Hallucinations, cognitive decline, and death in Alzheimer's disease

The relation of psychotic symptoms to cognitive decline and mortality in Alzheimer's disease (AD) was examined during a mean of 2.2 years in 478 persons selected from clinical settings. Psychotic symptoms were ascertained at baseline and cognition was assessed semiannually with nine tests from which a global measure was formed. In analyses that controlled for age, sex, race, and education, hallucinations (29.6%), especially visual ones, were associated with more rapid global cognitive decline and increased mortality, even after controlling for baseline level of cognition and use of antipsychotic medication, and the association with mortality increased with higher level of education. Delusions and misperceptions were not strongly related to cognitive decline or mortality. The results suggest that hallucinations in Alzheimer's disease, particularly visual ones, are associated with more rapid progression.     

Incidence of and risk factors for hallucinations and delusions in patients with probable AD

OBJECTIVE: To examine the incidence of and risk factors for hallucinations and delusions associated with patients clinically diagnosed with probable AD. BACKGROUND: Estimates of the incidence of psychosis in AD range widely from 10% to 75%. The risk factors for psychosis of AD are not known, although multiple studies indicate that AD patients with psychosis demonstrate greater cognitive and functional impairment. METHODS: The authors conducted psychiatric evaluations of 329 patients with probable AD from the University of California at San Diego Alzheimer's Disease Research Center to determine the incidence of hallucinations and delusions. They examined data from annual clinical and neuropsychological evaluations to determine whether there were specific risk factors for the development of hallucinations and delusions. RESULTS: Using Cox survival analyses, the cumulative incidence of hallucinations and delusions was 20.1% at 1 year, 36.1% at 2, 49.5% at 3, and 51.3% at 4 years. Parkinsonian gait, bradyphrenia, exaggerated general cognitive decline, and exaggerated semantic memory decline were significant predictors. Age, education, and gender were not significant predictors. CONCLUSIONS: The authors found a relatively high incidence of hallucinations and delusions in patients diagnosed with probable AD and suggest that specific neurologic signs, cognitive abilities, and accelerated decline may be predictive markers for their occurrence.     

Nursing home placement, day care use, and cognitive decline in Alzheimer's disease

OBJECTIVE: People with Alzheimer's disease are often placed in a nursing home, sometimes after using adult day care services. How affected persons function during this potentially difficult transition is not well understood. The aim of this study was to examine the associations of day care use and nursing home placement with the rate of cognitive decline in Alzheimer's disease. METHOD: The participants were 432 older persons with Alzheimer's disease who were recruited from health care settings in the Chicago area. At baseline, they lived in the community and were using day care services a mean 1.7 days per week. At 6-month intervals for up to 4 years, they completed nine cognitive tests from which a composite measure of global cognition was derived. RESULTS: On average, cognition declined at a gradually increasing rate during the study period. Nursing home placement was associated with a decrease in the level of cognition and an acceleration in the rate of cognitive decline. Day care use at baseline was not related to cognitive decline in initial analyses, but it interacted with nursing home placement such that higher level of day care use substantially reduced association of placement with accelerated cognitive decline. Education interacted with placement such that more schooling was associated with a greater increase in cognitive decline upon nursing home placement, but prior day care use also attenuated this association. CONCLUSIONS: Nursing home placement is associated with accelerated short-term cognitive decline in Alzheimer's disease. Prior experience in adult day care may lessen this association.     

Premorbid reading activity and patterns of cognitive decline in Alzheimer disease

BACKGROUND: Educational and occupational attainment have been associated with progression of Alzheimer disease in some studies. One hypothesis about this association is that education and occupation are markers for lifelong participation in cognitively stimulating activities like reading. OBJECTIVE: To assess the relation of premorbid reading activity with patterns of cognitive decline in Alzheimer disease. METHODS: During a 4-year period, 410 persons with Alzheimer disease had annual clinical evaluations, which included administration of 17 cognitive function tests from which global, verbal, and nonverbal summary measures were derived. At baseline, a knowledgeable informant was questioned about the affected person's reading frequency and access to reading materials before dementia onset. RESULTS: A composite measure of premorbid reading activity was developed. It had moderately high internal consistency and was positively correlated with education and baseline level of cognitive function. In analyses that controlled for baseline cognitive function, education, and other demographic variables, higher level of premorbid reading activity was associated with more rapid decline on the global cognitive and verbal measures but not on the nonverbal measure. CONCLUSIONS: These results suggest that both the extent and nature of premorbid cognitive experiences may affect how Alzheimer disease pathology is clinically expressed.     

Neuropsychiatric Symptoms and Global Functional Impairment along the Alzheimer's Continuum

Background/Aims: Neuropsychiatric symptoms in Alzheimer's disease (AD) are highly prevalent. We sought to determine whether neuropsychiatric symptoms were related to global functional impairment at baseline and over a 3-year period in older normal control (NC), mild cognitive impairment (MCI) and mild AD dementia subjects. Methods: Eight hundred and twelve subjects (229 NC, 395 MCI, 188 AD) from the Alzheimer's Disease Neuroimaging Initiative study underwent cognitive and behavioral assessments over 3 years. Results: Greater hallucinations, anxiety and apathy were associated with greater global functional impairment at baseline, while the presence of hallucinations and apathy at baseline was associated with greater global functional impairment over time across all subjects. The following neuropsychiatric symptoms were not significantly associated with global functioning: delusions, agitation, depression, euphoria, disinhibition, irritability, aberrant motor behaviors, sleep and appetite. Conclusions: These results suggest that increased baseline hallucinations, apathy and anxiety are associated with current and future disease progression in AD.     

Neuropathological substrates of psychiatric symptoms in prospectively studied patients with autopsy-confirmed dementia with lewy bodies

OBJECTIVE: This investigation was undertaken to clarify the neuropathological substrates of key psychiatric symptoms in dementia with Lewy bodies. METHOD: The authors studied 112 autopsy-confirmed cases of dementia with Lewy bodies in patients who had had annual standardized clinical evaluations until their death. The relationships of persistent psychiatric symptoms (visual hallucinations, delusions, depression) to plaques (Consortium to Establish a Registry for Alzheimer's Disease protocol), tangles (Braak staging), and Lewy bodies (consensus Lewy body staging) were evaluated. In addition, symptom frequency and persistent symptoms were compared in the patients with Lewy body dementia and 90 patients with autopsy-confirmed Alzheimer's disease studied prospectively during life. RESULTS: The main neuropathological correlate of persistent visual hallucinations was the presence of less severe tangle pathology, but there was no significant association between tangle pathology and persistent delusions. Lewy body staging was associated with the presence of persistent visual hallucinations and persistent delusions. All baseline psychiatric features were significantly more frequent in dementia with Lewy bodies than in Alzheimer's disease, as were persistent visual hallucinations, but patients who had dementia with Lewy bodies and severe tangle pathology had a clinical symptom profile more similar to that of Alzheimer's disease patients and were less likely to have neocortical Lewy bodies. CONCLUSIONS: The modest proportion of patients with Lewy body dementia and more severe tangle pathology resembled Alzheimer's disease patients clinically. Unlike Alzheimer's disease, dementia with Lewy bodies showed a significant inverse association between tangle burden and psychosis.     

Epidemiology of and risk factors for psychosis of Alzheimer's disease: a review of 55 studies published from 1990 to 2003

OBJECTIVE: The authors reviewed studies published between 1990 and 2003 that reported the prevalence, incidence, and persistence of, as well as the risk factors associated with, psychosis of Alzheimer's disease. METHOD: PubMed and PsycINFO databases were searched by using the terms "psychosis and Alzheimer disease" and "psychosis and dementia." Empirical investigations presenting quantitative data on the epidemiology of and/or risk factors for psychotic symptoms in Alzheimer's disease were included in the review. A total of 55 studies, including a total of 9,749 subjects, met the inclusion criteria. RESULTS: Psychosis was reported in 41% of patients with Alzheimer's disease, including delusions in 36% and hallucinations in 18%. The incidence of psychosis increased progressively over the first 3 years of observation, after which the incidence seemed to plateau. Psychotic symptoms tended to last for several months but became less prominent after 1 year. African American or black ethnicity and more severe cognitive impairment were associated with a higher rate of psychosis. Psychosis was also associated with more rapid cognitive decline. Some studies found a significant association between psychosis and age, age at onset of Alzheimer's disease, and illness duration. Gender, education, and family history of dementia or psychiatric illness showed weak or inconsistent relationships with psychosis. CONCLUSIONS: Psychotic symptoms are common and persistent in patients with Alzheimer's disease. Improved methods have advanced the understanding of psychosis in Alzheimer's disease, although continued research, particularly longitudinal studies, may unveil biological and clinical associations that will inform treatments for these problematic psychological disturbances.     

Which Alzheimer patients are at risk for rapid cognitive decline?

In the current study of 1062 Alzheimer's disease (AD) patients, we employed receiver operating characteristic curve analysis to identify characteristics of patients at increased risk for rapid cognitive decline. The patients are participants at one of the nine Alzheimer's Disease Research Centers of California. Rapid decline was defined as a 3-point or greater loss on the Mini-Mental State Examination (MMSE) per year, post visit. The independent variables were age at clinic visit, age at symptom onset of AD, MMSE at patient visit, years of education, gender, ethnicity, living arrangement, presence of aphasia, delusions, hallucinations, and extrapyramidal signs. Receiver operating characteristic curve analysis indicated that AD patients presenting with moderate to severe aphasia, age at clinic visit of 75 years or less, and an MMSE greater than 7 were at increased risk for rapid cognitive decline. This information could help clinicians target these patients for pharmacologic interventions, facilitate long-term care planning, and potentially create savings by delaying or stabilizing the course of the disease.     

Lipid lowering agents are associated with a slower cognitive decline in Alzheimer's disease

BACKGROUND: Data from epidemiological studies and animal models imply that disturbances in cholesterol metabolism are linked to Alzheimer's disease susceptibility. Lipid lowering agents (LLAs) may have implications for the prevention of Alzheimer's disease. OBJECTIVE: To investigate whether LLAs are associated with a slower cognitive decline in Alzheimer's disease. METHODS: An observational study in 342 Alzheimer patients followed in a memory clinic for 34.8 months (mean age 73.5 years, mini-mental state examination score (MMSE) 21.3 at entry); 129 were dyslipaemic treated with LLAs (47% with statins), 105 were untreated dyslipaemic, and 108 were normolipaemic. The rate of cognitive decline was calculated as the difference between the first and last MMSE score, divided by the time between the measurements, expressed by year. Patients were divided into slow and fast decliners according to their annual rate of decline (lower or higher than the median annual rate of decline in the total population). RESULTS: Patients treated with LLAs had a slower decline on the MMSE (1.5 point/year, p = 0.0102) than patients with untreated dyslipaemia (2.4 points/year), or normolipaemic patients (2.6 points/year). Patients with a slower decline were more likely to be treated with LLAs. Logistic regression analysis, with low annual cognitive decline as the dependent variable, showed that the independent variable LLA (treated with or not) was positively associated with the probability of lower cognitive decline (odds ratio = 0.45, p = 0.002). CONCLUSIONS: LLAs may slow cognitive decline in Alzheimer's disease and have a neuroprotective effect. This should be confirmed by placebo controlled randomised trials in patients with Alzheimer's disease and no dyslipaemia.     

Agitation and other noncognitive abnormalities in Alzheimer's disease.

Agitation and other noncognitive abnormalities in patients with Alzheimer's disease are present in at least 50% of patients and are a serious problem for caregivers. Agitation can be divided into aggressive agitation, physically nonaggressive agitation, and verbal agitation. Persecutory delusions of suspiciousness and stealing are the most common psychotic symptoms. Auditory and visual hallucinations are also associated with delusions. Similar to delusions are misidentifications, which are false beliefs probably secondary to agnosia. They occur in one third of patients with dementia of the Alzheimer type in the form of the belief that strangers are living in the home and misidentification of the patient's home and reflection in the mirror. Passive personality changes are present early in the disease, whereas agitation and psychotic symptoms occur with disease progression and predict a more rapid rate of cognitive decline. Agitation and wandering are related to more severe cognitive impairment and psychosocial variables, and neurochemical variables that may be related to behavior disturbance require further study. There are few systematic studies of behavioral or environmental interventions for behavioral symptoms in patients with Alzheimer's disease. Current treatment emphasizes education of families, the formation of Alzheimer units in the nursing home, and adjunctive psychotropic agents to treat well-defined target symptoms.     

Delusions and hallucinations are associated with worse outcome in Alzheimer disease

BACKGROUND: Delusions and hallucinations are common in Alzheimer disease (AD) and there are conflicting reports regarding their ability to predict cognitive decline, functional decline, and institutionalization. According to all previous literature, they are not associated with mortality. OBJECTIVE: To examine whether the presence of delusions or hallucinations has predictive value for important outcomes in AD. DESIGN, SETTING, AND PARTICIPANTS: A total of 456 patients with AD at early stages (mean Folstein Mini-Mental State Examination [MMSE] score of 21 of 30 at entry) were recruited and followed up semiannually for up to 14 years (mean, 4.5 years) in 5 university-based AD centers in the United States and Europe. Using the Columbia University Scale for Psychopathology in AD (administered every 6 months, for a total of 3266 visit-assessments, average of 7.2 per patient), the presence of delusions and hallucinations was extracted and examined as time-dependent predictors in Cox models. The models controlled for cohort effect, recruitment center, informant status, sex, age, education, a comorbidity index, baseline cognitive and baseline functional performance, behavioral symptoms, and use of neuroleptics and cholinesterase inhibitors. MAIN OUTCOME MEASURES: Cognitive (Columbia MMSE score of < or =20/57 [approximate Folstein MMSE score of < or =10/30]), functional (Blessed Dementia Rating Scale [parts I and II] score of > or =10), institutionalization equivalent index, and death. RESULTS: During the full course of follow-up, 38% of patients reached the cognitive, 41% the functional, 54% the institutionalization, and 49% the mortality end point. Delusions were noted for 34% of patients at baseline and 70% at any evaluation. Their presence was associated with increased risk for cognitive (risk ratio [RR], 1.50; 95% confidence interval [CI], 1.07-2.08) and functional decline (RR, 1.41; 95% CI, 1.02-1.94). Hallucinations were present in 7% of patients at initial visit and in 33% at any visit. Their presence was associated with increased risk for cognitive decline (RR, 1.62; 95% CI, 1.06-2.47), functional decline (RR, 2.25; 95% CI, 1.54-2.27), institutionalization (RR, 1.60; 95% CI, 1.13-2.28), and death (RR, 1.49; 95% CI, 1.03-2.14). CONCLUSIONS: Delusions and hallucinations are very common in AD and predict cognitive and functional decline. Presence of hallucinations is also associated with institutionalization and mortality.     

Isolated hallucinosis in Alzheimer's disease is associated with African-American race

OBJECTIVES: The aim of this investigation was to study the relationship between isolated hallucinosis and race in Alzheimer's disease. METHODS: This was a cross-sectional, case control study carried out at the Neuropsychiatry Service, outpatient clinic at the Johns Hopkins School of Medicine, USA. The participants were 237 community-residing patients with probable Alzheimer's disease according to NINCDS/ADRDA criteria were included in the study. 9 patients with isolated hallucinosis were compared to a control group of 228 patients who had neither delusions nor hallucinations. Patients with only delusions or both delusions and hallucinations were excluded based on prior research. Patients were assessed clinically for the presence of hallucinations using the DSM-IV glossary definitions. They were also rated on standardized measures of cognitive impairment, depression, functional impairment, and general health. RESULTS: There was a significant association between hallucinations and race in patients with Alzheimer's disease. Before adjustment for other variables, the African-American race conferred a 5.5-fold (95% CI = 1.4-21.6; p = 0.02) increased risk for isolated hallucinosis. After adjustment for multiple other variables, this risk increased further to 27.2-fold (95% CI = 1.6-457.3; p = 0.02). CONCLUSIONS: African-American patients with Alzheimer's disease are more likely to have isolated hallucinations than Caucasian patients even after statistical adjustment for multiple confounding variables, which might distort this association. This finding has implications for our understanding of the etio-pathogenesis of hallucinations in Alzheimer's disease and for meeting health service needs of African-American patients.     

Risperidone, olanzapine and quetiapine in the treatment of behavioral and psychological symptoms in patients with Alzheimer's disease: preliminary findings from a naturalistic, retrospective study

The objectives of this retrospective, naturalistic study were to provide preliminary data on the effects of 6 months treatment with risperidone, olanzapine and quetiapine on behavioral disturbances, within a sample of outpatients with mild to moderate Alzheimer's disease, and on predictors of response. Between July 2005 and December 2005, data were collected from 58 consecutive outpatients with a DSM-IV-TR diagnosis of Alzheimer's disease with behavioral disturbances, who received a 6-month treatment with risperidone, olanzapine or quetiapine. Primary outcome measures were Neuropsychiatric Inventory (NPI) total score and its items forming the basic core of behavioral disturbances in Alzheimer's disease: delusions, hallucinations and agitation/aggressiveness. Secondary outcome measures were Mini-Mental State Examination (MMSE), Activities of Daily Living, Instrumental Activities of Daily Living and Clinical Insight Rating scale. Correlations between baseline MMSE score and improvements in behavioral disturbances were investigated. At 6 months mean NPI total score had fallen 43.5% in the risperidone group, 45.6% in the olanzapine group and 33.3% in the quetiapine group, with no significant between-group differences. Global cognitive function showed no significant change from baseline to end-point. Incidence of adverse events was low. A significant correlation was found between MMSE score and NPI total score and NPI item agitation decreases. Risperidone, olanzapine and quetiapine produced significant improvements in behavioral disturbances and were well tolerated. No significant differences emerged among treatments. The preliminary results also suggest that baseline cognitive function might influence treatment response.     

The effects of olanzapine in reducing the emergence of psychosis among nursing home patients with Alzheimer's disease

BACKGROUND: Elderly patients with Alzheimer's disease (AD) commonly exhibit psychotic symptoms, prompting clinicians to administer antipsychotics. This article compares the effects of olanzapine and placebo in the emergence of hallucinations or delusions in AD patients with symptoms of agitation/aggression but little or no psychotic symptomatology at baseline. METHOD: A multicenter, double-blind, placebo-controlled study was conducted in nursing home patients with AD according to DSM-IV criteria and symptoms of agitation/aggression and/or psychosis. Patients (N = 206) were randomly assigned to receive either placebo or fixed-dose olanzapine (5, 10, or 15 mg/day) for up to 6 weeks. This article analyzes data from a subgroup of patients (N = 165) with no or minimal delusions and/or hallucinations at baseline as measured by the Neuropsychiatric Inventory-Nursing Home Version (NPI/NH). Three subsets of patients were identified on the basis of their symptoms at baseline: those with no clinically significant hallucinations, those with no clinically significant delusions, and those with no clinically significant delusions or hallucinations. RESULTS: Of the patients without hallucinations or delusions at baseline (N = 75), the placebo-treated patients showed significantly greater development of these symptoms compared with olanzapine-treated patients overall (NPI/NH hallucinations + delusions mean change score, +2.73 vs. +0.27, p = .006). Similarly, of the patients without baseline hallucinations (N = 153), the placebo-treated patients showed greater hallucinations score increases than did olanzapine-treated patients overall (+1.25 vs. +0.33, p = .026), whereas patients without baseline delusions (N = 87) showed no significant treatment effects. Olanzapine had a favorable safety profile in each patient subset. CONCLUSION: These results suggest that, overall, olanzapine effectively attenuated emergence of psychosis in a short-term trial of patients with Alzheimer's disease.     

Progression of parkinsonism and loss of cognitive function in Alzheimer disease

OBJECTIVE: To assess the relation between parkinsonism and cognitive function in Alzheimer disease from cross-sectional and longitudinal perspectives. DESIGN: Prospective cohort study with annual clinical evaluations during a 4-year period. SETTING: Alzheimer disease clinic in an urban medical center. PARTICIPANTS: Four hundred ten persons with clinically diagnosed Alzheimer disease. MAIN OUTCOME MEASURES: Global and specific measures of cognitive function and parkinsonism. RESULTS: Higher levels of parkinsonism at baseline were reliably associated with lower levels of cognitive function at baseline and with more rapid cognitive decline during the 4-year study period. However, the associations were small, with baseline parkinsonism accounting for less than 10% of the variation either in baseline cognitive function or in the rate of cognitive decline. By contrast, rates of change in parkinsonism and cognitive function were strongly correlated, with 70% or more shared variance in the rates of change in many models. The association was observed with diverse measures of cognition and parkinsonism and was not explained by demographic variables or use of neuroleptic medications. CONCLUSION: In Alzheimer disease, progressive worsening of parkinsonism is more strongly associated with cognitive decline than previously recognized. Arch Neurol. 2000.     

Alzheimer's disease with delusions and hallucinations: neuropsychological and electroencephalographic correlates

We longitudinally evaluated the neuropsychological functions, rate of progression, and waking EEG findings in 17 patients with probable Alzheimer's disease (AD) with delusions and hallucinations, and compared them with those of matched AD patients without delusions and hallucinations. AD patients with delusions and hallucinations had a more rapid rate of decline, as measured by the Mini-Mental State Examination, a specific defect in receptive language, and a greater frequency of aggression and hostility. Visual EEG analysis showed that these patients had a significantly greater proportion of moderately abnormal EEGs, and spectral analysis confirmed the increased amount of delta and theta activity. These data demonstrate that AD patients with delusions and hallucinations have a greater degree of cerebral dysfunction and a relatively focal neuropsychological defect, which may indicate a localized pathologic abnormality.     

Prospective study of relations between cortical Lewy bodies, poor eyesight, and hallucinations in Alzheimer's disease.

The presence of hallucinations is included in some, but not all, of the sets of clinical diagnostic criteria that have been proposed for dementia associated with cortical Lewy bodies. These criteria were developed from retrospective casenote analyses. This prospective, longitudinal study suggests that, in patients with Alzheimer's disease, cortical Lewy bodies are associated with more persistent and severe hallucinations, independently of any association with severity of cognitive decline. Poor eyesight contributes to the severity but not the persistence of the hallucinations.     

Relationship of behavioral and psychological symptoms to cognitive impairment and functional status in Alzheimer's disease

OBJECTIVE: This cross-sectional study examined the relationship of behavioral and psychological symptoms to cognitive and functional impairment in Alzheimer's disease (AD). DESIGN: One hundred and fourteen patients were evaluated consecutively at a university-affiliated outpatient memory disorders clinic and diagnosed with possible or probable Alzheimer's disease (AD) according to NINCDS-ADRDA criteria. Subjects were assessed with the Behavioral Pathology in Alzheimer's Disease Scale (BEHAVE-AD), Revised Memory and Behavior Problem Checklist (RMBPC), Blessed Dementia Scale (BDS), and Mini-Mental State Examination (MMSE). RESULTS: Several symptoms of behavioral pathology showed associations with MMSE scores, including activity disturbances, delusions, and hallucinations. After controlling for the variance associated with the MMSE, activity disturbances, diurnal disturbances, delusions, and hallucinations were linked with BDS scores. CONCLUSIONS: The results suggest that some non-cognitive symptoms may be related to the neurobiologic mechanisms underlying the increased cognitive dysfunction in AD. Specific symptoms of behavioral pathology may also impact a patient's ability to perform important self-maintenance behaviors.     

Factors associated with psychotic symptoms in Alzheimer's disease

OBJECTIVES—Many clinical and biological factorshave been reported to be associated with the presence of psychosis inpatients with Alzheimer's disease, although the associations werevariable. The aim of this study was to clarify factors associated withthe presence of psychosis in patients with Alzheimer's disease.
METHODS—Psychiatric functioning was studied in 228 patients with Alzheimer's disease based on the results of thebehavioural pathology in Alzheimer's disease rating scale or theneuropsychiatric inventory. The effects of sex, education level, age,duration of illness, cognitive function, and apolipoprotein E genotypewere investigated for dichotomous psychotic status with a multiplelogistic regression analysis.
RESULTS—Of the 228 patients with Alzheimer'sdisease, 118 (51.8%) showed evidence of delusions or hallucinations.Of these, 94 had delusions only, three had hallucinations only, and 21 had both. Older age, female sex, longer duration of illness, and moresevere cognitive impairment were the factors independently associated with the presence of psychosis. The presence of psychosis was notsignificantly related to either educational level or apolipoprotein E genotype.
CONCLUSIONS—Age, sex, and severity of illness wereindependent factors associated with the presence of psychosis inpatients with Alzheimer's disease. The reason why some patients withAlzheimer's disease develop psychosis remains unclear. There may bedistinctive subtypes of Alzheimer's disease or the presence ofindividual factors which affect the development of psychosis.

     

Depressive symptoms,cognitive decline,and risk of AD in older persons

BACKGROUND: Cross-sectional and retrospective case-control studies suggest an association of depression symptoms with cognitive impairment and AD, but there have been few prospective studies and their results have been inconsistent. METHODS: Participants are Catholic clergy members who were aged > or =65 years and who did not have clinical evidence of AD. During a 7-year period, they underwent annual clinical evaluations that included clinical classification of AD and detailed cognitive function testing from which global and specific measures of cognition were derived. Number of depressive symptoms was assessed at baseline with a modified, 10-item Center for Epidemiologic Studies Depression Scale (CES-D). The association of CES-D score with incident AD, using proportional hazards models, and cognitive decline, using random effects models, was examined. RESULTS: At baseline, participants reported an average of about one depressive symptom on the CES-D scale (range, 0 to 8). During the 7 years of follow-up, 108 persons developed AD. In analyses that controlled for selected demographic and clinical variables including baseline level of cognitive function, CES-D score was associated with both risk of AD and rate of cognitive decline. For each depressive symptom, risk of developing AD increased by an average of 19%, and annual decline on a global cognitive measure increased by an average of 24%. CONCLUSIONS: The results raise the possibility that depressive symptoms in older persons may be associated with risk of developing AD.