Late-Life Depression, Mild Cognitive Impairment, and Dementia

ORIGINAL CONTRIBUTION
Late-Life Depression, Mild Cognitive Impairment,

and Dementia
Edo Richard, MD, PhD; Christiane Reitz, MD, PhD; Lawrence H. Honig, MD, PhD;
Nicole Schupf, PhD; Ming X. Tang, PhD; Jennifer J. Manly, PhD; Richard Mayeux, MD, MSc;
Devangere Devanand, MD; José A. Luchsinger, MD, MPH
Objective: To evaluate the association of late-life de- egories of MCI (amnestic and nonamnestic), and demen-
pression with mild cognitive impairment (MCI) and de- tia (probable Alzheimer disease and vascular dementia,
mentia in a multiethnic community cohort. including possible Alzheimer disease with stroke).
Design and Setting: A cohort study was conducted Results: Baseline depression was associated with preva-
in Northern Manhattan, New York, New York. lent MCI (odds ratio, 1.4; 95% CI, 1.1-1.9) and demen-
tia (2.2; 1.6-3.1). Baseline depression was associated with
Participants: A total of 2160 community-dwelling Medi- an increased risk of incident dementia (hazard ratio [HR],
care recipients aged 65 years or older were included in 1.7; 95% CI, 1.2-2.3) but not with incident MCI (0.9; 0.7-
the study. 1.2). Persons with MCI and coexisting depression at base-
line had a higher risk of progression to dementia (HR,
Methods: Depression was assessed using the 10-item 2.0; 95% CI, 1.2-3.4), especially vascular dementia (4.3;
version of the Center for Epidemiological Studies De- 1.1-17.0), but not Alzheimer disease (1.9; 1.0-3.6).
pression scale (CES-D) and defined by a CES-D score of
4 or more. We used logistic regression for cross- Conclusion: The association of depression with preva-
sectional association analyses and proportional hazards lent MCI and with progression from MCI to dementia, but
regression for longitudinal analyses. not with incident MCI, suggests that depression accom-
panies cognitive impairment but does not precede it.
Main Outcome Measures: Mild cognitive impair-
ment dementia, and progression from MCI to dementia JAMA Neurol. 2013;70(3):383-389. Published online
were the main outcome measures. We also used subcat- December 31, 2012. doi:10.1001/jamaneurol.2013.603
D
Author Affiliations:
EPRESSIVE SYMPTOMS OC- ting,11 but a population-based study found
Department of Neurology, cur in 40% to 50% and no association.9 Author Aff
Academic Medical Center, major depression in 10% The mechanisms behind the associa- Departmen
University of Amsterdam, to 20% of patients with tion between depression and cognitive de- Academic M
Amsterdam, the Netherlands Alzheimer disease (AD).1 cline have not been elucidated, and differ- University
(Dr Richard); Depressive symptoms occur in 3% to 63% ent mechanisms have been proposed.8,12,13 Amsterdam
Gertrude H. Sergievsky Center (Dr Richard
(Drs Reitz, Honig, Schupf,
of individuals with mild cognitive impair- Depression could be a risk factor for de- Gertrude H
Tang, Manly, and Mayeux), ment (MCI).2 This wide range is prob- mentia, an early dementia symptom, a re- (Drs Reitz,
Departments of Neurology ably attributable to sample differences action to cognitive and functional disabil- Tang, Manl
(Drs Honig, Manly, and (hospital vs population based) and opera- ity, or a symptom of a related risk factor, Departmen
Mayeux), Psychiatry tionalization of MCI and depression cri- such as cerebrovascular disease. Vascular Honig, Man
(Drs Mayeux and Devanand), teria.2 Case-control studies and longitu- factors have been linked to late-life depres- Psychiatry
and Medicine (Dr Luchsinger), dinal studies have shown an increased sion, and cerebrovascular disease might be Devanand)
and Departments of Luchsinger
Epidemiology (Drs Schupf, dementia risk in persons with depression an important contributor to MCI, demen- of Epidemi
Mayeux, and Luchsinger) and history,3 although a few longitudinal stud- tia, and depression in late life.14-17 How- Mayeux, an
Biostatistics (Dr Tang), ies reported no increased dementia risk.4-6 ever, there is a paucity of data examining Biostatistics
Joseph P. Mailman School of Increased MCI risk in depression was re- the association between depression and Joseph P. M
Public Health, Columbia cently reported in population-based stud- MCI. An association between depressive Public Heal
University Medical Center, ies,7,8 but this was not confirmed in 2 other symptoms and AD was observed in a co- University
New York, New York; and New York,
Division of Geriatric Psychiatry,
population-based studies.9,10 Increased risk hort of elderly individuals recruited in Division of
New York State Psychiatric of progression to dementia in patients with 1992-1994.18,19 Our aim in this study was New York S
Institute, New York MCI and depression has been reported in to explore the cross-sectional and longi- Institute, N
(Dr Devanand). prospective studies in a memory clinic set- tudinal associations of depression with Devanand)
JAMA NEUROL/ VOL 70 (NO. 3), MAR 2013 WWW.JAMANEURO.COM

383
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MCI and dementia and the progression from MCI to de- tion criteria26; and vascular dementia, using the NINDS–
mentia in a newer cohort recruited in 1999-2001 in the Association Internationale pour la Recherché et l’Enseignement
same community. en Neurosciences (NINDS-AIREN) criteria.27 Individuals not
fulfilling these criteria were categorized as other dementia, in-
cluding those with dementia with Lewy bodies, dementia as-
METHODS sociated with traumatic brain injury, and dementia not other-
wise specified. Probable AD was diagnosed when the clinical
PARTICIPANTS history suggested AD, and no other contributors to dementia
were found. Possible AD was diagnosed when AD was consid-
Participants were recruited by random sampling of healthy Medi- ered the most likely contributor to dementia, but there were
care eligible persons older than 65 years in several low- other contributing factors. We analyzed 3 dementia outcomes:
income neighborhoods with a high proportion of Hispanics in all dementia, AD (including probable and possible AD without
Northern Manhattan. They were part of the Washington Heights– cerebrovascular disease by history), and vascular dementia, in-
Inwood Columbia Aging Project (WHICAP)—a population- cluding cases fulfilling NINDS-AIREN criteria and patients with
based cohort in which clinical and epidemiologic data are a diagnosis of possible AD in whom cerebrovascular disease his-
collected at regular intervals and vital status is continually tory was considered to contribute to dementia (VaD). The ra-
updated.20 This report pertains to a cohort recruited in 1999 tionale for this classification of the outcome was that late-life
to 2001. The geographic study area was Manhattan north of depression has been linked to cerebrovascular disease, also
145th Street. Lists of persons in receipt of Medicare or Medic- known as vascular depression,15 and we sought to separate cases
aid in this area were obtained from the Health Care Financing of dementia with a vascular component from cases without a
Administration. Potential participants were drawn by system- vascular component based on clinical assessment and consen-
atic random sampling into one of 6 strata formed on the basis sus diagnosis. Mild cognitive impairment was ascertained by
of ethnicity (Hispanics, non-Hispanic blacks, and non- the Petersen criteria28 as previously described29 and was fur-
Hispanic whites) and age (65-74 and ⱖ75 years). Participants ther characterized as amnestic MCI and nonamnestic MCI as
who reported a physician diagnosis of dementia were ex- previously described.30
cluded. The total number recruited was 2183. Individuals who
completed the baseline visit with neuropsychological and de- COVARIATES
pressive symptoms information are included in this analysis
(N=2160). Follow-up visits were scheduled with intervals of Age was calculated from the date of birth to the baseline evalu-
18 to 24 months. Neuropsychological testing according to a stan- ation. Ethnic group was determined by US census criteria. Edu-
dardized protocol was performed at baseline and then at 18- cational level was measured in years. The APOE genotypes were
to 24-month intervals. determined as described by Hixson and Vernier31 with slight
modification. We classified persons as either homozygous/
ASSESSMENT OF DEPRESSION heterozygous or APOEε4 negative.
We adjusted for vascular risk factors using a modification
Presence of depressive symptoms was assessed at baseline and of a composite score shown to predict dementia.32 This score
follow-up visits using the short version (Boston form) of the includes diabetes mellitus, hypertension, current smoking, low
Center for Epidemiological Studies Depression (CES-D) scale.21 high-density lipoprotein levels, and high waist to hip ratio, with
This is a 10-item questionnaire with questions to be answered ranges from 0 to 18.
by yes (1 point) or no (0 points), leading to a total score of 0
to 10. A cutoff of 4 points or more on this scale has been used STATISTICAL ANALYSIS
to ascertain depression in studies, including a 1992 co-
hort.22,23 We used absent or mild depression as the reference Baseline variables were compared between individuals with
for comparison. Change in depression was assessed at first fol- (CES-D ⱖ4) and without (CES-D ⬍4) depression, using the
low-up. The CES-D comprises items that can be subclassified 2-tailed unpaired t test or the ␹2 test where appropriate. The
as depressed affect (I felt depressed, I felt lonely, I felt sad), posi- cross-sectional associations between the presence of depres-
tive affect (I was happy, I enjoyed life), somatic/vegetative signs sive symptoms and MCI or dementia (and their subtypes) at
(I felt that everything I did was an effort, my sleep was rest- baseline were assessed using logistic regression models. Pro-
less), and interpersonal distress (People were unfriendly, I felt portional hazards models were used for longitudinal analyses.
people disliked me).24 Affirmative responses in these ques- The time-to-event variable was the time from baseline to inci-
tions scored as yes (1) or no (0) were added, with the excep- dent dementia or MCI. Individuals who did not develop MCI
tion of the positive affect items, which were scored inversely. or dementia were right-censored at the time of their last visit.
Symptoms of 1 cluster were scored as present if 1 or more of To assess whether depression in patients with MCI at baseline
the questions were answered affirmatively. We used this clas- increased the risk of progression to dementia, proportional haz-
sification of the CES-D items to conduct secondary analyses ards models were used. For all analyses, 3 basic models were
examining symptom type as the exposure. used. Model 1 was adjusted for age and sex; model 2 was ad-
justed additionally for educational level, ethnicity, and APOE
ASSESSMENT OF MCI AND DEMENTIA genotype; and model 3 was adjusted additionally for the vas-
cular risk score. The rationale for model 1 was the adjustment
The diagnoses of dementia and MCI were made on the basis of of basic demographics, the rationale for model 2 was the ad-
all available clinical and neuropsychological information by con- justment for nonmodifiable predictors of dementia in our co-
sensus of a panel of neurologists, neuropsychologists, and psy- hort, and the rationale for model 3 was the adjustment for vas-
chiatrists according to international guidelines. A diagnosis of cular burden. Model 3 was used to explore the potential
dementia was based on the Diagnostic and Statistical Manual of mediation of vascular disease in the relationship between de-
Mental Disorders (Third Edition Revised)25 criteria; AD, using pression and dementia; attenuation of the effect estimates in
the National Institute of Neurological Disorders and Stroke this model was interpreted as evidence of mediation, not
(NINDS)–Alzheimer’s Disease and Related Disorders Associa- confounding.

384

Table 1. Baseline Characteristics of Participants
2183 Participants recruited With and Without Depression
21 Had incomplete CES-D Depressed, Not Depressed,

2 Had insufficient data
CES-D ⱖ4 CES-D ⬍4
Characteristic (n = 452) (n = 1708) P Value
2160 With complete data
Age, mean (SD), y 77.7 (7.2) 76.7 (7.0) .01
Male sex, % 36.2 22.1 ⬍.001
Educational level, 9.0 (4.8) 10.6 (4.8) ⬍.001
217 429 1514 mean (SD), y
Baseline Had prevalent Had prevalent Normal cognition
dementia MCI Ethnicity, %
White 25.4 30.8
Black 23.7 34.9 ⬍.001
Hispanic 49.8 32.7
Vascular risk factors, %
362 67
Hypertension 48.4 48.0 .91
Follow-up Had stable Had incident
MCI dementia Diabetes mellitus 19.7 19.3 .84
Total cholesterol level, 200.3 (39.2) 198.4 (39.0) .45
mean (SD), mg/dL
Smoking 10.0 10.4 .86
BMI ⬎30 28.6 28.6 .99
1113 304 97 Depressed episode in the 32.5 11.7 ⬍.001
Normal cognition Had incident Had incident past, %
MCI dementia
Antidepressant use, % 19.5 4.8 ⬍.001
APOE ε4 allele, % 28.9 27.0 .47
43
Had incident Abbreviations: BMI, body mass index (calculated as weight in kilograms
dementia divided by height in meters squared); CES-D, Center for Epidemiological
Studies–Depression.
SI conversion factor: To convert total cholesterol to millimoles per liter,
multiply by 0.0259.
Figure. Flowchart of the study. CES-D indicates Center for Epidemiological
Studies Depression scale; MCI, mild cognitive impairment.
ence of depressive symptoms not meeting depression
criteria (CES-D ⬍4) was not associated with prevalent
RESULTS MCI.
There were 2160 of 2183 individuals (98.9%) with com- Relationship of Depression
plete data on the CES-D at baseline; they were included With Prevalent Dementia
in the study (Figure). Of these, 452 participants (20.9%)
had a CES-D score of 4 or more and 1708 participants Dementia was diagnosed at baseline in 217 participants;
(79.1%) had a CES-D score less than 4. Individuals with 164 individuals (75.1%) received a diagnosis of possible
depression were older, were more likely to be male, had or probable AD (probable, 126 [58.1%]), 33 received a
fewer years of education, were more likely to be His- diagnosis of VaD (15.2%), and 20 received a diagnosis
panic, and were more likely to use antidepressants of other dementia (9.2%; including dementia with Lewy
(Table 1). Five hundred fifty-nine participants (25.9%) bodies, toxic cause, and several rare causes of demen-
did not have a follow-up visit after the baseline assess- tia). Participants with dementia were depressed twice as
ment. These people were older (78.3 vs 76.5 years, often as were those without dementia (odds ratio, 2.2;
P⬍.001) and less educated (9.5 vs 10.5 years, P⬍ .001) 95% CI, 1.6-3.1), and this association was stronger for
than the participants with follow-up, but there was no VaD compared with AD (Table 2). There was marked
significant difference in depression (eTable 1; http://www attenuation of the odds ratio relating depression and
.jamaneuro.com). VaD in the model adjusting for a vascular risk score.
The presence of depressive symptoms not meeting the
CROSS-SECTIONAL ANALYSES depression criteria was not associated with prevalent
dementia.
Relationship of Depression
With Prevalent MCI LONGITUDINAL ANALYSES
At baseline, 429 participants fulfilled MCI criteria: 222 Relationship of Baseline Depression
of these (51.7%) had amnestic MCI and 207 people With Incident MCI
(48.3%) had nonamnestic MCI. Participants with MCI
were more often depressed than were those who were Of 1514 participants without dementia or MCI at base-
cognitively intact ( Table 2 ); this association was line, there were 1156 individuals (76.4%) with fol-
strongest for nonamnestic MCI but was not significant low-up for longitudinal analyses with MCI as an out-
for amnestic MCI and was only slightly attenuated with come. During an average follow-up of 5.4 years (range,
adjustment for vascular burden (Table 2). The pres- 1.1-10.1 years), MCI developed in 304 individuals, of

385

Table 3. Longitudinal Analyses Using Proportional Hazards Models Relating Depression With Incident MCI and Dementia a
No. HR (95% CI)

Characteristic At Risk Cases Model 1 Model 2 b Model 3 c
MCI as Outcome
All MCI (n = 304)
No depression 1209 257 1 [Reference] 1 [Reference] 1 [Reference]
Depression 266 47 0.9 (0.7-1.2) 0.8 (0.6-1.2) 1.0 (0.7-1.5)
Amnestic MCI (n = 151)
Depression 248 29 1.1 (0.7-1.7) 1.0 (0.6-1.6) 1.3 (0.8-2.1)
Nonamnestic MCI (n = 153)
Depression 237 18 0.7 (0.4-1.1) 0.6 (0.3-1.0) 0.8 (0.4-1.4)
Dementia as Outcome
All dementia (n = 207)
Depression 376 52 1.7 (1.2-2.3) 1.6 (1.1-2.3) 1.8 (1.2-2.7)
AD without vascular component (n = 167)
Depression 366 42 1.7 (1.2-2.5) 1.6 (1.1-2.4) 1.9 (1.2-2.9)
VaD, including AD with stroke (n = 29)
Depression 331 7 1.6 (0.7-3.8) 1.3 (0.5-3.5) 1.7 (0.5-5.6)
Abbreviations: AD, Alzheimer disease; HR, hazard ratio; MCI, mild cognitive impairment; VaD, vascular dementia.
a Model 1 was adjusted for age and sex; model 2 was additionally adjusted for educational level and ethnicity; and model 3 was adjusted for age, sex, and
vascular risk factors.
b Based on a sample of 1645 individuals in whom APOE genotype was available.
c Based on a sample of 1399 individuals in whom the vascular risk score could be determined, including all 5 risk factors.
Table 4. Longitudinal Analyses Relating Depression With Incident Dementia Among Participants With MCI at Baseline a
No. HR (95% CI)

Depression 103 22 2.0 (1.2-3.4) 1.8 (1.0-3.1) 1.8 (0.9-3.5)
Depression 96 15 1.9 (1.0-3.6) 1.7 (0.9-3.3) 1.7 (0.8-3.9)
Depression 86 5 4.3 (1.1-17.0) 4.3 (1.0-18.5) 3.7 (0.8-17.2)
Abbreviations: AD, Alzheimer disease; HR, hazard ratio; VaD, vascular dementia.
b Based on a sample of 1645 individuals in whom the APOE genotype was available.
were analyzed separately, the HRs relating depression COMMENT

to progression to dementia were similar (amnestic MCI:
HR, 2.1; 95% CI, 1.0-4.3 vs nonamnestic MCI: 2.4; 1.1-
5.7). There were no significant differences between We found that depression was related to a higher risk of
amnestic and nonamnestic MCI in the HR relating prevalent MCI and dementia, incident dementia, and
depression to incident AD or VaD. In analyses with progression from prevalent MCI to dementia, but not to
the CES-D as an ordinal scale, no association between incident MCI. We also found that the association of
a score of 0 or 1 or of 2 or 3 (some depressive symp- depression with prevalent dementia and with progres-
toms) and incident dementia was found. Analysis sion from MCI to dementia was stronger for VaD com-
using the different clusters of symptoms within the pared with AD and was driven mostly by depressive
CES-D showed again that depressed affect was associ- affect.
ated with increased incident dementia risk (HR, 2.1; Results of previous studies4-6,18,33,34 evaluating the as-
95% CI, 1.1-4.0). sociation of late-life depression with incident dementia

387

Table 3. Longitudinal Analyses Using Proportional Hazards Models Relating Depression With Incident MCI and Dementia a
No. HR (95% CI)

MCI as Outcome
All MCI (n = 304)
Depression 266 47 0.9 (0.7-1.2) 0.8 (0.6-1.2) 1.0 (0.7-1.5)
Amnestic MCI (n = 151)
Depression 248 29 1.1 (0.7-1.7) 1.0 (0.6-1.6) 1.3 (0.8-2.1)
Nonamnestic MCI (n = 153)
Depression 237 18 0.7 (0.4-1.1) 0.6 (0.3-1.0) 0.8 (0.4-1.4)
Dementia as Outcome
Depression 376 52 1.7 (1.2-2.3) 1.6 (1.1-2.3) 1.8 (1.2-2.7)
Depression 366 42 1.7 (1.2-2.5) 1.6 (1.1-2.4) 1.9 (1.2-2.9)
Depression 331 7 1.6 (0.7-3.8) 1.3 (0.5-3.5) 1.7 (0.5-5.6)
Abbreviations: AD, Alzheimer disease; HR, hazard ratio; MCI, mild cognitive impairment; VaD, vascular dementia.
b Based on a sample of 1645 individuals in whom APOE genotype was available.
Table 4. Longitudinal Analyses Relating Depression With Incident Dementia Among Participants With MCI at Baseline a
No. HR (95% CI)

Depression 103 22 2.0 (1.2-3.4) 1.8 (1.0-3.1) 1.8 (0.9-3.5)
Depression 96 15 1.9 (1.0-3.6) 1.7 (0.9-3.3) 1.7 (0.8-3.9)
Depression 86 5 4.3 (1.1-17.0) 4.3 (1.0-18.5) 3.7 (0.8-17.2)
Abbreviations: AD, Alzheimer disease; HR, hazard ratio; VaD, vascular dementia.
b Based on a sample of 1645 individuals in whom the APOE genotype was available.
were analyzed separately, the HRs relating depression COMMENT

to progression to dementia were similar (amnestic MCI:
HR, 2.1; 95% CI, 1.0-4.3 vs nonamnestic MCI: 2.4; 1.1-
5.7). There were no significant differences between We found that depression was related to a higher risk of
amnestic and nonamnestic MCI in the HR relating prevalent MCI and dementia, incident dementia, and
depression to incident AD or VaD. In analyses with progression from prevalent MCI to dementia, but not to
the CES-D as an ordinal scale, no association between incident MCI. We also found that the association of
a score of 0 or 1 or of 2 or 3 (some depressive symp- depression with prevalent dementia and with progres-
toms) and incident dementia was found. Analysis sion from MCI to dementia was stronger for VaD com-
using the different clusters of symptoms within the pared with AD and was driven mostly by depressive
CES-D showed again that depressed affect was associ- affect.
ated with increased incident dementia risk (HR, 2.1; Results of previous studies4-6,18,33,34 evaluating the as-
95% CI, 1.1-4.0). sociation of late-life depression with incident dementia

387

have been inconsistent. Studies2 evaluating the association between depressive symptoms and cognitive im-
tion of depression with MCI are inconsistent as well. An pairment (MCI or dementia).
increased risk of MCI in individuals with depression was Different explanations for the relationship between late-
recently reported,7,8 although 2 other studies9,10 reported life depression and dementia have been suggested.3,12,13
no association. Increased risk of developing dementia in Late-life depression could be an early symptom in the pro-
MCI with depressive symptoms has been reported11 in a gression to dementia; depression could affect the thresh-
hospital-based series, but population-based studies9,35 old for dementia to become manifest or could be a reac-
until now could not confirm this association as we did. tion to cognitive impairment. Depression could also be
We found that depression was related to prevalent but a causal risk factor for dementia through hippocampal
not incident MCI. It seems reasonable to postulate that damage mediated by the influence of depression on the
persons with prevalent MCI have a more advanced stage hypothalamic-pituitary-adrenal axis.39-41 Finally, com-
of cognitive impairment accompanied by depression, mon risk factors contributing to an increased risk of de-
whereas persons with incident MCI have earlier cogni- pression and dementia, such as cerebrovascular disease,
tive impairment not accompanied by depression. This could explain the association between the two.42 We could
could explain our findings and some of the inconsisten- not address the exact mechanisms linking depression and
cies in the literature. dementia, but our results support the hypothesis that late-
Our finding that depression was associated cross sec- life depression accompanies the occurrence of cognitive
tionally with both MCI and dementia and longitudi- decline and does not precede it. Our finding that the as-
nally only with dementia suggests that depression de- sociation of depression with probable AD was weaker
velops with the transition from normal cognition to compared with all AD (probable and possible) and VaD
dementia. This agrees with a study18 reporting that, in suggests that other pathologic conditions with AD may
nondemented elderly persons, depression is more com- be more likely to manifest as depression.
mon with increasing cognitive impairment. This specu-
lation is further supported by the observation that the Accepted for Publication: April 3, 2012.
association of depression with incident dementia was at- Published Online: December 31, 2012. doi:10.1001
tenuated when persons with MCI at baseline were ex- /jamaneurol.2013.603
cluded and by our observation that persons with MCI and Correspondence: José A. Luchsinger, MD, MPH, De-
depression were more likely to develop dementia. partment of Medicine, Columbia University Medical Cen-
A potential link between depression and dementia in ter, PH9 Center, 630 W 168th St, New York, NY 10032
late life is through vascular factors, as postulated in the ([email protected]).
vascular depression hypothesis.15 Depression is associ- Author Contributions: Study concept and design: Richard,
ated with vascular risk factors16,17 and with cerebrovas- Reitz, Manly, Mayeux, Devanand, and Luchsinger. Ac-
cular lesions on neuroimaging.36,37 Our findings that de- quisition of data: Honig, Schupf, Manly, Mayeux, and
pression is more strongly associated with VaD than AD Luchsinger. Analysis and interpretation of data: Richard,
(both cross sectionally and longitudinally in partici- Reitz, Honig, Tang, Devanand, and Luchsinger. Drafting
pants with MCI at baseline) and that this relationship is of the manuscript: Richard and Luchsinger. Critical revi-
attenuated in models adjusting for vascular burden sug- sion of the manuscript for important intellectual content:
gest that cerebrovascular disease has a role in this asso- Reitz, Honig, Schupf, Tang, Manly, Mayeux, Devanand,
ciation. Most studies that examined depression as a pre- and Luchsinger. Statistical analysis: Richard, Reitz, Tang,
dictor of dementia generally did not attempt to separate and Luchsinger. Obtained funding: Manly, Mayeux, and
AD from VaD. However, these results should be inter- Luchsinger. Administrative, technical, and material sup-
preted with caution because of the possibility of chance port: Manly, Mayeux, Devanand, and Luchsinger. Study
findings resulting from multiple subanalyses, because of supervision: Schupf and Devanand.
the lack of neuroimaging data, and because we did not Conflict of Interest Disclosures: None reported.
find an association of individual vascular risk factors with Online-Only Material: The eTable is available at http:
depression at baseline. Depressed mood seemed to drive //www.jamaneuro.com.
the association, which is in line with reports that de-
pressed mood alone predicts dementia.18 We could not
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Late-Life Depression, Mild Cognitive Impairment,

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JAMA NEUROL/ VOL 70 (NO. 3), MAR 2013 WWW.JAMANEURO.COM

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21 Had incomplete CES-D Depressed, Not Depressed,

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No. HR (95% CI)

No. HR (95% CI)

were analyzed separately, the HRs relating depression COMMENT

JAMA NEUROL/ VOL 70 (NO. 3), MAR 2013 WWW.JAMANEURO.COM

©2013 American Medical Association. All rights reserved.

No. HR (95% CI)

No. HR (95% CI)

were analyzed separately, the HRs relating depression COMMENT

JAMA NEUROL/ VOL 70 (NO. 3), MAR 2013 WWW.JAMANEURO.COM

©2013 American Medical Association. All rights reserved.

JAMA NEUROL/ VOL 70 (NO. 3), MAR 2013 WWW.JAMANEURO.COM

©2013 American Medical Association. All rights reserved.

JAMA NEUROL/ VOL 70 (NO. 3), MAR 2013 WWW.JAMANEURO.COM

©2013 American Medical Association. All rights reserved.

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