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Background Alzheimer disease (AD) is considered a leading cause of death, but few studies have examined the contribution of AD to mortality based on follow-up of representative US cohorts. Objective To examine mortality rates, duration of survival, causes of death, and the contribution of AD to the risk of mortality in an aging community-based cohort, controlling for other predictors. Design Fifteen-year prospective epidemiological study. Mortality rates per 1000 person-years and the population-attributable risk of mortality were determined. Cox proportional hazards models were used to estimate relative risk of mortality due to AD, adjusting for relevant covariates. Death certificates were abstracted for listed causes of death. Setting A largely blue-collar rural community in southwestern Pennsylvania. Participants A community-based cohort of 1670 adults 65 years and older at study enrollment. Main Outcome Measure Mortality. Results In the overall cohort, AD was a significant predictor of mortality, with a hazard ratio of 1.4 after adjusting for covariates. The population-attributable risk of mortality from AD was 4.9% based on the same model. Examining the sexes separately, AD increased mortality risk only among women. Death certificates of AD subjects were more likely to list dementia/AD, other brain disorders, pneumonia, and dehydration, and less likely to include cancer. Conclusions Alzheimer disease was responsible for 4.9% of the deaths in this elderly cohort. Alzheimer disease increased the risk of mortality 40% in the cohort as a whole and separately in women but not in men. The mean (SD) duration of survival with AD was 5.9 (3.7) years, and longer with earlier age at onset. [ABSTRACT FROM AUTHOR]

Objective: Persons with mild cognitive impairment (MCI) and Alzheimer disease (AD) are at heightened risk for future decisional incapacity. We sought to characterize advance care planning (ACP) rates over time in individuals who had no advance directives (living will or durable power of attorney) in place when they initially presented for a cognitive evaluation., Design: Retrospective analysis of data that had been prospectively collected., Setting: Alzheimer's Disease Research Center memory disorders clinic., Participants: Persons (N = 127) with a diagnosis of MCI or early AD (n = 72) or moderate to severe AD (n = 55) and no advance directives upon initial presentation for a cognitive evaluation., Measurements: Extraction of responses to items pertaining to ACP assessed during annual semistructured interviews., Results: By 5 years of follow-up, 39% of the sample had initiated ACP, with little difference by baseline diagnosis. Younger subjects (younger than 65 years) were significantly more likely to initiate advance directives (43%) than older subjects (37%). This age effect was more pronounced in men than in women as well as in married subjects, those with a family history of dementia, those with no depressive disorder, and subjects with moderate to severe AD (versus those with MCI or early AD) at baseline., Conclusion: Only a minority of subjects initiated ACP. The findings suggest the need for interventions aimed at enhancing ACP completion rates, particularly among older adults with cognitive impairment, since these individuals may have a time-limited opportunity to plan for future medical, financial, and other major life decisions.

Background: Psychotic symptoms in Alzheimer disease (AD + P) identify a heritable phenotype associated with greater cognitive impairment. Knowing when the cognitive course of AD + P subjects diverges from that of subjects without psychosis would enhance understanding of how genetic variation results in AD + P and its associated cognitive burden. This study seeks to determine whether the degree of cognitive impairment and cognitive decline in early AD predicts subsequent AD + P onset., Methods: 361 subjects with possible or probable AD or mild cognitive impairment (MCI) without psychosis were evaluated every 6 months until psychosis onset., Results: Severity of cognitive dysfunction was a strong predictor of AD + P up to two years prior to psychosis onset. Cognition did not decline more rapidly prior to onset of AD + P., Conclusions: Individuals who will develop AD + P already demonstrate excess cognitive impairment during the mild stages of disease. Genetic variation and brain pathophysiology may lead to a cognitive risk phenotype which is present prior to dementia onset.

Objective: To examine the prevalence and sociodemographic correlates of written advance planning among patients with or at risk for dementia-imposed decisional incapacity., Design: Retrospective, cross-sectional., Setting: University-based memory disorders clinic., Participants: Persons with a consensus-based diagnosis of mild cognitive impairment (N = 112), probable or possible Alzheimer disease (AD; N = 549), and nondemented comparison subjects (N = 84)., Intervention: N/A., Measurements: Semistructured interviews to assess durable power of attorney (DPOA) and living will (LW) status upon initial presentation for a dementia evaluation., Results: Sixty-five percent of participants had a DPOA and 56% had a LW. Planning rates did not vary by diagnosis. European Americans (adjusted odds ratio = 4.75; 95% CI, 2.40-9.38), older adults (adjusted odds ratio = 1.05; 95% CI, 1.03-1.07) and college graduates (adjusted odds ratio = 2.06; 95% CI, 1.33-3.20) were most likely to have a DPOA. Findings were similar for LW rates., Conclusions: Although a majority of persons with and at risk for the sustained and progressive decisional incapacity of AD are formally planning for the future, a substantial minority are not.

Profound behavioral changes in persons with dementia often negatively affect the quality of marital relationships. Yet, little is known about the extent to which the marital relationship may be affected when the care recipient has milder degrees of cognitive impairment. This study characterizes marital quality among 27 adults who live with a spouse with mild cognitive impairment (MCI). This study demonstrates that at mild levels of cognitive impairment, specific behaviors in the affected person are distressing and may degrade the quality of the marital relationship. These results have implications for clinical practice and the delivery of health care and social services to these families. It is important to develop interventions to address the needs of these individuals and their caregivers. Results of this study suggest the need for mental health interventions designed to preserve the quality of these marital relationships.

Several independent linkage studies have mapped a broad susceptibility region for Alzheimer's disease (AD) on the long arm of chromosome 10. There are several biological candidate genes in this region, including choline acetyltransferase (CHAT). A number of studies have examined the role of CHAT genetic variants with AD risk and age-at-onset (AAO), but the results are equivocal. We examined the association of three Single Nucleotide Polymorphisms (SNPs) in the CHAT gene in 1001 white sporadic late-onset AD (LOAD) cases and 708 white controls. We also examined the role of these three SNP with quantitative traits of AD including AAO, disease duration, and Mini-Mental State Examination (MMSE) score. We observed both allelic and genotypic associations of the intron 9 SNP with AD risk in the total sample (p = 0.029 for genotype and p = 0.028 for allele frequency differences) as well as among non-APOE*4 carriers (p = 0.007 for genotype and p = 0.006 for allele frequency differences). Three-site haplotype analysis confirmed that haplotypes determined by the intron 9 SNP were associated with either risk (p = 0.0009) or protective (p = 0.0082) effects among non-APOE*4 carriers. The three CHAT SNPs also showed a modest association with MMSE score. Our data suggest that genetic variation in the CHAT gene may be associated with AD risk and quantitative traits related to AD.

In addition to genetic effects on disease risk, age-at-onset (AAO) of Alzheimer's disease (AD) is also genetically controlled. Using AAO as a covariate, a linkage signal for AD has been detected on chromosome 14q32 near the alpha1-antichymotrypsin (ACT) gene. Previously, a signal peptide polymorphism (codon -17A>T) in the ACT gene has been suggested to affect AD risk, but with inconsistent findings. Given that a linkage signal for AAO has been detected near ACT, we hypothesized that ACT genetic variation affects AAO rather than disease risk and this may explain the previous inconsistent findings between ACT genetic variation and AD risk. We examined the impact of the ACT signal peptide polymorphism on mean AAO in 909 AD cases. The ACT polymorphism was significantly associated with AAO and this effect was independent of the APOE polymorphism. Mean AAO among ACT/AA homozygotes was significantly lower than that in the combined AT+TT genotype group (p = 0.019) and this difference was confined to male AD patients (p = 0.002). Among male AD patients, the ACT/AA genotype was also associated with shorter disease duration before death as compared to the ACT/AT+TT genotypes (p = 0.012). These data suggest that the ACT gene may affect AAO and disease duration of AD.

Background: While the deleterious psychosocial and mental health effects of dementia caregiving are firmly established, very little is known about the burdens or psychiatric outcomes of providing care to a spouse with less severe cognitive impairment, such as mild cognitive impairment (MCI). We characterized the nature and level of caregiver burden and psychiatric morbidity in spouses of persons diagnosed with MCI., Methods: Interview assessments were completed on a cohort of 27 spouses of persons with a recent diagnosis of MCI. Patient medical records were reviewed to collect information regarding the MCI patient's medical history., Results: Respondents endorsed elevated levels of both task-related responsibilities and subjective caregiver burden. Depression and anxiety symptom levels also showed some elevations. Measures of caregiver burden were significantly associated with depression and anxiety levels. In particular, even after controlling for demographic risk factors for distress, nursing task burden was correlated with elevated depressive symptoms, and greater lifestyle constraints were correlated with higher anxiety levels., Conclusions: Although caregiver burden and psychiatric morbidity levels were lower than those typically observed in family dementia caregiving samples, our findings suggest that MCI caregivers have already begun to experience distress in association with elevated caregiving burden. These individuals may be ideal targets for selective preventive interventions to maximize their psychological well-being as caregiving burdens related to their spouses' cognitive impairment increase., (Copyright (c) 2005 John Wiley & Sons, Ltd)

Objectives: To identify characteristics of older primary care patients who were cognitively impaired and who underwent mental status testing by their physicians., Design: Cross-sectional and retrospective analysis., Setting: Seven small-town primary care practices., Participants: A total of 1,107 patients with a mean+/-standard deviation age of 76.3+/-6.6, screened using the Mini-Mental State Examination (MMSE); medical records reviewed., Measurements: Demographics, MMSE, medical record information. Odds ratios (OR) with 95% confidence intervals (CI), adjusted for age, sex, and education., Results: Thirty-one percent of the sample had MMSE scores of less than 25. Among these patients, physicians documented memory loss in only 23% which was significantly more often than in the higher scoring group (OR=1.9, 95% CI=1.3-2.8), basic activity of daily living (ADL) impairment in 7.9% (OR=2.4, 95% CI=1.3-4.4), instrumental ADL (IADL) impairment in 6.7% (OR=2.2, 95% CI=1.1=4.2), dementia in 12.2% (OR=3.7, 95% CI=2.0-6.8), and prescription of cholinesterase inhibitors in 7.6% (OR=4.4, 95% CI=1.9-10.2). Physicians recorded mental status testing largely in patients with research MMSE scores of 24 to 28, significantly more often when they also documented memory loss (OR=3.8, 95% CI=2.5-5.6) or impaired IADLs (OR=2.7, 95% CI=1.4-5.2), diagnosed dementia (OR=4.9, 95% CI=2.8-8.6), referred to specialists (OR=6.3, 95% CI=2.5-16.2) or social services (OR=3.6, 95% CI=1.8-7.3), or prescribed cholinesterase inhibitors (OR=8.5, 95% CI=4.2-17.5)., Conclusion: Physicians noted impairment in a minority of impaired patients. They tested mental status in those with documented cognitive and functional difficulties, in very mildly impaired patients, and in those for whom they intervened.

Objective: To estimate the prevalence and examine the course of mild cognitive impairment (MCI), amnestic type, using current criteria, within a representative community sample., Methods: Retroactive application of MCI criteria to data collected during a prospective epidemiologic study was performed. The subjects were drawn from voter registration lists, composing a cohort of 1,248 individuals with mean age of 74.6 (5.3) years, who were nondemented at entry and who were assessed biennially over 10 years of follow-up. The Petersen amnestic MCI criteria were operationalized as 1) impaired memory: Word List Delayed Recall score of <1 SD below mean; 2) normal mental status: Mini-Mental State Examination score of 25+; 3) normal daily functioning: no instrumental impairments; 4) memory complaint: subjective response to standardized question; 5) not demented: Clinical Dementia Rating Scale score of <1., Results: At the five assessments, amnestic MCI criteria were met by 2.9 to 4.0% of the cohort. Of 40 persons with MCI at the first assessment, 11 (27%) developed dementia over the next 10 years. Over each 2-year interval, MCI persons showed increased risk of dementing (odds ratio = 3.9, 95% CI = 2.1 to 7.2); 11.1 to 16.7% progressed to Alzheimer disease and 0 to 5.0% progressed to other dementias. Over the same intervals, 11.1 to 21.2% of those with MCI remained MCI; of 33.3 to 55.6% who no longer had MCI, half had reverted to normal., Conclusions: In this community-based sample, 3 to 4% of nondemented persons met MCI operational criteria; despite increased risk of progressing to dementia, a substantial proportion also remained stable or reverted to normal during follow-up. Amnestic MCI as currently defined is a high-risk but unstable and heterogeneous group.

The authors examined the pattern of use of psychiatric medication as prescribed by community physicians in 1,155 patients with probable Alzheimer's disease (AD) referred to the Alzheimer's Disease Research Center of Pittsburgh between April 1983 and July 2000. The use of antidepressants and of sedatives, hypnotics, and anxiolytics (SHA) increased over time, while the use of antipsychotics decreased. The increased use of antidepressants and decreased use of antipsychotics may reflect the growing evidence that newer antidepressants (e.g., selective serotonin reuptake inhibitors) can be used to treat not only mood-related disorders, but also abnormal behavior (e.g., aggression, agitation) and sleep disorders in AD. Although the use of SHA has a proven deleterious effect on patients with AD, their use has increased over the past two decades.

Objective: To examine the risk factors for mild cognitive impairment (MCI) in a longitudinal population study-the Cardiovascular Health Study Cognition Study., Design: We examined the factors that in the period 1991 through 1994 predicted the development of MCI in all participants of the Cardiovascular Health Study Cognition Study. Further examination was conducted in the Pittsburgh, Pa, cohort (n = 927), where participants with MCI were classified as having either the MCI amnestic-type or the MCI multiple cognitive deficits-type., Setting: Multicenter population study., Patients: This study includes all participants of the Cardiovascular Health Study Cognition Study (n = 3608) who had a magnetic resonance imaging (MRI) scan of the brain between 1991 and 1994, and detailed neuropsychological, neurological, and medical evaluations to identify the presence of MCI or dementia in the period 1998 to 1999. The mean time between the closest clinical examination to the MRI and the diagnostic evaluation for cognitive disorders was 5.8 years for the Cardiovascular Health Study Cognition Study cohort and 6.0 years for the Pittsburgh cohort., Main Outcome Measures: Risk factors for MCI at the time of the MRI were identified using logistic regression, controlling for age, race, educational level, baseline Modified Mini-Mental State Examination and Digit Symbol Test scores, measurements of depression, MRI findings (atrophy, ventricular volume, white matter lesions, and infarcts), the presence of the apolipoprotein E (APOE) epsilon4 allele, hypertension, diabetes mellitus, and heart disease., Results: Mild cognitive impairment (n = 577) was associated with race (African American), low educational level, low Modified Mini-Mental State Examination and Digit Symbol Test scores, cortical atrophy, MRI-identified infarcts, and measurements of depression. The MCI amnestic-type was associated with MRI-identified infarcts, the presence of the APOE epsilon4 allele, and low Modified Mini-Mental State Examination scores. The MCI multiple cognitive deficits-type was associated with low Modified Mini-Mental State Examination and Digit Symbol Test scores., Conclusions: The development of MCI is associated with measurements of cognition and depression, racial and constitutional factors, and cerebrovascular disease. Early cognitive deficits seem to be a common denominator for the 2 forms of MCI; the presence of cerebrovascular disease and the APOE epsilon4 allele is associated with the amnestic type of MCI.

Objective: To examine the prevalence of mild cognitive impairment (MCI) and its diagnostic classification in the Cardiovascular Health Study (CHS) Cognition Study., Design: The CHS Cognition Study is an ancillary study of the CHS that was conducted to determine the presence of MCI and dementia in the CHS cohort., Setting: Multicenter population study., Patients: We examined 3608 participants in the CHS who had undergone detailed neurological, neuropsychological, neuroradiological, and psychiatric testing to identify dementia and MCI., Main Outcome Measures: The prevalence of MCI was determined for the whole cohort, and specific subtypes of MCI were examined in detail only at the Pittsburgh, Pa, center (n = 927). Mild cognitive impairment was classified as either MCI amnestic-type or MCI multiple cognitive deficits-type., Results: The overall prevalence of MCI was 19% (465 of 2470 participants); prevalence increased with age from 19% in participants younger than 75 years to 29% in those older than 85 years. The overall prevalence of MCI at the Pittsburgh center was 22% (130 of 599 participants); prevalence of the MCI amnesic-type was 6% and of the MCI multiple cognitive deficits-type was 16%., Conclusions: Twenty-two percent of the participants aged 75 years or older had MCI. Mild cognitive impairment is a heterogeneous syndrome, where the MCI amnestic-type is less frequent than the MCI multiple cognitive deficits-type. Most of the participants with MCI had comorbid conditions that may affect their cognitive functions.

Context: The concept of active life expectancy, the number of years a person can expect to live without disability, is used for the first time, to our knowledge, to examine the effect of Alzheimer disease (AD) on total life expectancy with different degrees of disability., Objectives: To estimate and compare total life expectancy and average duration lived with different degrees of disability, between persons with and without AD., Design: Ten-year prospective epidemiologic study., Setting: A largely blue-collar rural community in Southwestern Pennsylvania., Participants: A population-based cohort of 1201 subjects (at the beginning of follow-up) with a mean age of 75 years., Main Outcome Measures: At age 70 and every 2 years thereafter, among persons with AD and nondemented persons, (1) the total expectancy of remaining life and (2) the duration lived with different numbers of impaired instrumental activities of daily living (IADLs), grouped as 0 to 1, 2 to 5, and 6 to 7 impairments., Results: Alzheimer disease greatly shortened the total life expectancy to a similar extent in men and women, with the most pronounced reduction among those who were younger. Besides their shorter survival, men and women with AD spent more absolute years, and also a greater proportion of their remaining lives, with 6 to 7 IADL impairments than did their nondemented age peers. Nondemented women spent more years with 2 to 5 IADL impairments than nondemented men, while women with AD spent more years with 6 to 7 IADL impairments than men with AD., Conclusion: The concept of active life expectancy adds a useful new dimension to the study of outcomes in AD.