Acta Psychiatr Scand 2014: 1–7 All rights reserved DOI: 10.1111/acps.12328
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA PSYCHIATRICA SCANDINAVICA
Incident subjective memory complaints and the risk of subsequent dementia Luck T, Luppa M, Matschinger H, Jessen F, Angermeyer MC, Riedel-Heller SG. Incident subjective memory complaints and the risk of subsequent dementia. Objective: In this study, we aimed to analyze the association between new—incident—subjective memory complaints (SMC) and risk of subsequent dementia in a general population sample aged 75+ years. Method: Data were derived from follow-up (FUP) waves I-V of the population-based Leipzig Longitudinal Study of the Aged (LEILA75+). We used the Kaplan–Meier survival method to estimate dementia-free survival times of individuals with and without incident SMC and multivariable Cox proportional hazards regression to assess the association between incident SMC and risk of subsequent dementia, controlled for covariates. Results: Of 443 non-demented individuals, 58 (13.1%) developed dementia during a subsequent 5.4-year follow-up period. Participants with incident SMC showed a significantly higher progression to dementia (18.5% vs. 10.0%; P = 0.010) and a significantly shorter mean dementia-free survival time than those without (6.2 vs. 6.8 years; P = 0.008). The association between incident SMC and risk of subsequent dementia remained significant in the multivariable Cox analysis (adjusted hazard ratio = 1.8; P = 0.028). Conclusion: Our findings suggest higher progression to dementia and shorter dementia-free survival in older individuals with incident SMC. These findings support the notion that such subjective complaints should be taken seriously in clinical practice as possible early indicators of incipient dementia.
T. Luck1,2, M. Luppa1,
H. Matschinger1, F. Jessen3,4, M. C. Angermeyer5,6, S. G. Riedel-Heller1 1 Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, 2LIFE - Leipzig Research Center for Civilization Diseases, University of Leipzig, 3Department of Psychiatry, University of Bonn, 4 German Center for Neurodegenerative Diseases, DZNE, Bonn, Germany, 5Center for Public Mental Health, G€osing a. W., Austria and 6Department of Public Health, University of Cagliary, Italy
Key words: dementia; outcome; old-age; epidemiology; early intervention Tobias Luck, Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Philipp-Rosenthal-Str. 55, D—04103 Leipzig, Germany. E-mail: [email protected]
Accepted for publication August 5, 2014
Significant outcomes
• New—incident—subjective memory complaints in individuals aged 75 years and older were associ• •
ated with a significantly increased risk of progression to dementia and a significantly shorter dementia-free survival. These findings support the notion that such subjective complaints should be taken seriously in clinical practice as possible early indicators of incipient dementia. A periodic screening for new subjective memory complaints in primary care as well as a close monitoring of the cognitive performance in those with such complaints might then help to improve early detection of dementia.
Limitations
• Generalizability of our results may be limited because a significant number of individuals invited to •
participate in the study refused participation, were shielded by their relatives, could not be located, or had to be excluded from analysis because of missing information. Subjective memory complaints were measured only by a simple question. Using a more comprehensive assessment covering additional important information on the subjective perceived memory impairment might have had strengthen the association between incident SMC and the risk of subsequent dementia we found. 1
Luck et al. Introduction
Material and methods
Findings from an increasing number of prospective studies demonstrate that subjective memory complaints (SMC) can be an early indicator for the development of clinically manifest dementia in older age (e.g., 1–9). Such findings, however, also show that the predictive value of SMC for subsequent dementia and Alzheimer’s disease dementia (AD) can be dependent on several factors: Treves et al. (6), for example, have found that particularly those individuals with SMC have an increased risk of developing dementia, which have a lower cognitive status at entry as well as an older age at onset and a shorter duration of the memory complaints. Other findings suggest that SMC are predictive for incident dementia or AD especially in women (5), in older individuals with a high level of education, and/or in whom objective cognitive impairments are not yet apparent (1, 7). Also, it could be observed that SMC are particularly predictive for dementia and AD, when they are accompanied by a sense of concern (e.g., 2–4). Another important factor that may also affect findings on an association between SMC and risk of subsequent dementia is the time when SMC are diagnosed: Previous findings from prospective studies usually rely on prevalent SMC cases with rather unclear onset of the complaints. A common approach in such studies with prevalent cases is to assess the onset of the subjective cognitive complaints retrospectively. This approach, however, may be associated with some inaccuracy as there is a high chance of recall bias particularly in those who are already afflicted with cognitive impairment. An alternative approach is to assess the association between SMC and risk of subsequent dementia based on incident SMC cases. Under the hypothesis that SMC are the very first perceived symptoms of a potential dementia process, this approach may allow for more precise statements concerning the course of such a dementia process.
Sample
Aims of the study
In this study, we therefore sought to particularly analyze the association between incident subjective memory complaints and risk of subsequent dementia. We provide data based on a population-based sample of elderly aged 75 years and older. 2
We studied participants in the Leipzig Longitudinal Study of the Aged (LEILA75+), a populationbased study on the epidemiology of dementia and cognitive impairment. Overall, a total of 1692 individuals aged 75 years and older and residing in the Leipzig-South district were initially selected for study participation. Of these, 1500 communitydwelling ones were identified by systematic random sampling from an age-ordered list provided by the local registry office. Another 192 institutionalized individuals were included by proportion by systematic random sampling from age-ordered lists of the four institutions in the study area. All participants provided written informed consent to participate in the study. The study protocol was approved by the local ethics committee. Also, the authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. The whole study design of the LEILA75+ has been described in detail elsewhere (10). The study covered a period of 8 years, including a baseline (1997/01–1998/6) and five follow-up assessments (1998/07–2005/04), on average every 1.4 years. Among the initially selected sample of 1692 individuals, 1265 (74.6%) participated in the study. The remaining individuals refused participation (n = 242; 14.2%), had died before participation (n = 57; 3.4%), could not be located (n = 15; 0.9%), or were shielded by their relatives (n = 113; 6.7%). The respondents of the study did not differ from the non-respondents in terms of age (Mann– Whitney U = 263553.000, P = 0.455) or gender (v² = 0.391, df = 1, P = 0.532). Baseline assessments subsequently showed that 220 respondents had dementia according to DSMIV criteria (11). Another 359 participants had prevalent SMC or missing information on SMC status, leaving an analysis pool of 686 individuals (see Fig. 1). Among these individuals, 504 also participated in follow-up wave I. Follow-up I assessments showed that 28 of these participants had incident dementia. Another 33 participants had missing information on SMC status at followup I or were lost to the subsequent follow-up waves without any information regarding dementia status, leaving a final pool of 443 individuals for the analysis of incident SMC and the risk of subsequent dementia (see Fig. 1).
Incident memory complaints and risk of dementia
BL
TOTAL SAMPLE AT BASELINE n = 1692
Non-participants (BL)
PARTICIPANTS AT BASELINE
Refused Only proxy interviews Deceased Not located
n = 1265
INCLUSION FOR ANALYSIS
n = 242 n = 113 n = 57 n = 15
Exclusion from analysis (BL) Dementia n = 220 SMC n = 352 No information on SMC n = 7
n = 686 Non-participants (FUP)
FUP I
PARTICIPANTS AT FUP I n = 504
Refused Only proxy interviews Deceased Not located Other reasons
n = 50 n = 50 n = 75 n=6 n=1
Exclusion from analysis (FUP) INCLUSION FOR ANALYSIS OF INCIDENT SMC AND RISK OF SUBSEQUENT DEMENTIA n = 443
Dementia n = 28 No information on SMC n = 2 No information on dementia status after Follow-up I n = 31 No dementia detected at FUP waves II-V
INCIDENT DEMENTIA CASES DETECTED AT FUP WAVES II-V n = 58 FUP V
Fig. 1. Sample attrition and sample.
Data collection and assessment procedures
Structured clinical interviews at baseline and subsequent follow-up were conducted in participants’ homes by trained psychologists and physicians. In addition, structured third-party interviews were conducted with proxies. The main assessment instrument was the Structured Interview for Diagnosis of Dementia of Alzheimer type, Multi-infarct Dementia and Dementia of other Aetiology according to DSMIII-R, DSM-IV, and ICD-10 (SIDAM) (12, 13). The SIDAM includes a cognitive test battery, a third-party rating of psychosocial impairment with a 14-item scale of activities of daily living (SIDAM-ADL scale) and also a summary clinical diagnostic impression. The 55-item cognitive test battery includes the 30 items of the Mini-Mental State Examination (MMSE) (14). Overall, the test battery covers four domains of cognitive functioning: orientation, memory, intellectual abilities, and higher cortical functioning. We applied age- and education-specific norms for the cognitive domains to evaluate cognitive impairment (15).
Observed to end of follow-up period Died before end of follow-up period Refused or otherwise unable to complete follow-up
n = 204 n = 108
n = 73
BL, baseline; FUP, follow-up; SMC, subjective memory complaints
If it was not possible to administer the SIDAM (e.g., because of death or severe weakness of the participants), a comprehensive structured proxy interview was offered. This included the Clinical Dementia Rating scale [CDR, (16)]. Subjective memory complaints (SMC) were evaluated prior to cognitive testing by asking the participant: ‘Do you have problems with your memory?’ or—in case of the comprehensive structured proxy interview—by asking the proxy: ‘Does he/she has problems with his/her memory?’. We identified depressive symptoms using the German version of the 20-item Center of Epidemiologic Studies Depression Scale [CES-D, (17, 18)]. A standardized interview provided information on sociodemographic and other characteristics. Dates of death were obtained from relatives or from the official registry office. Diagnosis of dementia
Baseline and follow-up dementia status was agreed at consensus conferences that included physicians and psychologists. A clinical dementia diagnosis 3
Luck et al. was made according to DSM-IV criteria (11). The cognitive criteria were based either on results of the SIDAM cognitive test battery (12) or—if SIDAM test results were not available and only proxy interviews were conducted—on CDR data (16). Statistical analysis
The statistical analyses were performed using Predictive Analytics Software (PASW), version 20.0 (IBM Corp., Armonk, NY, USA) and STATA, version 13.1 (STATA Corp. College Station, TX, USA). All analyses employed an alpha level for statistical significance of 0.05 (two-tailed). Group differences were analyzed using Mann–Whitney U-test and chi-squared test as appropriate. We used the Kaplan–Meier survival method to estimate dementia-free survival times of the participants with and without incident SMC at follow-up I. As incident SMC could only be diagnosed at the times of assessment, we assigned SMC onset by convention at the midpoint between the time of the follow-up I assessment (when SMC was diagnosed) and the time of the previous baseline assessment. To compare dementia-free survival times of the participants with and without incident SMC, we set the starting time for those without incident SMC also at the midpoint between the times of the follow-up I and the baseline assessment. Moreover, as incident dementia could also only be diagnosed at the times of assessment, we also assigned dementia onset by convention at the midpoint between the time of the follow-up assessment when dementia was diagnosed and the time of the previous assessment. Kaplan– Meier survival method censored participants at the time of their last evaluation if they died or dropped out of the study without developing dementia, or if they had not developed dementia by the end of follow-up V. We used the log rank test to evaluate differences in the survival distributions of the subgroups with and without incident SMC. Finally, we used a multivariable Cox proportional hazards regression to assess the association of SMC status at follow-up I and risk of subsequent dementia, controlled for age, gender, education, and cognitive performance (MMSE-score) at follow-up I as covariates. For each variable included in the regression model, we calculated hazard ratios (HRs) and Wald 95% confidence intervals (CIs). Schoenfeld residuals were calculated to test the proportional hazards assumption of the Cox proportional hazards models. 4
Results Characteristics of the sample
A total of 443 participants that were dementia-free at follow-up I and had no SMC at baseline were included in the analyses (see Fig. 1). The mean age of the sample was 82.3 years (SD = 4.4); 327 (73.8%) of the participants were female. Incident SMC at follow-up I was found in 36.6% (n = 162) of the participants. Individuals with incident SMC showed a significantly lower MMSE performance at follow-up I than those without (mean score/ SD = 26.8/3.2 vs. 27.7/2.4, Mann–Whitney U = 19180.500, P = 0.005). Incident subjective memory complaints and the risk of subsequent dementia
Of the included sample of 443 dementia-free individuals at follow-up I, 58 (13.1%) developed dementia during the subsequent follow-up waves II–V (mean follow-up period = 5.4 years/ SD = 0.3 years). The mean dementia-free survival time of the study sample, as estimated by Kaplan– Meier survival analysis, was 6.6 years (95% CI 6.4–6.8). Individuals with incident SMC at follow-up I showed a significantly higher progression to dementia during the subsequent follow-up waves (n = 30/162 vs. n = 28/281; 18.5% vs. 10.0%, v² = 6.608, df = 1, P = 0.010) and a shorter dementia-free survival time than those without (mean = 6.2 years, 95% CI 5.9–6.5 vs. mean = 6.8 years, 95% CI 6.6–7.0; log rank: v² = 7.015, df = 1, P = 0.008; see Fig. 2). The association between incident SMC and risk of subsequent dementia also remained significant in multivariable Cox regression analysis with adjustment for covariates (adjusted HR = 1.8, 95% CI 1.1–3.1, P = 0.028; see Table 1). The proportional hazards assumption was met for all included variables (global test: v² = 9.09, df = 7, P = 0.246). Discussion
In this study, we sought to analyze the association between incident subjective memory complaints (SMC) and risk of subsequent dementia in a population-based sample of elderly (75+ years). Our findings indicate a significantly increased progression to dementia in individuals with incident SMC. These findings thus corroborate findings from previous studies based on prevalent SMC cases. The study of Waldorff et al. (8), for example, that followed a sample of general practitioners’ patients aged 65 years and older for
Incident memory complaints and risk of dementia
Cumulative dementia-free survival
1.0
Log rank test: X ² = 7.015 df = 1; P = 0.008
0.9
0.8
——— Individuals without incident SMC ——— Individuals with incident SMC
Fig. 2. Kaplan–Meier curves of dementia-free survival of individuals with and without incident subjective memory complaints (SMC).
0.7
+
0
Censored data
2
4
6
Time (years)
a period of 4 years found a more than two times higher risk of a subsequent dementia diagnosis in those with SMC at baseline (adjusted HR = 2.27 vs. 1.82 in our study). Also, the study of Wang et al. (9) that examined the association between subjective memory deterioration and future dementia (follow-up period of 5 years) in a community-based sample of cognitively unimpaired elderly (65+ years) reported HRs of developing dementia of 6.0, 3.2, and 1.6 for those participants who reported a subjective memory deterioration at the ages of 70, 75, and 80 years. Other studies particularly focussed on the association of SMC with future AD. The study of Geerlings et al. (1), for example, that followed a community-based sample of non-demented persons aged 65–84 years over an average follow-up period of 3.2 years observed an significantly increased risk of developing AD (adjusted odds ratio = 2.71) in individuals with SMC who had Table 1. Multivariable Cox proportional hazards regression of time to incident dementia (n = 443) Characteristics at FUPI
Wald
df
HR (95% CI)
P value
Age, every additional year Gender, female vs. male Education* Medium vs. low High vs. low Incident SMC, yes vs. no MMSE, every additional point CES-D, every additional point
28.186 7.202
1 1
1.17 (1.10–1.24) 5.01 (1.54–16.25)
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA PSYCHIATRICA SCANDINAVICA
Incident subjective memory complaints and the risk of subsequent dementia Luck T, Luppa M, Matschinger H, Jessen F, Angermeyer MC, Riedel-Heller SG. Incident subjective memory complaints and the risk of subsequent dementia. Objective: In this study, we aimed to analyze the association between new—incident—subjective memory complaints (SMC) and risk of subsequent dementia in a general population sample aged 75+ years. Method: Data were derived from follow-up (FUP) waves I-V of the population-based Leipzig Longitudinal Study of the Aged (LEILA75+). We used the Kaplan–Meier survival method to estimate dementia-free survival times of individuals with and without incident SMC and multivariable Cox proportional hazards regression to assess the association between incident SMC and risk of subsequent dementia, controlled for covariates. Results: Of 443 non-demented individuals, 58 (13.1%) developed dementia during a subsequent 5.4-year follow-up period. Participants with incident SMC showed a significantly higher progression to dementia (18.5% vs. 10.0%; P = 0.010) and a significantly shorter mean dementia-free survival time than those without (6.2 vs. 6.8 years; P = 0.008). The association between incident SMC and risk of subsequent dementia remained significant in the multivariable Cox analysis (adjusted hazard ratio = 1.8; P = 0.028). Conclusion: Our findings suggest higher progression to dementia and shorter dementia-free survival in older individuals with incident SMC. These findings support the notion that such subjective complaints should be taken seriously in clinical practice as possible early indicators of incipient dementia.
T. Luck1,2, M. Luppa1,
H. Matschinger1, F. Jessen3,4, M. C. Angermeyer5,6, S. G. Riedel-Heller1 1 Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, 2LIFE - Leipzig Research Center for Civilization Diseases, University of Leipzig, 3Department of Psychiatry, University of Bonn, 4 German Center for Neurodegenerative Diseases, DZNE, Bonn, Germany, 5Center for Public Mental Health, G€osing a. W., Austria and 6Department of Public Health, University of Cagliary, Italy
Key words: dementia; outcome; old-age; epidemiology; early intervention Tobias Luck, Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Philipp-Rosenthal-Str. 55, D—04103 Leipzig, Germany. E-mail: [email protected]
Accepted for publication August 5, 2014
Significant outcomes
• New—incident—subjective memory complaints in individuals aged 75 years and older were associ• •
ated with a significantly increased risk of progression to dementia and a significantly shorter dementia-free survival. These findings support the notion that such subjective complaints should be taken seriously in clinical practice as possible early indicators of incipient dementia. A periodic screening for new subjective memory complaints in primary care as well as a close monitoring of the cognitive performance in those with such complaints might then help to improve early detection of dementia.
Limitations
• Generalizability of our results may be limited because a significant number of individuals invited to •
participate in the study refused participation, were shielded by their relatives, could not be located, or had to be excluded from analysis because of missing information. Subjective memory complaints were measured only by a simple question. Using a more comprehensive assessment covering additional important information on the subjective perceived memory impairment might have had strengthen the association between incident SMC and the risk of subsequent dementia we found. 1
Luck et al. Introduction
Material and methods
Findings from an increasing number of prospective studies demonstrate that subjective memory complaints (SMC) can be an early indicator for the development of clinically manifest dementia in older age (e.g., 1–9). Such findings, however, also show that the predictive value of SMC for subsequent dementia and Alzheimer’s disease dementia (AD) can be dependent on several factors: Treves et al. (6), for example, have found that particularly those individuals with SMC have an increased risk of developing dementia, which have a lower cognitive status at entry as well as an older age at onset and a shorter duration of the memory complaints. Other findings suggest that SMC are predictive for incident dementia or AD especially in women (5), in older individuals with a high level of education, and/or in whom objective cognitive impairments are not yet apparent (1, 7). Also, it could be observed that SMC are particularly predictive for dementia and AD, when they are accompanied by a sense of concern (e.g., 2–4). Another important factor that may also affect findings on an association between SMC and risk of subsequent dementia is the time when SMC are diagnosed: Previous findings from prospective studies usually rely on prevalent SMC cases with rather unclear onset of the complaints. A common approach in such studies with prevalent cases is to assess the onset of the subjective cognitive complaints retrospectively. This approach, however, may be associated with some inaccuracy as there is a high chance of recall bias particularly in those who are already afflicted with cognitive impairment. An alternative approach is to assess the association between SMC and risk of subsequent dementia based on incident SMC cases. Under the hypothesis that SMC are the very first perceived symptoms of a potential dementia process, this approach may allow for more precise statements concerning the course of such a dementia process.
Sample
Aims of the study
In this study, we therefore sought to particularly analyze the association between incident subjective memory complaints and risk of subsequent dementia. We provide data based on a population-based sample of elderly aged 75 years and older. 2
We studied participants in the Leipzig Longitudinal Study of the Aged (LEILA75+), a populationbased study on the epidemiology of dementia and cognitive impairment. Overall, a total of 1692 individuals aged 75 years and older and residing in the Leipzig-South district were initially selected for study participation. Of these, 1500 communitydwelling ones were identified by systematic random sampling from an age-ordered list provided by the local registry office. Another 192 institutionalized individuals were included by proportion by systematic random sampling from age-ordered lists of the four institutions in the study area. All participants provided written informed consent to participate in the study. The study protocol was approved by the local ethics committee. Also, the authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. The whole study design of the LEILA75+ has been described in detail elsewhere (10). The study covered a period of 8 years, including a baseline (1997/01–1998/6) and five follow-up assessments (1998/07–2005/04), on average every 1.4 years. Among the initially selected sample of 1692 individuals, 1265 (74.6%) participated in the study. The remaining individuals refused participation (n = 242; 14.2%), had died before participation (n = 57; 3.4%), could not be located (n = 15; 0.9%), or were shielded by their relatives (n = 113; 6.7%). The respondents of the study did not differ from the non-respondents in terms of age (Mann– Whitney U = 263553.000, P = 0.455) or gender (v² = 0.391, df = 1, P = 0.532). Baseline assessments subsequently showed that 220 respondents had dementia according to DSMIV criteria (11). Another 359 participants had prevalent SMC or missing information on SMC status, leaving an analysis pool of 686 individuals (see Fig. 1). Among these individuals, 504 also participated in follow-up wave I. Follow-up I assessments showed that 28 of these participants had incident dementia. Another 33 participants had missing information on SMC status at followup I or were lost to the subsequent follow-up waves without any information regarding dementia status, leaving a final pool of 443 individuals for the analysis of incident SMC and the risk of subsequent dementia (see Fig. 1).
Incident memory complaints and risk of dementia
BL
TOTAL SAMPLE AT BASELINE n = 1692
Non-participants (BL)
PARTICIPANTS AT BASELINE
Refused Only proxy interviews Deceased Not located
n = 1265
INCLUSION FOR ANALYSIS
n = 242 n = 113 n = 57 n = 15
Exclusion from analysis (BL) Dementia n = 220 SMC n = 352 No information on SMC n = 7
n = 686 Non-participants (FUP)
FUP I
PARTICIPANTS AT FUP I n = 504
Refused Only proxy interviews Deceased Not located Other reasons
n = 50 n = 50 n = 75 n=6 n=1
Exclusion from analysis (FUP) INCLUSION FOR ANALYSIS OF INCIDENT SMC AND RISK OF SUBSEQUENT DEMENTIA n = 443
Dementia n = 28 No information on SMC n = 2 No information on dementia status after Follow-up I n = 31 No dementia detected at FUP waves II-V
INCIDENT DEMENTIA CASES DETECTED AT FUP WAVES II-V n = 58 FUP V
Fig. 1. Sample attrition and sample.
Data collection and assessment procedures
Structured clinical interviews at baseline and subsequent follow-up were conducted in participants’ homes by trained psychologists and physicians. In addition, structured third-party interviews were conducted with proxies. The main assessment instrument was the Structured Interview for Diagnosis of Dementia of Alzheimer type, Multi-infarct Dementia and Dementia of other Aetiology according to DSMIII-R, DSM-IV, and ICD-10 (SIDAM) (12, 13). The SIDAM includes a cognitive test battery, a third-party rating of psychosocial impairment with a 14-item scale of activities of daily living (SIDAM-ADL scale) and also a summary clinical diagnostic impression. The 55-item cognitive test battery includes the 30 items of the Mini-Mental State Examination (MMSE) (14). Overall, the test battery covers four domains of cognitive functioning: orientation, memory, intellectual abilities, and higher cortical functioning. We applied age- and education-specific norms for the cognitive domains to evaluate cognitive impairment (15).
Observed to end of follow-up period Died before end of follow-up period Refused or otherwise unable to complete follow-up
n = 204 n = 108
n = 73
BL, baseline; FUP, follow-up; SMC, subjective memory complaints
If it was not possible to administer the SIDAM (e.g., because of death or severe weakness of the participants), a comprehensive structured proxy interview was offered. This included the Clinical Dementia Rating scale [CDR, (16)]. Subjective memory complaints (SMC) were evaluated prior to cognitive testing by asking the participant: ‘Do you have problems with your memory?’ or—in case of the comprehensive structured proxy interview—by asking the proxy: ‘Does he/she has problems with his/her memory?’. We identified depressive symptoms using the German version of the 20-item Center of Epidemiologic Studies Depression Scale [CES-D, (17, 18)]. A standardized interview provided information on sociodemographic and other characteristics. Dates of death were obtained from relatives or from the official registry office. Diagnosis of dementia
Baseline and follow-up dementia status was agreed at consensus conferences that included physicians and psychologists. A clinical dementia diagnosis 3
Luck et al. was made according to DSM-IV criteria (11). The cognitive criteria were based either on results of the SIDAM cognitive test battery (12) or—if SIDAM test results were not available and only proxy interviews were conducted—on CDR data (16). Statistical analysis
The statistical analyses were performed using Predictive Analytics Software (PASW), version 20.0 (IBM Corp., Armonk, NY, USA) and STATA, version 13.1 (STATA Corp. College Station, TX, USA). All analyses employed an alpha level for statistical significance of 0.05 (two-tailed). Group differences were analyzed using Mann–Whitney U-test and chi-squared test as appropriate. We used the Kaplan–Meier survival method to estimate dementia-free survival times of the participants with and without incident SMC at follow-up I. As incident SMC could only be diagnosed at the times of assessment, we assigned SMC onset by convention at the midpoint between the time of the follow-up I assessment (when SMC was diagnosed) and the time of the previous baseline assessment. To compare dementia-free survival times of the participants with and without incident SMC, we set the starting time for those without incident SMC also at the midpoint between the times of the follow-up I and the baseline assessment. Moreover, as incident dementia could also only be diagnosed at the times of assessment, we also assigned dementia onset by convention at the midpoint between the time of the follow-up assessment when dementia was diagnosed and the time of the previous assessment. Kaplan– Meier survival method censored participants at the time of their last evaluation if they died or dropped out of the study without developing dementia, or if they had not developed dementia by the end of follow-up V. We used the log rank test to evaluate differences in the survival distributions of the subgroups with and without incident SMC. Finally, we used a multivariable Cox proportional hazards regression to assess the association of SMC status at follow-up I and risk of subsequent dementia, controlled for age, gender, education, and cognitive performance (MMSE-score) at follow-up I as covariates. For each variable included in the regression model, we calculated hazard ratios (HRs) and Wald 95% confidence intervals (CIs). Schoenfeld residuals were calculated to test the proportional hazards assumption of the Cox proportional hazards models. 4
Results Characteristics of the sample
A total of 443 participants that were dementia-free at follow-up I and had no SMC at baseline were included in the analyses (see Fig. 1). The mean age of the sample was 82.3 years (SD = 4.4); 327 (73.8%) of the participants were female. Incident SMC at follow-up I was found in 36.6% (n = 162) of the participants. Individuals with incident SMC showed a significantly lower MMSE performance at follow-up I than those without (mean score/ SD = 26.8/3.2 vs. 27.7/2.4, Mann–Whitney U = 19180.500, P = 0.005). Incident subjective memory complaints and the risk of subsequent dementia
Of the included sample of 443 dementia-free individuals at follow-up I, 58 (13.1%) developed dementia during the subsequent follow-up waves II–V (mean follow-up period = 5.4 years/ SD = 0.3 years). The mean dementia-free survival time of the study sample, as estimated by Kaplan– Meier survival analysis, was 6.6 years (95% CI 6.4–6.8). Individuals with incident SMC at follow-up I showed a significantly higher progression to dementia during the subsequent follow-up waves (n = 30/162 vs. n = 28/281; 18.5% vs. 10.0%, v² = 6.608, df = 1, P = 0.010) and a shorter dementia-free survival time than those without (mean = 6.2 years, 95% CI 5.9–6.5 vs. mean = 6.8 years, 95% CI 6.6–7.0; log rank: v² = 7.015, df = 1, P = 0.008; see Fig. 2). The association between incident SMC and risk of subsequent dementia also remained significant in multivariable Cox regression analysis with adjustment for covariates (adjusted HR = 1.8, 95% CI 1.1–3.1, P = 0.028; see Table 1). The proportional hazards assumption was met for all included variables (global test: v² = 9.09, df = 7, P = 0.246). Discussion
In this study, we sought to analyze the association between incident subjective memory complaints (SMC) and risk of subsequent dementia in a population-based sample of elderly (75+ years). Our findings indicate a significantly increased progression to dementia in individuals with incident SMC. These findings thus corroborate findings from previous studies based on prevalent SMC cases. The study of Waldorff et al. (8), for example, that followed a sample of general practitioners’ patients aged 65 years and older for
Incident memory complaints and risk of dementia
Cumulative dementia-free survival
1.0
Log rank test: X ² = 7.015 df = 1; P = 0.008
0.9
0.8
——— Individuals without incident SMC ——— Individuals with incident SMC
Fig. 2. Kaplan–Meier curves of dementia-free survival of individuals with and without incident subjective memory complaints (SMC).
0.7
+
0
Censored data
2
4
6
Time (years)
a period of 4 years found a more than two times higher risk of a subsequent dementia diagnosis in those with SMC at baseline (adjusted HR = 2.27 vs. 1.82 in our study). Also, the study of Wang et al. (9) that examined the association between subjective memory deterioration and future dementia (follow-up period of 5 years) in a community-based sample of cognitively unimpaired elderly (65+ years) reported HRs of developing dementia of 6.0, 3.2, and 1.6 for those participants who reported a subjective memory deterioration at the ages of 70, 75, and 80 years. Other studies particularly focussed on the association of SMC with future AD. The study of Geerlings et al. (1), for example, that followed a community-based sample of non-demented persons aged 65–84 years over an average follow-up period of 3.2 years observed an significantly increased risk of developing AD (adjusted odds ratio = 2.71) in individuals with SMC who had Table 1. Multivariable Cox proportional hazards regression of time to incident dementia (n = 443) Characteristics at FUPI
Wald
df
HR (95% CI)
P value
Age, every additional year Gender, female vs. male Education* Medium vs. low High vs. low Incident SMC, yes vs. no MMSE, every additional point CES-D, every additional point
28.186 7.202
1 1
1.17 (1.10–1.24) 5.01 (1.54–16.25)
