Literature Review Resources

Late-Life Depression Is Not Associated With Dementia-Related Pathology

Robert S. Wilson, Patricia A. Boyle, Ana W. Capuano, Raj C. Shah, George M. Hoganson, Sukriti Nag, and David A. Bennett

Rush University Medical Center

Objective: To test the hypothesis that late-life depression is associated with dementia-related pathology. Method: Older participants (n � 1,965) in 3 longitudinal clinical-pathologic cohort studies who had no cognitive impairment at baseline underwent annual clinical evaluations for a mean of 8.0 years (SD � 5.0). The authors defined depression diagnostically, as major depression during the study period, and psychomet- rically, as elevated depressive symptoms during the study period, and established their relation to cognitive outcomes (incident dementia, rate of cognitive decline). A total of 657 participants died and underwent a uniform neuropathologic examination. The authors estimated the association of depression with 6 dementia- related markers (tau tangles, beta-amyloid plaques, Lewy bodies, hippocampal sclerosis, gross and micro- scopic infarcts) in logistic regression models. Results: In the full cohort, 9.4% were diagnosed with major depression and 8.6% had chronically elevated depressive symptoms, both of which were related to adverse cognitive outcomes. In the 657 persons who died and had a neuropathologic examination, higher beta-amyloid plaque burden was associated with higher likelihood of major depression (present in 11.0%; OR � 1.392, 95% CI � 1.088, 1.780) but not with elevated depressive symptoms (present in 11.3%; OR � 0.919, 95% CI � 0.726, 1.165). None of the other pathologic markers was related to either of the depression measures. Neither dementia nor antidepressant medication modified the relation of pathology to depression. Conclusion: The results do not support the hypothesis that major depression is associated with dementia-related pathology.

Keywords: depression, longitudinal study, clinical-pathologic study, dementia, antidepressant medication

Depression is associated with an increased risk of developing of dementia (Byers & Yaffe, 2011; Jorm, 2001; Ownby, Crocco, Acevedo, John, & Loewenstein, 2006) for reasons that are not

clear. The most parsimonious explanation is that they share com- mon pathologic mechanisms, with depression a prodromal mani- festation of the same pathologies that eventually cause dementia (Barnes et al., 2012; Brommelhoff et al., 2009; Heser et al., 2013; Lenoir et al., 2011; Li et al., 2011; Panza et al., 2010). Clinical- pathologic research has generally not suggested an association between depressive symptoms and dementia-related pathologies (Royall & Palmer, 2013; Wilson et al., 2003; Wilson, Capuano, et al., 2014). However, there is evidence that major depression is associated with neuritic plaques and neurofibrillary tangles (Rapp et al., 2006), suggesting that depression may need to reach some threshold of severity before its association with dementia-related pathology is detectable. Support for this idea has been mixed in subsequent studies (Rapp et al., 2008; Tsopelas et al., 2011), possibly due to differences in depression criteria or the confound- ing influence of other factors such as dementia or antidepressant medication use.

In the present study, we test the hypothesis that depression is associated with common pathologic conditions linked to late-life dementia. Analyses are based on data from three longitudinal clinical-pathologic cohort studies that included annual clinical evaluations and brain autopsy at death. A total of 1,963 persons had no cognitive impairment at enrollment and valid data on depression, which was defined in two ways: major depression diagnosed during the study and persistently elevated depressive symptoms during the study. During follow-up, 657 individuals died and underwent a brain autopsy, and measures of six dementia- related neurodegenerative and cerebrovascular conditions were derived from a uniform neuropathologic examination. In a series of logistic regression models, we estimated the association of each

This article was published Online First August 3, 2015. Robert S. Wilson, Rush Alzheimer’s Disease Center, Department of

Neurological Sciences and Department of Behavioral Sciences, Rush Uni- versity Medical Center; Patricia A. Boyle, Rush Alzheimer’s Disease Center, Department of Behavioral Sciences, Rush University Medical Center; Ana W. Capuano, Rush Alzheimer’s Disease Center, Department of Neurological Sciences, Rush University Medical Center; Raj C. Shah, Rush Alzheimer’s Disease Center, Department of Family Medicine, Rush University Medical Center; George M. Hoganson, Rush Alzheimer’s Dis- ease Center, Rush University Medical Center; Sukriti Nag, Rush Alzhei- mer’s Disease Center, Department of Pathology, Rush University Medical Center; David A. Bennett, Rush Alzheimer’s Disease Center, Department of Neurological Sciences, Rush University Medical Center.

This research was supported by National Institutes of Health grants R01AG17917, P30AG10161, R01AG15819, R01AG33678, and R01AG34374, and by the Illinois Department of Public Health. The funding organizations had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; or prepa- ration, review, or approval of the manuscript. We thank the many Illinois residents for participating in the Rush Memory and Aging Project and the many Catholic nuns, priests, and monks for participating in the Religious Orders Study; Traci Colvin, MPH, and Karen Skish, MS, for study coor- dination; John Gibbons, MS, and Greg Klein, MS, for data management; and Alysha Kett, MS, for statistical programming.

Correspondence concerning this article should be addressed to Robert S. Wil- son, Rush Alzheimer’s Disease Center, Rush University Medical Center, 600 South Paulina Street, Suite 1038, Chicago, IL 60612. E-mail: [email protected]

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Neuropsychology © 2015 American Psychological Association 2016, Vol. 30, No. 2, 135–142 0894-4105/16/$12.00 http://dx.doi.org/10.1037/neu0000223

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neuropathologic marker with depression and tested whether these associations were modified by the presence of dementia or use of antidepressant medications.

Methods

Participants

Analyses are based on individuals from three ongoing longitu- dinal clinical-pathologic cohort studies. The Religious Orders Study began in 1994. It involves older Catholic priests, nuns, and monks from more than 40 groups across the United States (Ben- nett, Schneider, Arvanitakis, & Wilson, 2012; Wilson, Bienias, Evans, & Bennett, 2004). The Rush Memory and Aging Project began in 1997 and includes older lay persons from the Chicago area (Bennett et al., 2005; Bennett, Schneider, Buchman, et al., 2012). The Minority Aging Research Study began in 2004. Par- ticipants are older Black persons in the Chicago area recruited from the community and the clinical core of the Rush Alzheimer’s Disease Core Center (Arvanitakis, Bennett, Wilson, & Barnes, 2010; Barnes, Shah, Aggarwal, Bennett, & Schneider, 2012). At baseline, persons in each study were at least 50 years old, had not previously been diagnosed with dementia, and agreed to annual clinical evaluations. All persons in the Religious Orders Study and Rush Memory and Aging Project and a subset of those in the Minority Aging Research Study also agreed to brain autopsy at death. All participants provided written informed consent after a thorough discussion with study personnel. The institutional review board of Rush University Medical Center approved each study.

At the time of these analyses, 2,444 individuals had completed the baseline clinical evaluation and been found to have no cogni- tive impairment. There were 44 deaths before the first annual follow-up evaluation and 97 persons had been in the study less than one year. Of the remaining 2,303 individuals who were eligible for follow-up, 1,965 (85.3%) had follow-up data and were included in analyses. They had a mean age at baseline of 76.3 years (SD � 7.5) and a mean of 16.1 years of education (SD � 3.7); 73.8% were women. During a mean of 8.0 years of annual follow-up (SD � 5.0), 764 persons died. Of these, 683 (89.4%) had a brain autopsy, and a uniform neuropathologic examination had been completed on the first consecutive 657 individuals who died at a mean age of 87.9 (SD � 6.7). Compared to the 1,310 participants without neuropathologic data, the 657 neuropathologi- cally examined individuals were older at baseline (79.1 vs. 74.9, t[1,428.9] � 12.5, p � .001), had more years of education (16.5 vs. 15.9, t[1,965] � 3.5, p � .001), and were more apt to be men (33.3% vs. 22.6%, �2[1] � 26.1, p � .001) and have elevated depressive symptoms on the Center for Epidemiological Studies Depression scale (11.3% vs. 7.3%, �2[1] � 8.9, p � .003) but the subgroups did not differ in rate of major depression (11.0% vs. 8.6%, �2[1] � 2.8, p � .095).

Clinical Evaluation

Each year participants had a uniform clinical evaluation that included a structured medical history, detailed cognitive testing, and a neurologic examination. Following the evaluation, an expe- rienced clinician diagnosed dementia according to the criteria of the joint working group of the National Institute of Neurological

and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (McKhann et al., 1984). These require a history of cognitive decline and impairment in at least two cognitive domains.

Assessment of Depression

We defined depression in two ways. The first was major de- pression according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 3rd ed, revised (American Psychi- atric Association, 1987) implemented with a subset of questions from the Diagnostic Interview Schedule (Robins, Helzer, Croughan, & Ratcliff, 1981) at each annual evaluation. All participants were asked “In the past month, has there been a period of 2 weeks or more during which you felt sad, blue, or depressed, or when you lost interest and pleasure in things you usually cared about?” A yes response elicited questions about the presence of eight other symp- toms of depression during this period (e.g., appetite, sleep, energy, concentration, guilt), and the presence of four or more of these additional depressive symptoms led to a diagnosis of major de- pression (American Psychiatric Association, 1987). Persons were classified as depressed if they met these criteria at any point during the study. To complement this diagnostic definition of depression, we used a psychometric definition that required persistent symp- toms. At each evaluation, participants completed a 10-item version (Kohout, Berkman, Evans, & Cornoni-Huntley, 1993) of the Cen- ter for Epidemiological Studies Depression Scale (Radloff, 1977). Individuals were asked if they had experienced each of 10 depres- sive symptoms in the past week (e.g., “I felt like everything I did was an effort”). Because the accepted depression cutoff score of 16 on the original Center for Epidemiological Studies Depression Scale represents approximately 27% of the total possible score (i.e., 16/60 � 0.267), we chose a depression cutoff score of 3 on the 10-item Center for Epidemiological Studies Depression Scale, which represents 30% of the total possible score and required a mean score of 3 or more symptoms across all evaluations as a psychometric indicator of depression. Medications were coded each year using the Medi-Span Master Drug Database (Medi-Span, Inc., 1995).

Assessment of Cognitive Function

As part of each annual clinical evaluation, a battery of 19 cognitive performance tests was administered by a research assis- tant in an approximately one hour session. The cognitive assess- ment was designed to support clinical classification of dementia and allow measurement of change in cognitive function over time. Two tests were used exclusively for clinical classification: the Mini-Mental State Examination (Folstein, Folstein, & McHugh, 1975), a measure of global cognitive function, and Complex Ide- ational Material (Kaplan, Goodglass, & Weintraub, 1983), a mea- sure of auditory verbal comprehension. The other 17 tests were used diagnostically and in longitudinal analyses. Episodic memory was assessed with seven measures: immediate and delayed recall of Story A from Logical Memory of the Wechsler Memory Scale—revised (Wechsler, 1987) and the East Boston story (Albert et al., 1991; Wilson, Beckett, et al., 2002) and Word List Memory, Word List Recall, and Word List Recognition from the test battery developed by the Consortium to Establish a Registry for Alzhei-

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136 WILSON ET AL.

mer’s disease (Welsh et al., 1994). Semantic memory was assessed with a 15-item short form (Welsh et al., 1994) of the Boston Naming Test, a measure of verbal fluency that involved naming examples of two categories (animals, vegetables) in separate 1-min trials (Welsh et al., 1994; Wilson, Beckett, et al., 2002), and a 15-item word recognition task that required pronunciation of words with atypical spelling sound correspondence (Wilson, Beck- ett, et al., 2002). Working memory was measured with Digit Span Forward and Digit Span Backward from the Wechsler Memory Scale—revised (Wechsler, 1987) and Digit Ordering which re- quired listening to strings of digits and saying them back in ascending order (Wilson, Beckett, et al., 2002). Number Compa- rision (Ekstrom, French, Harman, & Kermen, 1976; Wilson, Beck- ett, et al., 2002) and the oral version of the Symbol Digit Modal- ities Test (Smith, 1982) were used to measure perceptual speed. A 15-item form of Judgment of Line Orientation (Benton, Sivan, Hamsher, Varney, & Spreen, 1994) and a 16-item form of Stan- dard Progressive Matrices (Raven, Court, & Raven, 1992) assessed visuospatial ability.

The presence or absence of impairment in five cognitive do- mains (orientation, attention, memory, language, perception) was determined by a neuropsychologist after review of all cognitive data and ratings of each domain generated by an algorithm (Ben- nett, Schneider, et al., 2006; Wilson, Boyle, Yang, James, & Bennett, 2015). Those with impairment in any cognitive domain at baseline were excluded from analyses.

To accommodate a wide range of cognitive ability and thereby minimize floor and ceiling artifacts, we analyzed change in cog- nitive function over time with a composite measure of global cognition based on all 17 tests. Raw scores on the individual tests of cognitive function were converted to z scores, using the baseline means and standard deviations of all persons in the parent studies. The z scores were then averaged to create a composite measure of global cognition, as previously described (Wilson, Beckett, et al., 2002; Wilson, Boyle, et al., 2015).

Neuropathologic Examination

Persons died a mean of 0.8 year after the last clinical assessment (SD � 1.0) and the brain was removed a mean of 8.6 hr following death (SD � 7.0). As previously detailed (Bennett, Schneider, Wilson, Bienias, & Arnold, 2004; Bennett et al., 2006), tissue preservation and sectioning and quantification of pathologic data followed a standard protocol that was implemented by individuals who were unaware of all clinical information. One-cm slabs were cut from the cerebral hemispheres (coronally) and cerebellar hemi- spheres (sagitally) and the brainstem was removed at the level of the mamillary bodies and bisected midpons.

All slabs were inspected for gross infarcts. We fixed slabs from one cerebral and cerebellar hemisphere and slabs from the other hemisphere with suspected infarcts in 4% paraformaldehyde. We histologically confirmed suspected infarcts and classified them as acute, subacute, or chronic. In nine regions (six cortical, two subcortical, one brainstem) of one hemisphere, we used 6-um paraffin-embedded hematoxylin and eosin stained sections to iden- tify microscopic infarcts. Chronic gross and microscopic infarcts were each treated as binary variables in analyses.

We used immunohistochemistry and computer-assisted sam- pling to assess beta-amyloid plaques and tau-tangles in eight brain

regions: anterior cingulate cortex, entorhinal cortex, CA1/subicu- lum, dorsal lateral prefrontal cortex, superior frontal cortex, infe- rior parietal cortex, inferior temporal cortex, and primary visual cortex (Bennett et al., 2004). Beta-amyloid was labeled with an N-terminus-directed monoclonal antibody (1:1,000, 10D5; Elan Pharmaceuticals, Dublin, Ireland), and tau-immunoreactive tangles were quantified with an antipaired helical filament-tau antibody clone AT8 (1:2,000; Thermo Scientific, Rockford, IL). The re- gional values were averaged to form continuous composite mea- sures of beta-amyloid burden (with a square root transformation) and tau-tangle density, as previously described (Bennett et al., 2004).

A monoclonal antibody to phosphorylated alpha-synuclein (1: 20,000; Wako Chemical U.S.A. Inc., Richmond, VA) was used to identify Lewy bodies in six regions: substantia nigra, entorhinal cortex, anterior cingulate cortex, inferior parietal cortex, midfron- tal cortex, and superior or middle temporal cortex (Wilson et al., 2011). Hippocampal sclerosis was defined as severe neuronal loss in the pyramidal cell layer of the subiculum or any hippocampal subfield (Wilson, Yu et al., 2013).

Statistical Analysis

In the full cohort, we assessed the relation of each depression measure to likelihood of developing incident dementia in logistic regression models and to rate of global cognitive decline in mixed- effects models. These and all subsequent analyses were adjusted for age, gender, and education. We assessed the relation of the postmortem pathologic measures to the depression measures in logistic regression models. Logistic regression models were also used to test whether dementia or antidepressant medication use modified the association between the pathologic markers and depression measures.

Results

Depression

In the full cohort (n � 1,965), there were 184 (9.4%) persons who were diagnosed with major depression at some point during the study and 169 (8.6%) persons who had a mean of three or more depressive symptoms on the Center for Epidemiological Studies Depression Scale during the study. The two measures were corre- lated, with 76 individuals meeting both definitions, 1,686 meeting neither definition, 108 with major depression but not chronically elevated depressive symptoms, 93 with elevated depressive symp- toms but not major depression, and two missing data on depressive symptoms, �2(1) � 275.8, p � .001. As shown in Table 1, those with depression by either definition had less education and a lower baseline level of global cognition than those without depression and were more likely to be women. In support of their validity, both measures were associated with antidepressant medication use (see Table 1).

Depression and Dementia

Because binary indicators of depression have been related to cognitive outcomes in previous research (Byers & Yaffe, 2011; Jorm, 2001; Ownby et al., 2006), the first analytic aim was to

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137DEPRESSION AND DEMENTIA-RELATED PATHOLOGY

assess whether the depression measures were related to cognitive outcomes as further test of their validity. During a mean of 8.0 years of follow-up (SD � 5.0), 346 individuals developed incident dementia, and we constructed separate logistic regression models to test whether the depression measures were related to likelihood of incident dementia. These and all subsequent analyses were adjusted for the potentially confounding effects of age, gender, and educational attainment. Both major depression and elevated de- pressive symptoms during the study were associated with higher likelihood of developing dementia (see Table 2).

At baseline, the composite measure of global cognition ranged from �1.49 to 1.49 (M � 0.26, SD � 0.43 skewness � �0.30), with higher scores indicating better cognitive functioning. We constructed mixed-effects models (Laird & Ware, 1982) to test whether the depression measures were related to trajectories of global cognitive decline. As shown in Table 2, both depression measures were associated with lower level of cognitive function at baseline and faster rate of cognitive decline during follow-up.

Dementia-Related Pathology

A total of 657 individuals died and underwent a brain autopsy and uniform neuropathologic examination. The composite measure of tau tangle density ranged from 0.0 to 32.2 (M � 4.6, SD � 5.3) with at least some level of tau present in 656 persons (99.9%). Because of its skewed distribution, we used the square root of the composite measure of beta-amyloid burden. At least some amyloid was detected in 565 persons (86.0%; M � 1.5, SD � 1.2, range � 0.0 –4.7). There were Lewy bodies in 22.1%, hippocampal sclero- sis in 6.2%, one or more chronic gross infarcts in 31.4%, and one or more chronic microscopic infarcts in 28.3%. There was some postmortem evidence of dementia-related pathology in all individ- uals: 41 persons (6.2%) had one postmortem marker, 259 (39.4%)

had two markers, 219 (33.3%) had three markers, 109 (10.6%) had four markers, 27 (4.1%) had five markers, and two (0.3%) had all six markers.

Depression and Pathology

In the neuropathologically examined group, 72 individuals (11.0%) met criteria for major depression at some point during the study and 74 (11.3%) had chronically elevated depressive symp- toms on the Center for Epidemiological Studies Depression Scale. There were 33 individuals who met both definitions of depression, 544 who met neither, 39 with major depression but not persistently elevated depressive symptoms, and 41 with elevated depressive symptom but not major depression, �2(1) � 96.7, p � .001.

To test whether dementia-related pathology was associated with depression, we regressed each depression measure on the 6 patho- logic markers in separate logistic models adjusted for age at death, gender, and education (see Table 3). Higher beta-amyloid plaque burden was associated with higher odds of major depression but not with elevated depressive symptoms. The other pathologic markers were not related to either depression measure.

Modifying Factors

Because previous research has suggested that the association of neuropathologic markers to depression might depend on the pres- ence or absence of dementia (Rapp et al., 2006, 2008; Tsopelas et al., 2011), we tested whether dementia modified the association of each pathological measure with each depression measure (see Table 4). There was no evidence that the relation of pathology to depression differed in those with versus without dementia.

There is evidence in animal research that the deleterious effects of chronic stress on the brain are modified by antidepressant

Table 1 Characteristics of Persons in the Full Cohort With and Without Depression by Diagnostic and Psychometric Definitions

Major depression Elevated depressive symptoms

Characteristic Yes (n � 184) No (n � 1,781) p Yes (n � 169) No (n � 1,794) p

Age, baseline 75.8 (7.3) 76.4 (7.5) 0.293 77.8 (7.1) 76.2 (7.5) 0.006 Education 14.9 (4.4) 16.3 (3.6) �.001 14.5 (4.1) 16.3 (3.7) �.001 Women, % 81.1 73.1 0.018 82.8 73.0 0.005 Antidepressant use, % 53.5 25.5 �.001 56.2 25.5 �.001 Global cognition, baseline 0.085 (0.455) 0.282 (0.427) �.001 0.068 (0.494) 0.282 (0.423) �.001

Note. Data are presented as M (SD) unless otherwise indicated. Two participants were missing data on depressive symptoms.

Table 2 Association of Depression With Incident Dementia and Cognitive Decline in the Full Cohort

Depression measure Cognitive outcome OR 95% CI Estimate SE p

Major depression Dementia 2.358 1.641, 3.388 Cognitive intercept �0.134 0.030 �.001 Cognitive slope �0.026 0.007 �.001

Elevated depressive symptoms Dementia 1.975 1.356, 2.874 Cognitive intercept �0.141 0.033 �.001 Cognitive slope �0.039 0.009 �.001

Note. Estimated from logistic and mixed-effects models adjusted for age at baseline, gender, and education. CI � confidence interval; OR � odds ratio; SE � standard error.

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138 WILSON ET AL.

medication (Czéh et al., 2001; Shakesby, Anwyl, & Rowan, 2002). Therefore, we tested whether the associations of the pathologic measures with depression were modified by use of antidepressant medications during the study. There was no evidence that antide- pressant medication use affected results.

Discussion

In a longitudinal clinical-pathologic study of more than 650 older persons without cognitive impairment at enrollment, we defined depression as major depression or elevated depressive symptoms during the study. Following brain autopsy, there was a uniform neuropathologic examination to quantify common dementia-related pathologies. None of the postmortem patho- logic markers was related to depression except for an associa- tion of beta-amyloid burden with major depression but not elevated depressive symptoms. Overall, the results do not sup- port the hypothesis that major depression is related to the neurodegenerative or cerebrovascular conditions underlying late-life dementia.

Evidence of an association between depression and dementia- related pathology comes mainly from 2 studies of prevalent de- mentia. In one of these, a history of major depression was asso- ciated with higher levels of hippocampal plaques and tangles (Rapp et al., 2006). In the other study, a diagnosis of depression was associated with higher burden of tangles but not plaques (Rapp et al., 2008). In both of these studies, however, the presence of dementia greatly complicates the diagnosis of depression be- cause self-report is less accurate due to impaired memory (Gilley & Wilson, 1997) and informant report is potentially biased due to

comorbid dementia. As a result, depressive symptoms are more difficult to disentangle from the dementia syndrome, and because of this criterion contamination, depressive symptoms may be more likely to show a spurious correlation with dementia-related pathol- ogy, particularly when other factors may be contributing to error in clinical classification of depression such as reliance on retrospec- tive report (Rapp et al., 2006) or use of depression diagnostic criteria that are insufficiently specified (Rapp et al., 2008). To avoid this potential source of bias, one clinical-pathologic study of late-life depression and AD pathology excluded individuals with dementia (Tsopelas et al., 2011). There was no association of semiquantitative ratings of plaques and tangles with late-life de- pression, but it is possible that excluding those with dementia affected results by restricting the range of AD pathology observed on postmortem examination. The present study confronted this issue in two ways. First, participants had no cognitive impairment at baseline and all dementia was incident, so that most of depres- sion data collection was from individuals without dementia. Sec- ond, we explicitly tested whether incident dementia modified the association between depression and the pathologic markers, and we found no evidence that it did. We suggest, therefore, that the lack of an association between major depression and dementia- related pathology in the present study, and the previous study that excluded dementia (Tsopelas et al., 2011), is probably substan- tially correct.

A challenge in clinical-pathologic research on late-life depres- sion is the potentially confounding influence of antidepressant medications. That is, antidepressant medication use might alter the impact of chronic depression on the brain (Czéh et al., 2001; Shakesby et al., 2002) or by reducing depressive symptoms, anti- depressant medication use might obscure an association between depression and pathologic markers. In the present analyses, how- ever, we found no evidence that antidepressant medication use modified the association between depression and the neuropatho- logic markers.

Major depression (Byers & Yaffe, 2011; Jorm, 2001; Ownby et al., 2006) and higher level of depressive symptoms (Barnes et al., 2012; Saczynski et al., 2010; Wilson, Barnes, et al., 2002) are each associated with higher risk of dementia, but neither major depres- sion in the present analyses nor level of depressive symptoms in previous analyses (Wilson et al., 2014) were related to postmortem markers of AD and other late-life dementias. This suggests that depression, whether defined diagnostically or psychometrically, somehow reduces cognitive reserve and that effective treatment of depression may bolster cognitive reserve. Previous clinical-

Table 3 Association of Dementia-Related Pathologies With Depression

Major depression Elevated depressive

symptoms

Pathologic marker OR 95% CI OR 95% CI

Tangle density 0.994 0.942, 1.047 0.987 0.933, 1.043 Amyloid plaques 1.392 1.088, 1.780 0.919 0.726, 1.165 Lewy bodies 1.344 0.735, 2.455 1.350 0.767, 2.377 Hippocampal sclerosis 0.758 0.220, 2.609 0.482 0.112, 2.081 Gross infarcts 1.218 0.686, 2.164 1.228 0.721, 2.092 Microinfarcts 1.108 0.614, 2.002 1.183 0.687, 2.039

Note. Estimated from two logistic regression models adjusted for age at death, gender, and education. CI � confidence interval; OR � odds ratio.

Table 4 Assessment of Whether Dementia Modified the Association of Pathology With Depression

Major depression Elevated depressive symptoms

Interaction term Estimate SE p Estimate SE p

Tangle density � Dementia �0.001 0.049 0.981 �0.081 0.055 0.139 Amyloid plaques � Dementia �0.006 0.251 0.980 �0.088 0.242 0.716 Lewy bodies � Dementia 0.478 0.593 0.420 �0.693 0.574 0.227 Hippocampal sclerosis � Dementia �0.659 1.307 0.614 �1.184 1.485 0.425 Gross infarcts � Dementia 0.338 0.561 0.547 1.068 0.563 0.058 Microinfarcts � Dementia �1.158 0.622 0.063 �0.084 0.560 0.881

Note. Estimated from 12 logistic regression models adjusted for age at death, gender, and education. SE � standard error.

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139DEPRESSION AND DEMENTIA-RELATED PATHOLOGY

pathologic (Soetanto et al., 2010; Wilson, Nag et al., 2013) and clinical-radiologic (Dotson, Davatzikos, Kraut, & Resnick, 2009; Koolschijn, van Haren, Lensvelt-Mulders, Hulshoff Pol, & Kahn, 2009; Sexton et al., 2012; Sexton, Mackay, & Ebmeier, 2009) research has associated depression with fronto-subcortical and limbic circuits that support regulation of emotional states. In addition, resting state functional connectivity studies have iden- tified abnormalities in major depression involving in particular the default mode network, affective network, and cerebellum (L. Wang, Hermens, Hickie, & Lagopoulos, 2012; Zeng et al., 2012; Ma, Zeng, Shen, Liu & Hu, 2013), and these functional abnormalities have been associated with cognitive decline (Z. Wang et al., 2015). Better understanding of the neurobiological bases of the relationship between late-life depression and cog- nition might suggest novel approaches to enhancing late-life cognitive health.

These data have important strengths and limitations. Results were mostly consistent with diagnostic and psychometric measures of depression, suggesting that they are reliable. There were high rates of participation in clinical follow-up and brain autopsy, minimizing bias due to selective attrition. Dementia classification was based on a uniform clinical assessment and accepted criteria applied by an experienced clinician and neuropathologic assess- ment was based on a uniform examination of multiple brain regions, reducing measurement error. A limitation is that results are based on a selected group of participants and may not gener- alize to other groups of older persons. In addition, it is possible that pathological changes in brainstem aminergic nuclei could be con- tributing to late-life depression, but previous clinical-pathologic research in these (Wilson, Nag et al., 2013) and other (Hendrick- sen, Thomas, Ferrier, Ince, & O’Brien, 2004; Syed et al., 2005) cohorts does not support this idea. Finally, treating depression as a binary variable allowed us to focus on moderately severe depres- sion, but it limited statistical power, which may have affected results, particularly for less common pathologic conditions such as hippocampal sclerosis.

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Received December 9, 2014 Revision received March 2, 2015

Accepted May 20, 2015 �

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