Alzheimer disease is one of the leading causes of death. Article

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1 Annals of Internal Medicine Article Survival after Initial Diagnosis of Alzheimer Disease Eric B. Larson, MD, MPH; Marie-Florence Shadlen, MD; Li Wang, MS; Wayne C. McCormick, MD, MPH; James D. Bowen, MD; Linda Teri, PhD; and Walter A. Kukull, PhD Background: Alzheimer disease is an increasingly common condition in older people. Knowledge of life expectancy after the diagnosis of Alzheimer disease and of associations of patient characteristics with survival may help planning for future care. Objective: To investigate the course of Alzheimer disease after initial diagnosis and examine associations hypothesized to correlate with survival among community-dwelling patients with Alzheimer disease. Design: Prospective observational study. Setting: An Alzheimer disease patient registry from a base population of persons age 60 years and older in the Group Health Cooperative, Seattle, Washington. Patients: 521 newly recognized persons with Alzheimer disease enrolled from 1987 to 1996 in an Alzheimer disease patient registry. Measurements: Baseline measurements included patient demographic features, Mini-Mental State Examination score, Blessed Dementia Rating Scale score, duration since reported onset of symptoms, associated symptoms, comorbid conditions, and selected signs. Survival was the outcome of interest. Results: The median survival from initial diagnosis was 4.2 years for men and 5.7 years for women with Alzheimer disease. Men had poorer survival across all age groups compared with females. Survival was decreased in all age groups compared with the life expectancy of the U.S. population. Predictors of mortality based on proportional hazards models included a baseline Mini-Mental State Examination score of 17 or less, baseline Blessed Dementia Rating Scale score of 5.0 or greater, presence of frontal lobe release signs, presence of extrapyramidal signs, gait disturbance, history of falls, congestive heart failure, ischemic heart disease, and diabetes at baseline. Limitations: The base population, although typical of the surrounding Seattle community, may not be representative of other, more diverse populations. Conclusions: In this sample of community-dwelling elderly persons who received a diagnosis of Alzheimer disease, survival duration was shorter than predicted on the basis of U.S. population data, especially for persons with onset at relatively younger ages. Features significantly associated with reduced survival at diagnosis were increased severity of cognitive impairment, decreased functional level, history of falls, physical examination findings of frontal release signs, and abnormal gait. The variables most strongly associated with survival were measures of disease severity at the time of diagnosis. These results should be useful to patients and families experiencing Alzheimer disease, other caregivers, clinicians, and policymakers when planning for future care needs. Ann Intern Med. 2004;140: For author affiliations, see end of text. See editorial comment on pp Alzheimer disease is one of the leading causes of death in older people (1). One recent study suggests that 7.1% of all deaths in 1995 were attributable to Alzheimer disease, placing it on a par with cerebrovascular disease as the third leading cause of death (2). Estimates of predicted survival of persons who have received a diagnosis of Alzheimer disease should be useful for patients, caregivers, clinicians, and policy planners. Previous studies that relied on epidemiologic surveys had little opportunity to analyze clinical factors and also may not be generalizable to everyday clinical settings. Results from other studies that were based on convenience samples of persons from specialized Alzheimer disease centers are probably subject to referral bias. Our study design allowed us to estimate the magnitude of the reduction in age-adjusted life expectancy attributable to Alzheimer disease in a cohort of patients similar to those encountered in the clinical setting where Alzheimer disease is initially recognized. It is not surprising that patients with Alzheimer disease probably have reduced survival compared with older persons without dementia (3 6). Certain characteristics, particularly male sex (7 11), initial dementia severity (5, 9, 12 17), presence of behavioral disturbances, wandering and falling (18), comorbid conditions (19), and presence of extrapyramidal signs (5, 20), are reported to be associated with decreased survival among patients with Alzheimer disease. In 1987, we began a prospective observational study to investigate the natural history of persons with newly diagnosed Alzheimer disease in a community-dwelling population (21). This report describes overall survival and examines the association between factors hypothesized to affect survival in 521 patients with Alzheimer disease newly recognized between 1987 and 1996 and followed until time of death or METHODS Cases From 1987 to 1996, an Alzheimer s disease patient registry enrolled persons receiving care in the Seattle and western King County clinics of the Group Health Cooperative (a well-established staff-model health maintenance organization with an enrollment population base age 60 years and older of ) in Washington. The research protocol for this study was reviewed and approved by the health maintenance organization and the University of Washington s institutional review boards American College of Physicians 501 Downloaded From: by a Penn State University Hershey User on 06/26/2015

2 Article Survival after Initial Diagnosis of Alzheimer Disease Context The prognosis in patients with Alzheimer disease may be associated with specific patient characteristics observed shortly after diagnosis. Contribution Severity of initial cognitive impairment and deterioration in the Mini-Mental State Examination score during the first year after diagnosis were strongly associated with decreased survival. Men had shorter survival than women across all age groups. Frontal lobe release signs, gait disturbances, falling, congestive heart failure, and diabetes were all associated with decreased survival. Implications Early appraisal of patients with Alzheimer disease may help set expectations and priorities for planning patient care. The Editors The registry s objective was to identify all persons enrolled in the base population with newly recognized symptoms of possible dementia (for example, memory loss, confusion, or wandering). The goal of enrollment was to assemble a series of incident cases from a defined population, that is, possible patients with dementia who had presented for medical care within the health maintenance organization 1 year or less before enrollment in the registry. Study methods have been reported previously (4, 21). The following strategy was used to detect possible incident cases. Research associates systematically searched for patients with symptoms of memory loss, confusion, or wandering; for tests or treatments potentially indicative of dementia (by review of computed tomography and magnetic resonance imaging logbooks); for discharge diagnoses from the hospital information system; for logbook records of visits to neurology, geriatrics, and mental health clinics; for emergency department logs; and for computerized clinic treatment record files. In addition, primary care physicians were invited to refer suspected new cases for evaluation through brochures and mailings describing the registry. These primary care physicians also received a monthly newsletter describing clinical research advances in aging and dementia and reminding them of our study. The process of patient identification through consensus diagnosis took an average of 12 weeks. A research assistant screened the medical charts of persons identified as potential cases. If the person s record contained any information indicating memory loss or other cognitive changes indicating that the person might have Alzheimer disease, the primary care physician was contacted to obtain permission to contact that person. Persons who were judged to possibly have newly recognized dementia were contacted to request that they participate in the program. After we obtained informed consent, the research nurse interviewed the person and began collecting data, usually in the home. A psychometrist research assistant administered standard neuropsychological testing. Persons who agreed to participate in the registry underwent a complete, standardized physical and neurologic examination, administered by one of the study physicians, and the usual laboratory work-up (including neuroimaging) to rule out other causes of dementia and complicating illnesses. Chronology of symptoms was determined by study clinicians from interviews of the patient and informants and by review of medical records. The examining physician from the registry estimated the duration of symptoms before evaluation to the nearest year after resolving any discrepant information through further questioning and by relating time frames to the patient s life events. All eligible persons met criteria of the revised third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) for dementia and criteria of the National Institute of Neurological and Communicative Disorders and Stroke Alzheimer s Disease and Related Disorders Association (22) for probable or possible Alzheimer disease at a consensus diagnosis conference that included at least 2 physicians (including the examining physician), a neuropsychologist, an epidemiologist, and study staff. On the basis of chart review, persons whose symptoms led to a diagnosis of dementia or Alzheimer disease more than 1 year before the time the registry detected them were excluded as not being incident cases. Of 1028 patients who consented to participate and who potentially could have been incident cases after chart review, 58 were excluded from the study before the standardized evaluation because of intervening death or acute illness. A total of 970 participants identified with suspected dementia (from 1987 to 1996) were evaluated and followed annually. When discrepant findings or clinical course indicated a possible change from the initial diagnosis, we reevaluated the person according to the standardized protocol, which included an evaluation by a study physician to verify or modify the initial diagnoses. Persons initially classified with possible or probable Alzheimer disease but who were subsequently given a different diagnosis were excluded from these analyses. Persons with more than one cause of dementia (so-called mixed dementia) were excluded from these analyses. Of the individuals with suspected dementia (n 970), 521 received a diagnosis of probable or possible Alzheimer disease (431 probable, 90 possible), 174 received diagnoses of other causes of dementia, and 237 did not meet DSM-III-R criteria for dementia within 18 months from their initial intake. The remaining 38 met diagnostic criteria of Alzheimer disease after at least 18 months of follow-up. Of the 174 persons with other causes of dementia, 74 were classified as having vascular dementia, 12 were classified as having alcohol-related causes, 54 were classified as having mixed and other causes (such as Parkinson disease or progressive supranuclear palsy), and 34 were classified as having unknown causes by April 2004 Annals of Internal Medicine Volume 140 Number 7

3 Survival after Initial Diagnosis of Alzheimer Disease Article DSM-III-R criteria. Duration of survival was assessed annually. The dates of death were available for all study participants who died during the study period. Mean ( SD) follow-up time was years (range, 0.2 to 14 years). The ethnic composition of the persons in the registry was 88% white, 8.7% black, and 3.3% Asian or Hispanic. The ethnic composition from the King County 1990 census was 84.8% white, 5.1% black, and 10.1% Asian or Hispanic. The overall ethnic composition of adults in the Group Health Cooperative was 90.2% white, 3.3% black, and 6.5% other. Study Variables The research nurse interviewed the patient and caregiver before scheduling an examination. The baseline information determined by questionnaire and physician interview included age (categorized as 75, 76 to 80, 81 to 85, and 85 years for analyses), sex (male vs. female), ethnicity (white, black, other), baseline systolic blood pressure ( 110 mm Hg, 110 to 160 mm Hg, and 160 mm Hg), and education ( 12 years, 12 years, 12 years, or unknown). As reported previously (4, 21), the severity of symptoms of Alzheimer disease was determined on the basis of the baseline Mini-Mental State Examination (MMSE) as continuous and categorical ( 17, 18 to 21, 22 to 24, or 25 points) variables (23) and baseline Dementia Rating Scale (DRS) as continuous and categorical ( 2, 2.5 to 3, 3.5 to 5, 5 points) variables (24). Symptoms of dementia (for example, agitation, paranoia, and wandering) were assessed with the Revised Memory and Behavior Problems Checklist (25, 26). Physical signs of frontal release reflexes and other neurologic changes associated with dementia (for example, glabellar sign and grasp reflex) were categorized as present or not present by the examining physician. Study physicians assessed the presence or absence of rigidity on the basis of passive range of motion of the right and left elbow and wrist joints. The presence of a gait disorder was also determined through observation by the study physicians. All persons completed a general medical history and a review of systems questionnaire administered by a trained interviewer (4, 21). Comorbid conditions included hypertension, diabetes, ischemic heart disease, congestive heart failure, and history of strokes. Onset of symptoms, as estimated at the time of diagnosis, and the age at enrollment into the study were used to calculate the reported duration of disease symptoms (defined as 1,1to3,or 3 years). Statistical Analysis Our general hypothesis was that the severity of Alzheimer disease at the time of diagnosis, as measured by cognitive and functional measures as well as symptoms of dementia, would be associated with survival. The event time was the time of death. Persons who were still alive at the end of the study on 12 September 2001 were censored at that time. Survival time was defined as the time from the initial date of diagnosis of Alzheimer disease until the date of death or study conclusion. Patients who did not receive in-person follow-up were tracked for vital status through Group Health Cooperative records, informant reports, or local newspaper obituaries. Variables investigated were 1) baseline MMSE score; 2) baseline DRS score; 3) psychiatric symptoms of paranoia or hallucinations at the time of evaluation; 4) behavioral disturbances, including agitation, irritability, or emotional lability; 5) frontal release signs, including glabellar, snout, or grasp; 6) extrapyramidal signs, including rigidity or tremor; 7) wandering; 8) falls; 9) gait disorder; 10) urinary incontinence; and 11) depression. Variables adjusted as potential confounders included 1) age, 2) sex, 3) ethnicity, 4) education, 5) ischemic heart disease, 6) congestive heart failure, 7) diabetes, 8) hypertension, and 9) stroke. To describe associations of baseline factors with mortality, we calculated both proportions of patients who died and the time until death by baseline variables. Survival time quartiles were used to describe the time until death when 25%, 50%, and 75% of patients died. Log-rank tests were used for testing the equality of survival among groups. We compared the estimated life expectancy, expressed in quartiles, of patients with Alzheimer disease in the study sample with the reported life expectancy of the U.S. population by sex and age strata (27). Cox proportional hazards regression models were used to examine how baseline characteristics affected risk for death during the study period (28). The associations of predictors and mortality are estimated, with adjustments by age, sex, and ethnicity. We also adjusted for medical conditions that were found to be associated with survival and repeated analyses on the predictors of interest. Schoenfeld residual tests (29) were used to evaluate the proportional hazard assumption. If the assumption failed, time-varying covariates were introduced. To help illustrate the findings, Kaplan Meier curves were estimated. All data were analyzed by using Stata software, version 7 (Stata Corp., College Station, Texas). A secondary investigation of potential interest to clinicians was determining whether patients who had greater cognitive decline during the first year after diagnosis had a higher risk for dying after the first year. Greater decline during the first year was defined as a decrease of 5 or more points in MMSE score (that is, MMSE score at diagnosis [baseline MMSE score] minus MMSE score at the first year). This value was chosen a priori to reflect clinically meaningful cognitive decline (30). The Cox proportional hazards model was used to estimate the risk for dying by adjusting for baseline MMSE scores, age at diagnosis, sex, ethnicity, and comorbid conditions. The Schoenfeld residual test was used to evaluate the proportional hazards assumptions. Sensitivity analyses (Appendix, available at were performed to evaluate potential biases that could be introduced because of missing data on follow-up MMSE scores and floor effect of low baseline MMSE scores. Logistic regression analyses were performed on the patients who had follow-up MMSE scores to ex- 6 April 2004 Annals of Internal Medicine Volume 140 Number 7 503

4 Article Survival after Initial Diagnosis of Alzheimer Disease Figure. Kaplan Meier survival estimates. A. By Mini-Mental State Examination (MMSE ) score categories. B. By Dementia Rating Scale (DRS ) categories. C. By presence or absence of gait disturbance. D. By presence or absence of wandering. plore which baseline factors predict greater decline during the first year (Appendix Table, available at On the basis of the risk factors for decline identified by logistic regression, we divided those with missing data on follow-up MMSEs into declined and nondeclined groups. Then, we repeated the Cox model to see whether any change in estimates resulted from adding those without follow-up MMSEs into the analytic sample. The Appendix Figure (available at is a Kaplan Meier survival graph of these results. Role of the Funding Sources The funding sources had no role in the design, conduct, or reporting of this study or in the decision to submit the manuscript for publication. RESULTS Table 1 shows quartile estimates of survival for patients with Alzheimer disease according to baseline characteristics. Median survival was longer for younger persons and women but did not vary by education level. Patients age 85 years and older, with gait disturbance, wandering, and comorbid diabetes and congestive heart failure had the poorest survival (median survival times were 3.2 years, 3.5 years, 4.1 years, 3.8 years, and 3.0 years, respectively; P 0.01 for all comparisons [log-rank test]). Other predictors of decreased survival were male sex, lower MMSE score, higher (worse) DRS score, presence of frontal release signs, presence of extrapyramidal signs, history of falls, presence of urinary incontinence, history of ischemic heart disease, and history of stroke. Duration of survival among patients with Alzheimer disease did not differ by ethnicity, presence of hypertension, presence of psychiatric symptoms, presence of behavioral disturbances, presence of depression symptoms, or duration of dementia symptoms at the time of diagnosis. Table 2 compares the life expectancy of patients with Alzheimer disease in this study with that of the U.S. population (27). Patients with Alzheimer disease at 70 years of age had a significantly decreased survival compared with the life expectancy of the U.S. population. Median survival April 2004 Annals of Internal Medicine Volume 140 Number 7

5 Survival after Initial Diagnosis of Alzheimer Disease Article Table 1. Baseline Characteristics and Survival of Alzheimer Disease Participants* Variable Patients Patients Who Died Survival Time Quartiles P Value 25% 50% 75% n n (%) 4OOOOOOOOO y OOOOOOOOO3 Age 75 y (73) y (77) y (84) y (87) Sex Male (89) Female (76) Ethnicity White (82) Black (66) Other (71) Education 12 y (80) y (78) y (83) MMSE score (70) (77) (79) (91) DRS score (74) (76) (83) (89) Psychiatric symptoms No (79) Yes (83) Behavioral change No (80) Yes (81) Frontal release signs No (75) Yes (85) Extrapyramidal signs No (79) Yes (88) Gait disturbance No (78) Yes (87) Wandering No (80) Yes (90) Falls No (77) Yes (88) Urinary incontinence No (79) Yes (87) Depression No (80) Yes (81) Duration of symptoms 1 y (73) y (81) y (85) Ischemic heart disease No (77) Yes (89) Congestive heart failure No (79) Yes (90) History of strokes No (80) Yes (82) Hypertension No (82) Yes (76) Diabetes No (79) Yes (91) * DRS Dementia Rating Scale; MMSE Mini-Mental State Examination. Survival time quartiles describe the time until death when 25%, 50%, and 75% of patients died. The log-rank test was used to determine P values. The test was used to evaluate the equality of survival among groups. 6 April 2004 Annals of Internal Medicine Volume 140 Number 7 505

6 Article Survival after Initial Diagnosis of Alzheimer Disease Table 2. Comparison of Life Expectancy by Quartiles of Study Participants and U.S. Population* Life Expectancy Quartiles Age 70 y Age 75 y Age 80 y Age 85 y Age 90 y 75% 50% 25% 75% 50% 25% 75% 50% 25% 75% 50% 25% 75% 50% 25% 4OOOOOOOOOOOOOOOOOOOOOOOOOOO y OOOOOOOOOOOOOOOOOOOOOOOOOOO3 Women U.S. population Patients with Alzheimer disease (n 341) Men U.S. population Patients with Alzheimer disease (n 180) * The source of the data on life expectancy in the U.S. population is cited in Walter LC and Covinsky KE (27). Life expectancy quartiles presented in the table correspond to upper, middle, and lower quartiles of estimated survival at each age sex strata, that is, 75%, 50%, and 25% of the population will live less than the corresponding years listed, respectively. time for women with Alzheimer disease at 70 years of age was 8.0 years compared with 15.7 years for the U.S. population. Survival time for the 50% quartile (median) for men at 70 years of age was 4.4 years compared with 9.3 years for the U.S. population. Across all age groups, men had poorer survival than women. At progressively older ages, the absolute survival difference between patients with Alzheimer disease and the U.S. population diminished. For example, survival time for the 50% quartile (median) for women at 85 years of age was 3.9 years compared with 5.9 years for the U.S. population. Survival time for the 50% quartile (median) for men at 85 years of age was 3.3 years compared with 4.7 years for the U.S. population. As expected, survival declined with age, but the decline for men with Alzheimer disease with increasing age was less than for women. Median life expectancy for men with Alzheimer disease was 4.4 years at 70 years of age versus 3.3 years at 85 years of age, and median life expectancy for women was 8.0 years at 70 years of age versus 3.9 years at 85 years of age. Table 3 shows the hazard ratios of death according to the severity of symptoms and typical symptoms of dementia. Compared with the presence or absence of dementia signs and symptoms at baseline, measures of the severity of symptoms at the time of diagnosis were the strongest predictors of survival. The independent risk factors in proportional hazards models adjusted by age, sex, and ethnicity were low MMSE score, poor DRS score, presence of baseline frontal lobe release signs, presence of baseline gait disturbance, history of falls, congestive heart failure, history of diabetes, and history of ischemic heart disease. After adjustment for age, sex, ethnicity, ischemic heart disease, congestive heart failure, and diabetes, the presence of extrapyramidal signs and symptoms of wandering became more significant as independent risk factors for death. The hazard ratio of death for older age increased over time by an exponential factor. Comorbid conditions further reduced survival, with hazard ratios for death of 1.2 for ischemic heart disease, 1.3 for congestive heart failure, and 1.7 for diabetes. A 5-point or greater decline in the MMSE score after the first year of follow-up was also associated with a significantly increased risk for death. The estimated hazard ratio for death in patients with a 5-point or greater decline in MMSE score was between 1.60 and 1.66 in 4 models controlling for age, baseline MMSE score, sex, ethnicity, ischemic heart disease, congestive heart failure, and diabetes. In sensitivity analyses, we found that the floor effect of low baseline MMSE scores led to slight underestimates of the hazard ratio of death for the declined group, but missing data on follow-up MMSE scores did not. The Figure contains graphic illustrations of Kaplan Meier survival curves by MMSE score category, DRS category, presence or absence of gait disorder, and presence or absence of wandering at baseline. DISCUSSION In all age groups, patients with Alzheimer disease in our study had decreased survival compared with survival in the general U.S. population (27). Men had a median survival of 4.2 years from their initial diagnosis, and women had a median survival of 5.7 years. Our findings differ from estimates of median survival from the onset of symptoms of dementia in the Canadian Study of Aging (3.17 years for men and 3.36 years for women) (3). The shorter survival estimates in the Canadian study could relate to 2 issues. First, the patients in that study were older (average age, 83.8 years); second, because the study dealt with a population-based prevalence sample, it included a relatively greater proportion of persons with severe dementia and nursing home residents who were at later stages in the course of the natural history of this progressive disease (3). Also, sex was not associated with Alzheimer disease survival in the Canadian study (3). By contrast, we found the median life expectancy for a 70-year-old man with Alzheimer disease to be 4.4 years compared with 8.0 years for a woman of the same age with Alzheimer disease. This sex gap narrowed at more advanced ages. Our findings are April 2004 Annals of Internal Medicine Volume 140 Number 7

7 Survival after Initial Diagnosis of Alzheimer Disease Article Table 3. Hazard Ratios for Death by Mini-Mental State Examination Scores, Dementia Rating Scale Scores, and Associated Symptoms* Variable Multivariate Analysis Adjusted by Age, Sex, and Ethnicity Multivariate Analysis Adjusted by Age, Sex, Ethnicity, Ischemic Heart Disease, Congestive Heart Failure, and Diabetes Hazard Ratio P Value Hazard Ratio MMSE score ( ) ( ) ( ) ( ) ( ) ( ) DRS score ( ) ( ) ( ) ( ) ( ) ( ) Psychiatric symptoms Yes 1.08 ( ) ( ) 0.2 Behavioral change Yes 1.02 ( ) ( ) 0.2 Frontal release signs Yes 1.26 ( ) ( ) Extrapyramidal signs Yes 1.28 ( ) ( ) Gait disturbance Yes 1.50 ( ) ( ) Wandering Yes 1.41 ( ) ( ) Falls Yes 1.30 ( ) ( ) Urinary incontinence Yes 1.29 ( ) ( ) Depression Yes 0.96 ( ) ( ) 0.2 Duration of symptoms 1 y y 1.35 ( ) ( ) y 1.28 ( ) ( ) Ischemic heart disease No 1 Yes 1.30 ( ) Congestive heart failure No 1 Yes 1.48 ( ) History of stroke No 1 Yes 1.21 ( ) 0.2 Hypertension No 1 Yes 0.96 ( ) 0.2 Diabetes No 1 Yes 1.87 ( ) * DRS Dementia Rating Scale; MMSE Mini-Mental State Examination. Age, defined as the age at diagnosis of Alzheimer disease, was used as the time-varying covariate in the model (Age(t) age exp(0.03 t)). P Value consistent with previous reports that men with Alzheimer disease have approximately half the life expectancy estimated for women with Alzheimer disease (5, 7, 9 11, 31). Our sample and study design are arguably more typical of the persons clinicians see in everyday medical practice and who may be recognized as having typical symptoms and 6 April 2004 Annals of Internal Medicine Volume 140 Number 7 507

8 Article Survival after Initial Diagnosis of Alzheimer Disease signs of dementia. Our results are also consistent with our previously reported average survival from study entry (5.3 years) in a consecutive outpatient (convenience) sample of patients with existing Alzheimer disease in King County, Washington (18). As reported previously, the association between measures of the severity of Alzheimer disease symptoms and survival was strong (5, 9, 12 17). We found that the effect of cognitive performance scores and dementia severity scores on survival remained significant even after adjustment for age, sex, ethnicity, and presence of vascular comorbid conditions. Comorbid conditions, such as a history of diabetes, congestive heart failure, and ischemic heart disease, reduced survival of patients with Alzheimer disease in this cohort, with hazard ratios of 1.7, 1.3, and 1.2, respectively. In addition, survival was reduced by the symptoms and signs of the disease. Few studies of similar design have taken into account the influence of possible confounders, such as vascular disease comorbid conditions, on estimates of survival in Alzheimer disease. The data in Table 2 can be used as a reference to estimate age- and sex-adjusted life expectancy for patients with Alzheimer disease. The information in Table 3 can be used to estimate additional reductions in survival on the basis of the presence or absence of other signs and symptoms of dementia. A recent report also showed that the presence of a gait disorder was associated with increased risk for death in older persons (32). The presence of extrapyramidal signs can be a manifestation of Lewy body disease. Without neuropathologic data, we cannot rule out the possibility that some of our patients might have had concomitant Lewy body disease. Although symptoms of agitation, irritability, emotional lability, paranoia, or hallucinations affect the quality of life of patients with Alzheimer disease, survival did not differ among patients with or without these symptoms in our study. The relationship of psychiatric or behavioral symptoms and Alzheimer disease mortality has been difficult to study because of the variability of presentation of these symptoms during the natural history of the disease. Patients with early dementia can present with behavioral symptoms, such as wandering, that subside at later stages of the disease when mobility is diminished. Conversely, patients without behavioral symptoms at initial presentation can develop paranoid ideations and delusions at a later course of their illness. By only examining the influence of baseline psychiatric symptoms on the outcome of interest, we may not have captured the dynamic interactions of change in the frequency and intensity of behavioral symptoms on survival. We believe that our observations, if confirmed, would be of great interest to patients with Alzheimer disease and family members making plans for future care needs. The strengths of this study are the ability to examine demographic factors, signs and symptoms of dementia, measures of the severity of symptoms, and the presence of comorbid conditions in a community-based cohort. The study had a large sample size and relatively long duration of follow-up. We must caution, however, that this health maintenance organization based sample may not be representative of patients with Alzheimer disease in the U.S. population as a whole, although the demographic features of the sample do resemble those of the surrounding Seattle community. We think that the lack of association between duration of dementia symptoms and survival reflects the variability of self-reports and informant reports of duration for an illness that is typically insidious in onset and often difficult to distinguish from age-related decline. These measurement errors would bias the results toward the null. It would be useful to analyze the interrelationships of comorbid conditions and the actual cause of death for our participants. However, we do not have reliable data on causes of death. Because of the study design, we could not evaluate the potential confounding effect of use of drugs with potential psychiatric effects in this cohort. The most powerful predictors of reduced survival were a poor score on the MMSE and increased Alzheimer disease related functional impairment, as measured by the DRS. Baseline psychiatric symptoms or behavioral disturbances were not strongly associated with survival. The conventional wisdom that persons with Alzheimer disease who experience a rapid decline in cognitive performance in the first year will have a more malignant course is confirmed by our findings that an MMSE score decline of 5 points or more at 1 year of follow-up was associated with a 60% increased risk for death. Our findings suggest that a straightforward clinical evaluation consisting of the patient s history, a cognitive screening test, functional assessment from an informant, and a careful neurologic examination can detect features associated with prognosis for survival of patients with Alzheimer disease typically seen in clinical practice. From University of Washington and the Group Health Cooperative, Seattle, Washington. Grant Support: By National Institute on Aging grant AG and by a Minority Supplement to National Institute of Aging grant AG S1 to the University of Washington Alzheimer s Disease Patient Registry. Potential Financial Conflicts of Interest: None disclosed. Requests for Single Reprints: Eric B. Larson, MD, MPH, Center for Health Studies, 1730 Minor Avenue, Suite 1600, Seattle, WA ; , larson.e@ghc.org. Current author addresses and author contributions are available at References 1. Ganguli M, Rodriguez EG. Reporting of dementia on death certificates: a community study. J Am Geriatr Soc. 1999;47: [PMID: ] 2. Ewbank DC. Deaths attributable to Alzheimer s disease in the United States. Am J Public Health. 1999;89:90-2. [PMID: ] 3. Wolfson C, Wolfson DB, Asgharian M, M Lan CE, Ostbye T, Rockwood K, et al. A reevaluation of the duration of survival after the onset of dementia April 2004 Annals of Internal Medicine Volume 140 Number 7

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10 APPENDIX: SENSITIVITY ANALYSIS Sensitivity analyses were performed to examine potential biases that may have been introduced because of the inability to observe a decline in patients with no follow-up MMSE scores and in patients who had very low baseline MMSE scores. Sixtytwo patients survived for more than 1 year but did not have follow-up MMSEs. Logistic regression analyses were performed on the patients who had follow-up MMSE scores to explore which baseline factors predict significant cognitive decline during the first year. We found that only the baseline MMSE score was a significant predictor for the first year decline. Patients with baseline MMSE scores between 10 and 20 were 2 times more likely (odds ratio, 2.16 [95% CI, 1.43 to 3.27]; P 0.001) to decline during the first year than were the patients with baseline MMSE scores between 21 and 30. Therefore, on the basis of their baseline MMSE scores, we classified patients who had survived for more than 1 year but without follow-up MMSE scores (62 patients) into declined (22 patients) or nondeclined (40 patients) groups. Cox regression models, in which analysis time was truncated at the first year of follow-up, were performed on 4 different analytic samples. Model 1 was performed on declined (146) and nondeclined (273) patients; model 2 was performed on declined (144) and nondeclined (267) patients with baseline MMSE scores greater than 8; model 3 was performed on declined (146) patients, nondeclined (273) patients, and those without follow-up MMSE scores who survived for more than 1 year (62); and model 4 was performed on patients who were included in model 3 but who had baseline MMSE scores greater than 8 (267 nondeclined patients, 144 declined patients, and 56 patients with no follow-up). Results are presented in the Appendix Table. The floor effect (that is, patients who reached the low end of MMSE scoring at baseline and who were unable or less likely to decline at follow-up) leads to slightly underestimating the risk for dying for the declined group. The follow-up MMSE data on 62 patients that were missing at the 1-year follow-up were not found to bias the estimated risk for dying for the declined group. We note that of the 102 patients with no follow-up MMSE scores, 40 (39.2%) died during the first year after receiving a diagnosis of Alzheimer disease. The 40 patients who died earlier might have declined faster but were not observed during the first year. Thus, follow-up MMSE data on these patients could not be used in this analysis. Appendix Figure. Kaplan Meier survival estimates by cognitive decline. Current Author Addresses: Dr. Larson: Center for Health Studies, 1730 Minor Avenue, Suite 1600, Seattle, WA Drs. Shadlen and McCormick: Division of Gerontology and Geriatric Medicine, University of Washington School of Medicine, Harborview Medical Center, 325 9th Avenue, Box , Seattle, WA Ms. Wang: Division of General Internal Medicine, University of Washington Medical Center, 4225 Roosevelt Way NE, Suite 301, Box , Seattle, WA Dr. Bowen: Department of Neurology, University of Washington School of Medicine, 1959 NE Pacific Street, Box , Seattle, WA Dr. Teri: Department of Psychosocial and Community Health, University of Washington School of Nursing, rd Avenue NE, Suite 507, Seattle, WA Dr. Kukull: Department of Epidemiology, University of Washington School of Public Health, th Avenue NE, Suite 300, Seattle, WA Author Contributions: Conception and design: E.B. Larson, M.-F. Shadlen, L. Wang, J.D. Bowen, L. Teri, W.A. Kukull. Analysis and interpretation of the data: E.B. Larson, M.-F. Shadlen, L. Wang, W.C. McCormick, L. Teri, W.A. Kukull. Drafting of the article: E.B. Larson, M.-F. Shadlen, L. Wang, W.C. McCormick. Critical revision of the article for important intellectual content: E.B. Larson, M.-F. Shadlen, L. Wang, W.C. McCormick, J.D. Bowen, L. Teri, W.A. Kukull. Final approval of the article: E.B. Larson, M.-F. Shadlen, L. Wang, W.C. McCormick, J.D. Bowen, L. Teri, W.A. Kukull. Provision of study materials or patients: E.B. Larson, W.C. McCormick, J.D. Bowen, L. Teri, W.A. Kukull. Statistical expertise: L. Wang. Obtaining of funding: E.B. Larson, L. Teri, W.A. Kukull. Administrative, technical, or logistic support: E.B. Larson, W.C. McCormick, L. Teri. Collection and assembly of data: E.B. Larson, L. Wang, L. Teri, W.A. Kukull. E-510 American College of Physicians

11 Appendix Table. Hazard Ratios for Death on the Basis of Greater Cognitive Decline at 1 Year of Follow-up* Variable Model 1 Hazard Ratio Model 2 Hazard Ratio Model 3 Hazard Ratio Model 4 Hazard Ratio First year decline in MMSE score 5 points points 1.61 ( ) 1.65 ( ) 1.60 ( ) 1.66 ( ) Baseline MMSE score 0.95 ( ) 0.94 ( ) 0.94 ( ) 0.94 ( ) Age at diagnosis 1.05 ( ) 1.05 ( ) 1.04 ( ) 1.05 ( ) Sex Male Female 0.56 ( ) 0.58 ( ) 0.56 ( ) 0.57 ( ) Ethnicity White Black 0.64 ( ) 0.59 ( ) 0.67 ( ) 0.63 ( ) Other 0.77 ( ) 0.77 ( ) 0.71 ( ) 0.72 ( ) Ischemic heart disease 1 1 Yes 1.26 ( ) 1.29 ( ) 1.26 ( ) 1.30 ( ) Congestive heart failure 1 1 Yes 1.22 ( ) 1.18 ( ) 1.27 ( ) 1.22 ( ) Diabetes 1 1 Yes 1.97 ( ) 1.98 ( ) 1.75 ( ) 1.69 ( ) * MMSE Mini-Mental State Examination. Annals of Internal Medicine Volume Number E-511