depression is one of the most common health problems in the elderly , and non - major depression syndromes such as minor depression occur in 413% , dysthymia in 2% , and clinically significant symptoms of depression in 816% of patients , with major implications for quality of life , physical health , independent functioning , and costs . executive dysfunction is common in depressed elderly subjects , and depression is more prevalent among patients with alzheimer 's disease ( ad ) and other dementias than in non - demented elderly subjects ; furthermore , there is emerging evidence that mid - life depression is a risk factor for ad decades later . finally , in many studies , depression has been found to be a prodromal syndrome of early ad . psychosocial , genetic as well as brain changes probably contribute , and potential mechanisms include toxic stress , with the activation of the hypothalamic - pituitary - adrenal axis , hypercortisolaemia , inflammation , and hippocampus atrophy , monoaminergic changes , and cerebrovascular disease . there is evidence that ad pathology is a contributing factor to the development of depression in elderly subjects with and without ad , possibly associated with decreased serotonin , which is likely to be related to depression in ad   since serotonin influences the shifting in the processing of amyloid precursor protein towards amyloidogenic pathways . clinicopathological studies have reported more ad - type changes in ad patients with a previous history of depression compared to those without a history of depression . the same authors also reported increased tangle pathology in ad patients with comorbid depression compared to those without depression . recent studies using amyloid pet imaging have , to some extent , been consistent with these autopsy findings . however , autopsy studies of late - life depression without dementia have failed to find significantly more ad pathology in depressed compared to non - depressed elderly persons . thus , the association between depression and ad pathology is not clear . in cerebrospinal fluid ( csf ) , a characteristic pattern of metabolites of amyloid plaques [ low -amyloid 142 ( a42 ) ] and tau [ increased total tau ( t - tau ) and phosphorylated tau 181 ( p - tau ) ] has been consistently shown in patients with ad . however , the few studies that have explored whether ad - type changes in csf are associated with depression have not found associations with more severe depression in mild ad   or elderly non - demented women . taken together , there is inconsistent evidence regarding the role of ad - type pathological changes in depression . understanding the aetiology of depression in the elderly is important for diagnostic purposes as well as background information for the development of novel pharmacological strategies . we administered the cornell scale for depression in dementia ( csdd )   to 183 elderly subjects who had been referred to a memory clinic and diagnosed as having ad or subjective cognitive impairment [ sci ; i.e. normal cognitive functioning without a diagnosis of dementia or mild cognitive impairment ( mci ) ] , and measured csf levels of a42 , t - tau , and p - tau . the aim of this study was to test the hypothesis that ad - type changes , i.e. reduced a42 and increased t - tau and p - tau , are associated with depression in elderly subjects with and without ad . the base population for the study consisted of 1,154 referrals to the memory clinic at karolinska university hospital in huddinge , sweden , between 2007 and 2009 . inclusion criteria for the current project were : ( a ) age 60 years or older , ( b ) csdd administered , ( c ) lumbar puncture , and ( d ) diagnosis of ad or normal cognition ( i.e. sci ) . excluded were patients with : ( a ) physical disease significantly affecting cognitive performance , ( b ) life - threatening disease with expected reduced survival time , ( c ) mci , and ( d ) dementia due to diseases other than ad . all subjects signed informed consent prior to lumbar puncture , and the study was approved by the ethical committee at karolinska university hospital in huddinge ( 43/03 ) . participants underwent a medical examination and assessment of depression using the combined patient- and informant - based csdd , which has excellent psychometric properties in both demented and non - demented people . for this study , a cut - off score of > 6 was used to define depressed and non - depressed subjects , based on a validation study performed in denmark . the csdd was completed by a licensed geriatrician or psychiatrist , or a research nurse . for the dementia diagnosis , a standardized informant - based scale of the patients history of cognitive decline ( informant questionnaire on cognitive decline in the elderly )   was administered , and dementia was staged using global deterioration scales after a clinical medical examination including cognitive screening with the mini - mental state examination ( mmse ) . to aid in the diagnostic process , the majority of subjects completed a neuropsychological examination : tests of verbal abilities ( similarities and information ) , visuospatial abilities ( block design and rey - osterrieth copying ) , working memory ( digit span and corsi span ) , episodic memory ( learning and retention after 30 min , rey auditory learning test ) , and executive functioning ( digit symbol and trail making test ) . patients were diagnosed as having ad using icd 10 criteria after a consensus meeting with clinicians and neuropsychologists , taking into account all available information . in addition to the clinical assessment , brain imaging mri or ct according to a dementia protocol , routine blood tests , and csf analyses were performed ; furthermore , eeg was performed in a large subgroup . csf was obtained by lumbar puncture between the l3/l4 or l4/l5 intervertebral space using a 25-gauge needle and collected in 12-ml polypropylene tubes . within 2 h a small amount of csf was used for routine analysis , including total cells ( leucocytes and erythrocytes ) , total protein , and glucose . csf was aliquoted in polypropylene tubes of 0.5 or 1 ml and stored at 80c until further analysis . csf a42 , t - tau , and p - tau were measured by commercially available sandwich elisas ( innogenetics , ghent , belgium ) . we divided the subjects into four groups based on the presence or absence of depression in ad and sci . for the descriptive statistics presented in table 1 a  test and a pre - planned post hoc analysis have been used . the csf values were compared using simple logistic regression comparing depressed and non - depressed subjects with and without ad in two separate analyses . in addition , spearman 's correlation analyses were performed between the csdd score and each of the three csf measures in the total group and in the ad and sci groups separately . ordered logistic regression was used to analyze the association between csf measures and depression scores using the entire csdd scale . two models were used , adjusting for age and sex ( model 1 ) and age , sex , and mmse score ( model 2 ) . the base population for the study consisted of 1,154 referrals to the memory clinic at karolinska university hospital in huddinge , sweden , between 2007 and 2009 . inclusion criteria for the current project were : ( a ) age 60 years or older , ( b ) csdd administered , ( c ) lumbar puncture , and ( d ) diagnosis of ad or normal cognition ( i.e. sci ) . excluded were patients with : ( a ) physical disease significantly affecting cognitive performance , ( b ) life - threatening disease with expected reduced survival time , ( c ) mci , and ( d ) dementia due to diseases other than ad . all subjects signed informed consent prior to lumbar puncture , and the study was approved by the ethical committee at karolinska university hospital in huddinge ( 43/03 ) . participants underwent a medical examination and assessment of depression using the combined patient- and informant - based csdd , which has excellent psychometric properties in both demented and non - demented people . for this study , a cut - off score of > 6 was used to define depressed and non - depressed subjects , based on a validation study performed in denmark . the csdd was completed by a licensed geriatrician or psychiatrist , or a research nurse . for the dementia diagnosis , a standardized informant - based scale of the patients history of cognitive decline ( informant questionnaire on cognitive decline in the elderly )   was administered , and dementia was staged using global deterioration scales after a clinical medical examination including cognitive screening with the mini - mental state examination ( mmse ) . to aid in the diagnostic process , the majority of subjects completed a neuropsychological examination : tests of verbal abilities ( similarities and information ) , visuospatial abilities ( block design and rey - osterrieth copying ) , working memory ( digit span and corsi span ) , episodic memory ( learning and retention after 30 min , rey auditory learning test ) , and executive functioning ( digit symbol and trail making test ) . patients were diagnosed as having ad using icd 10 criteria after a consensus meeting with clinicians and neuropsychologists , taking into account all available information . in addition to the clinical assessment , brain imaging mri or ct according to a dementia protocol , routine blood tests , and csf analyses were performed ; furthermore , eeg was performed in a large subgroup . csf was obtained by lumbar puncture between the l3/l4 or l4/l5 intervertebral space using a 25-gauge needle and collected in 12-ml polypropylene tubes . within 2 h a small amount of csf was used for routine analysis , including total cells ( leucocytes and erythrocytes ) , total protein , and glucose . csf was aliquoted in polypropylene tubes of 0.5 or 1 ml and stored at 80c until further analysis . csf a42 , t - tau , and p - tau were measured by commercially available sandwich elisas ( innogenetics , ghent , belgium ) . we divided the subjects into four groups based on the presence or absence of depression in ad and sci . for the descriptive statistics presented in table 1 a  test and a pre - planned post hoc analysis have been used . the csf values were compared using simple logistic regression comparing depressed and non - depressed subjects with and without ad in two separate analyses . in addition , spearman 's correlation analyses were performed between the csdd score and each of the three csf measures in the total group and in the ad and sci groups separately . ordered logistic regression was used to analyze the association between csf measures and depression scores using the entire csdd scale . two models were used , adjusting for age and sex ( model 1 ) and age , sex , and mmse score ( model 2 ) . age , mmse score , and csdd score , but not gender , differed significantly between the groups . the pre - planned post hoc analyses showed that in ad and sci , the only significant difference was in the non - demented group , with a lower age in the depressed compared to the non - depressed subjects ( table 1 ) . the median values of the three csf measures in the four groups are shown in table 2 and figures 1 , 2 , 3 . as expected , in the ad groups , t - tau and p - tau were higher and a42 lower than in the non - ad groups ( all p values < 0.001 ) . t - tau differed significantly between ad patients with and without depression , with the depressed patients having lower values than the non - depressed ad patients , whereas p - tau and a42 did not differ significantly . in the sci group , both t - tau and p - tau were significantly lower in the depressed compared to the non - depressed group , whereas a42 did not differ significantly . the correlation analyses were consistent with the above - mentioned findings . in the total group , bivariate correlations showed a significant negative correlation between the csdd score and p - tau ( spearman 's  = 0.21 , p = 0.004 ) as well as t - tau (  = 0.25 , p = 0.001 ) , but not with a42 ( p = 0.25 ) . in the ad group , there was a trend towards a correlation between the csdd score and t - tau (  = 0.21 , p = 0.05 ) , whereas no significant correlations between the csdd score and csf measures were found in the sci group . the ordered regression analyses , adjusting for age and sex ( model 1 ) and for age , sex , and mmse score ( model 2 ) , showed similar findings ( table 3 ) . interpretations from model 2 show that for each 10-pg / l increase in p - tau , the odds for having more depressive symptoms decreases by 8% , and for each 100-pg / l increase in t - tau , the odds for having more depressive symptoms decreases by 15% ( p = 0.008 ) . the median values of the three csf measures in the four groups are shown in table 2 and figures 1 , 2 , 3 . as expected , in the ad groups , t - tau and p - tau were higher and a42 lower than in the non - ad groups ( all p values < 0.001 ) . t - tau differed significantly between ad patients with and without depression , with the depressed patients having lower values than the non - depressed ad patients , whereas p - tau and a42 did not differ significantly . in the sci group , both t - tau and p - tau were significantly lower in the depressed compared to the non - depressed group , whereas a42 did not differ significantly . the correlation analyses were consistent with the above - mentioned findings . in the total group , bivariate correlations showed a significant negative correlation between the csdd score and p - tau ( spearman 's  = 0.21 , p = 0.004 ) as well as t - tau (  = 0.25 , p = 0.001 ) , but not with a42 ( p = 0.25 ) . in the ad group , there was a trend towards a correlation between the csdd score and t - tau (  = 0.21 , p = 0.05 ) , whereas no significant correlations between the csdd score and csf measures were found in the sci group . the ordered regression analyses , adjusting for age and sex ( model 1 ) and for age , sex , and mmse score ( model 2 ) , showed similar findings ( table 3 ) . interpretations from model 2 show that for each 10-pg / l increase in p - tau , the odds for having more depressive symptoms decreases by 8% , and for each 100-pg / l increase in t - tau , the odds for having more depressive symptoms decreases by 15% ( p = 0.008 ) . in this study , analysis of the three different csf measures a42 , t - tau , and p - tau did not support the hypothesis that more severe ad pathologies such as amyloid plaques or tau pathologies are associated with more severe depression . in contrast , depressed patients tended to have lower p - tau levels and , in particular , lower t - tau levels than those without depression , indicating less tau pathology and neurodegeneration . these findings were found both in patients with a clinical diagnosis of ad and in subjects without dementia , using either continuous data or categories based on cut - off scores for the csdd and reference norms for csf values , and also after adjusting for potential confounders . one study reported on a population - based sample of 81 elderly women , 11 with major depression . a42 concentrations were higher among those with major depression compared to non - depressed women , whereas t - tau levels did not differ between the groups . p - tau was not measured in that study . in another study of patients with mild ad , apathy was associated with higher p - tau levels , but no associations between csf a42 , t - tau , or p - tau levels and the neuropsychiatric inventory depression item were found . thus , the current findings are consistent with previous csf studies suggesting that ad pathology does not contribute to depression in elderly subjects with or without ad . one previous clinicopathologic study reported more severe tau pathology in ad patients with comorbid depression compared to ad patients without depression . thus , it is possible that depression later in the disease course is more closely related to the underlying pathology , whereas other factors are more important in the earlier stages . however , the effect of depression on neurofibrillary tangle occurrence was rather small , and the interval between depression diagnosis at study inclusion and death was nearly 10 years . in another autopsy study , ad was the most frequent pathology , in particular among the 7 patients who developed dementia , but lewy body pathology and stroke were also common . although the study shows that ad and other pathologies probably contribute to dementia in patients with late - onset major depression , whether these pathologies are related to the symptoms of depression was not reported . finally , in a recent population - based clinicopathologic study of subjects who did not develop dementia during life , no association between ad - type changes and depression could be observed . in one such study , patients with remitted depression underwent detailed neuropsychological assessment and pittsburgh compound b ( pib ) imaging . two subjects with normal cognition showed pib retention in the normal range . in 3 of 6 patients with mci , the pib retention fell in the range of ad . however , associations between depression and pib binding were not reported , and thus it is unclear whether the increased binding was related to cognitive impairment as a prodrome of ad or to the remitted depression . in another pet study of non - demented subjects , a marker of amyloid plaques and neurofibrillary tangles was found to correlate with a self - report measure of depressive symptoms in both cognitively normal and mci subjects . methodological limitations of the current study include the cross - sectional design ; therefore , assumptions regarding causality can not be made . the study sample was selected from referrals to a university memory clinic , and thus generalizations to the population are not possible . in particular , the non - ad group consisted of sci subjects , with an increased proportion having an ad - type csf profile , and hence extrapolation to non - demented depressed elderly persons is difficult . the diagnosis of ad was clinical , and thus there is a possibility of misdiagnosis . however , the lack of association between ad markers and depression was independent of ad diagnosis ; therefore , inaccurate diagnosis is an unlikely explanation . our csf analyses did not support the hypothesis that depression is associated with more ad pathology , neither in subjects with ad nor in subjects without ad , suggesting that other factors are more important contributors to depression in the elderly . future studies should explore the role of potential aetiological factors for depression in the elderly , such as neuroinflammation and cerebrovascular disease as well as psychosocial factors . dr . aarsland serves on the scientific advisory board for diagenic ; he has received honoraria from lundbeck , novartis , diagenic , gsk , and ge health and research support from novartis , merck serono , and lundbeck .
backgroundthe aim of this study was to explore the relationship between cerebrospinal fluid alzheimer 's disease ( ad ) markers and depression in elderly people.methodwe included subjects with ad as well as persons with subjective cognitive impairment and normal cognition . 
 depression was assessed with the cornell scale for depression in dementia , and a cut - off score of > 6 was used to define depression . 
 cerebrospinal fluid was analyzed using commercially available assays for -amyloid 142 , total tau , and phosphorylated tau 181.resultsa total of 183 participants ( 66.7% female ) were included ( 92 with ad and 91 with subjective cognitive impairment ) , with a mean age ( sd ) of 67.6  7.4 years , a mini - mental state examination score of 26.0  4.0 , and a median cornell scale for depression in dementia score of 5 ( range 019 ) . 
 depression scores were not associated with higher phosphorylated tau 181 and total tau or reduced -amyloid 142 in ad or non - demented subjects.conclusionsthese results suggest that ad pathology does not contribute to depression , indicating that other factors may be more important . 
 further studies of the aetiology of depression in elderly people with and without ad are warranted .