac o s. Wi h he aim o unco e ing he mul icausali y and complexi y o Alzheime ’s
disease, his is he i s s udy o epo a signi ican associa ion be ween he p esence o
anhedonia (independen o a dep essi e diso de ) and isk o AD.
S udies ocusing on anhedonia as pa o a mood diso de sugges ha anhedonia
p edic s a signi ican wo se clinical p ognosis in subjec s wi h acu e co ona y synd ome [
40
],
whe e i doubles he isk o su e ing om ano he episode again [
41
,
42
]. P e ious li e a u e
has also sugges ed anhedonia o be a p edic o o dea h in pa ien s wi h sys olic hea
ailu e [
43
], pa ien s unde aking a co ona y s en implan a ion [
44
], and communi y-
dwelling adul s wi h ype-2 diabe es [45].
In . J. En i on. Res. Public Heal h 2021,18, 1370 8 o 12
Li e a u e abou anhedonia as a symp om (ou side he con ex o a mood episode) has
shown ha subjec s wi h anhedonia ha e a highe isk o ca dio ascula
diseases [16,40–44]
,
ype-2 diabe es [
46
], and mild cogni i e impai men (MCI) [
15
].Mo eo e , some expe imen-
al wo ks based on animal models sugges ha anhedonia may inc ease isk o AD [
47
–
49
].
The p esence o he symp om o anhedonia wi hou a majo dep essi e diso de
was associa ed wi h a six- imes highe isk o con e sion o AD in indi iduals wi h MCI.
Fu he mo e, his associa ion has no been ound in dep essed people wi h an app op i-
a e hedonic one [
16
]. A simila s udy conduc ed in he Ko ean Longi udinal S udy on
Cogni i e Aging and Demen ia (KLOSCAD), a p ospec i e mul icen e coho s udy in
adul s aged 60 yea s o olde [
50
], ound ha non-demen ed and non-clinically dep essed
pa icipan s wi h anhedonia we e a a i e- imes g ea e isk o global demen ia han hose
wi h an app op ia e hedonic one [
15
]. This s udy, hough, did no epo he speci ic isk
by sub ypes o demen ia (e.g., AD).
Ou s udy is he i s o analyze he associa ion be ween anhedonia and Alzheime ’s
disease in cogni i ely unimpai ed elde ly people wi hou clinical dep ession. In con as
wi h p e ious s udies [
45
] ha assessed anhedonia by means o sel - epo ed ques ion-
nai es, we used a semi-s uc u ed s anda dized ZARADEMP clinical in e iew whe e
GMS-AGECAT was included, which is speci ic o a psychoge ia ic popula ion. Con ol-
ling o clinically signi ican dep ession and he use o in e na ional and eliable clinical
ins umen s should inc ease he con idence in ou esul s, especially in hose conce ning
he independen ole o anhedonia om dep ession [15,16] as a genuine isk ac o o AD.
Some speci ic neu obiological pa hways migh be in ol ed in he associa ion be ween
anhedonia and AD. Fi s ly, we epo ed some e idence ha ound ha anhedonia inc eases
he isk o diabe es and ca dio ascula disease; bo h ha e been consis en ly associa ed
wi h an inc eased isk o AD [
45
]. Howe e , we con olled ou analysis o hose isk
ac o s, and he associa ion be ween anhedonia and inciden AD we e independen o hem.
O he wise, loss o pleasu e is ela ed wi h ewa d- ela ed de ici s [
51
], and di e en b ain
s uc u es ha e been sugges ed o be in ol ed, such as he p e on al co ex ( en omedial
and o bi o on al) [
52
], do sal and en al s ia um [
53
] (nucleus accumbens) [
54
–
56
], a ea
egmen al en al, amygdala [
57
], habenula [
58
], p ima ily media ed by dopamine gic
and glu ama e gic sys ems [
51
,
59
,
60
]. F om an expe imen al app oach, a “ icious cycle
o s ess” is desc ibed [
47
], wi h anhedonia being a sou ce o emo ional discom o in he
con ex o ulne abili y o s ess [
61
]. This clinical mani es a ion is capable o educing
he hippocampal olume [
12
,
13
] and dis up ing mic oglia unc ion h ough he ac i a ion
o he b ain neu oin lamma ion (a cy okine cascade and oxida i e s ess) [
14
,
48
], which
de e mines an inc eased isk o de eloping AD [
49
]. In u n, neu oin lamma ion migh
inc ease he se e i y o anhedonic symp oma ology [47].
I is s ill unknown i anhedonia is a genuine isk ac o o AD o a he an incipien
p od omal symp om o AD. As we we e p ima ily in e es ed in he implica ions o an-
hedonia in a cogni i ely in ac sample, we excluded hose cases wi h demen ia o mild
cogni i e de ici s a baseline. Addi ionally, in o de o s udy he ole o anhedonia ou -
side he con ex o a majo dep essi e episode, we con olled ou analysis o clinically
signi ican dep ession a baseline, as well as a his o y o dep ession and/o ea men wi h
an idep essan s. Thus, ou indings seem o sugges ha anhedonia as a symp om migh
be a po en ial independen isk ac o o AD.
Ne e heless, anhedonia could be a symp om o subsynd omal o mino dep ession,
which consis s o dep essi e symp oms ha do no mee he c i e ia o clinically signi ican
o majo dep ession. Subsynd omal dep ession has been associa ed wi h poo e ou comes
and an inc eased demen ia global isk [8]. Anhedonia could also be a symp om o apa hy
synd ome, which has consis en ly been ound o be a isk ac o o p og ession o demen ia
in di e en clinical samples [
62
]. Howe e , anhedonia e e s speci ically o he a ec i e
componen o apa hy, which could espond be e o ea men wi h an idep essan s han
beha io al apa hy. Fu u e s udies could a emp o unco e o a be e unde s anding o
he con ex o anhedonia as a isk ac o o AD. Fu he mo e, hey should also de e mine
In . J. En i on. Res. Public Heal h 2021,18, 1370 9 o 12
i he de ec ion o anhedonia in non-dep essed subjec s and i s ea men could ha e a
p e en i e e ec on AD isk.
Some o he limi a ions o his s udy a e a ibu able o a ela i ely sho ollow-up
pe iod. Longe pe iods o ime migh be needed o cla i y whe he anhedonia is a genuine
isk ac o o demen ia o a he a p od omal symp om. We did no analyze biochemical
ma ke s in he blood, se um, o ce eb ospinal luid, because ou s udy has an epidemi-
ological basis and ou main objec i e was o documen he associa ion be ween di e se
isk ac o s and inciden cases o demen ia in he elde ly popula ion, using se e al ins u-
men s speci ic o psychoge ia ic dwelle s [
18
]. Ne e heless, biochemical ma ke s migh
ha e helped us o unde s and he di e en pa hophysiological and psychopa hological
pa hways unde lying mechanisms be ween anhedonia and AD a bi be e , so u he
esea ch is needed. In addi ion, i is di icul o make a compa ison be ween ou esul s
and hose o o he epidemiological s udies, because o he di e se assessmen ins umen s
and de ini ions o anhedonia [
55
]. Anhedonia is some imes no p ope ly ope a ionalized
o conside ed o be equi alen o a educ ion in posi i e a ec o a loss o in e es and
hope ulness [43].
5. Conclusions
In conclusion, ou s udy sugges s ha anhedonia, independen o a mood diso de , is
a p obable psychopa hological isk ac o o AD. Thus, measu ing his symp om in daily
clinical p ac ice could p o ide a help ul, apid, and easy ool o clinicians o iden i y
hose cases a isk o AD. Those subjec s a isk should be kep unde obse a ion o e
ime and o e ed e ec i e demen ia p e en ion s a egies [
2
,
6
,
37
,
63
,
64
] in o de o p e en
p og ession o AD.
Au ho Con ibu ions:
D.V.-P. collabo a ed in he s udy concep ualiza ion and design, in es i-
ga ion, da a cu a ion, analysis, and in e p e a ion o da a; w i ing—o iginal d a p epa a ion;
w i ing— e iew
and edi ing; and isualiza ion. C.D.-l.-C. pa icipa ed in w i ing— e iew and
edi ing; supe ision; da a cu a ion; analysis and in e p e a ion o da a; isualiza ion; and unding
acquisi ion. B.O. pa icipa ed in he me hodology; o mal analysis; w i ing— e iew and edi ing; and
isualiza ion. R.L.-A. pa icipa ed in he s udy concep ualiza ion and me hodology; so wa e; alida-
ion; o mal analysis; da a cu a ion; and isualiza ion. A.L. pa icipa ed in supe ision, me hodology,
o mal analysis, in es iga ion, esou ces, p ojec adminis a ion, and unding acquisi ion. P.G.-G.
pa icipa ed in he da a cu a ion; in es iga ion; w i ing— e iew and edi ing; supe ision; and i-
sualiza ion. J.S. pa icipa ed in he s udy concep ualiza ion; me hodology; so wa e; alida ion;
o mal analysis; in es iga ion; esou ces; da a cu a ion; w i ing— e iew and edi ing; isualiza ion;
supe ision; and unding acquisi ion. All au ho s ha e ead and ag eed o he published e sion o
he manusc ip .
Funding:
Suppo ed by g an s om he Fondo de In es igación Sani a ia, Ins i u o de Salud Ca los
III, Spanish Minis y o Economy and Compe i i eness, Mad id, Spain (g an s 94/1562, 97/1321E,
98/0103, 01/0255, 03/0815, 06/0617, 12/02254, 16/00896, PI/19/01874, and G03/128), and om
he Fondo Eu opeo de Desa ollo Regional (FEDER) o he Eu opean Union “Una mane a de hace
Eu opa” (p ojec numbe PI16/00896) and Gobie no de A agón (g an B15_17R). B.O. is suppo ed by
he PERIS p og am 2016–2020 “Aju s pe a la Inco po acióde Cien í ics i Tecnólegs” (g an numbe
SLT006/17/00066), wi h he suppo o he Heal h Depa men o he Gene ali a de Ca alunya.
Ins i u ional Re iew Boa d S a emen :
The E hics Commi ee o Resea ch o A agón (CEICA)
app o ed his p ojec , in acco dance wi h Spanish Law (p o ocol code PI12/0073, app o ed on 19
Sep embe 2012).
In o med Consen S a emen :
In o med consen was ob ained om all subjec s in ol ed in he s udy.
Acknowledgmen s:
The au ho s acknowledge he con ibu ion o he lay in e iewe s, senio medi-
cal s uden s, and membe s o he ZARADEMP Wo kg oup who pa icipa ed in he s udy.