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Lack of a unitary operational definition of mild cognitive impairment (MCI) has resulted in mixed prevalence rates and unclear predictive validity regarding conversion to dementia and likelihood of reversion. We examined 1,721 nondemented participants aged 65 and older from the Adult Changes in Thought (ACT) community-based cohort. Participants were followed longitudinally through biennial visits (average years assessed = 5.38). Categorization of MCI was based on: 1) deviation of neuropsychological test scores from a benchmark based on either standard or individualized expectations of a participant's mean premorbid cognitive ability, and 2) cutoff for impairment (1.0 versus 1.5 standard deviations [sd] below benchmark). MCI prevalence ranged from 56-92%; using individualized benchmarks and less stringent cutoffs produced higher rates. During follow-up, 17% of the cohort developed dementia. Examination of sensitivity, specificity, and predictive validity revealed that the criterion of 1.5 sd from the standardized benchmark was optimal, but still had limited predictive validity. Participants meeting this criterion at their first visit were three times more likely to develop dementia and this increased to seven times if participants had this diagnosis at the second timepoint as well. Those who did not have an MCI diagnosis at their first visit, but did at their second, had a significant increase of risk (but to a lesser extent than those diagnosed at both visits), while those who had an MCI diagnosis at their first visit, but not their second, did not have a significantly increased risk. These results highlight how assessing MCI stability greatly improves prediction of risk.

Objectives: We estimated dementia incidence rates, life expectancies with and without dementia, and percentage of total life expectancy without dementia., Methods: We studied 3605 members of Group Health (Seattle, WA) aged 65 years or older who did not have dementia at enrollment to the Adult Changes in Thought study between 1994 and 2008. We estimated incidence rates of Alzheimer's disease and dementia, as well as life expectancies with and without dementia, defined as the average number of years one is expected to live with and without dementia, and percentage of total life expectancy without dementia., Results: Dementia incidence increased through ages 85 to 89 years (74.2 cases per 1000 person-years) and 90 years or older (105 cases per 1000 person-years). Life expectancy without dementia and percentage of total life expectancy without dementia decreased with age. Life expectancy with dementia was longer in women and people with at least a college degree. Percentage of total life expectancy without dementia was greater in younger age groups, men, and those with more education., Conclusions: Efforts to delay onset of dementia, if successful, would likely benefit older adults of all ages.

There are few studies on the incidence of dementia in representative minority populations in the United States; however, no population-based study has been conducted on Japanese American women. We identified 3045 individuals aged 65+ with at least 1 parent of Japanese descent living in King County, WA in the period 1992 to 1994, of whom 1836 were dementia-free and were examined every 2 years (1994 to 2001) to identify incident cases of all dementias, Alzheimer disease (AD), vascular dementia (VaD), and other dementias. Cox regression was used to examine associations with age, sex, years of education, and apolipoprotein (APOE)-ε4. Among 173 incident cases of dementia, the overall rate was 14.4/1000/y, with rates being slightly higher among women (15.9/1000) than men (12.5/1000). Rates roughly doubled every 5 years for dementia and AD; the age trend for VaD and other dementias was less consistent. Sex was not significantly related to incidence of dementia or its subtypes in adjusted models. There was a trend for an inverse association with increasing years of education. APOE-ε4 was a strong risk factor for all dementias [hazard ratio (HR)=2.89; 95% confidence interval (CI), 1.88-4.46], AD (HR=3.27; 95% CI, 2.03-5.28), and VaD (HR=3.33; 95% CI, 1.34-8.27). This study is the first to report population-based incidence rates for both Japanese American men and women.

Background: Alzheimer disease and other dementing disorders are major sources of morbidity and mortality in aging societies. Proven strategies to delay onset or reduce risk for dementing disorders would be greatly beneficial., Objective: To determine whether regular exercise is associated with a reduced risk for dementia and Alzheimer disease., Design: Prospective cohort study., Setting: Group Health Cooperative, Seattle, Washington., Participants: 1740 persons older than age 65 years without cognitive impairment who scored above the 25th percentile on the Cognitive Ability Screening Instrument (CASI) in the Adult Changes in Thought study and who were followed biennially to identify incident dementia., Measurements: Baseline measurements, including exercise frequency, cognitive function, physical function, depression, health conditions, lifestyle characteristics, and other potential risk factors for dementia (for example, apolipoprotein E epsilon4); biennial assessment for dementia., Results: During a mean follow-up of 6.2 years (SD, 2.0), 158 participants developed dementia (107 developed Alzheimer disease). The incidence rate of dementia was 13.0 per 1000 person-years for participants who exercised 3 or more times per week compared with 19.7 per 1000 person-years for those who exercised fewer than 3 times per week. The age- and sex-adjusted hazard ratio of dementia was 0.62 (95% CI, 0.44 to 0.86; P = 0.004). The interaction between exercise and performance-based physical function was statistically significant (P = 0.013). The risk reduction associated with exercise was greater in those with lower performance levels. Similar results were observed in analyses restricted to participants with incident Alzheimer disease., Limitations: Exercise was measured by self-reported frequency. The study population had a relatively high proportion of regular exercisers at baseline., Conclusion: These results suggest that regular exercise is associated with a delay in onset of dementia and Alzheimer disease, further supporting its value for elderly persons.

Objectives: To study whether subjective memory deterioration is associated with future dementia in older people., Design: A population-based prospective cohort study begun in 1994 with biennial follow-up interviews., Setting: Community-based members of Group Health Cooperative, a large health maintenance organization in the Seattle area., Participants: A sample of 1,883 subjects, dementia free, aged 65 and older, who scored 91 or higher on the 100-point Cognitive Ability Screening Instrument (CASI) at study entry., Measurements: Subjective memory was assessed by asking whether memory had changed on 5-point Likert scales (e.g., 1=definitely improved, 3=no change, 5=definitely deteriorated) with regard to five items: remembering names, faces, friends, and appointments and judging the time. The items were summed for a possible total score ranging from 5 to 25. Subjective memory deterioration was defined as present if the total score was 20 or above. Cognitive performance was measured using the CASI. Incident dementia cases were identified using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria., Results: Of 1,883 subjects, 126 developed dementia during 5 years of follow-up. Subjective memory deterioration was associated with cognitive decline and incident dementia. Age modified the association between subjective memory deterioration and future dementia. For persons reporting subjective memory deterioration at the ages of 70, 75, and 80, the hazard ratios of developing dementia were 6.0 (95% confidence interval (CI)=2.1-18), 3.2 (95% CI=1.6-6.2) and 1.6 (95% CI=0.86-3.1), respectively., Conclusion: Subjective memory deterioration was found to precede the development of dementia in older people with normal cognitive screening results. These findings suggest that a high level of subjective memory deterioration in persons with normal objective cognitive function may identify a subset of individuals at greater risk for developing dementia.

Context: Age-specific incidence rates for dementia and Alzheimer disease (AD) are important for research and clinical practice. Incidence estimates for the United States are few and vary with the population sampled and study design; we present data that will contribute to a consensus of these rates., Objectives: To provide age-specific incidence estimates for dementia and AD and to estimate the association of sex, educational level, and apolipoprotein E genotype with onset., Design: Prospective cohort study; begun in 1994 with follow-up interviews every 2 years., Setting: Members of community-based, large health maintenance organization with demographics consistent with the surrounding base population; diagnostic evaluation by university-based study clinicians., Subjects: Random sample of subjects aged 65 years or older from the base population; dementia free, nonnursing home residents. Of 5422 who were eligible, 2581 were enrolled, and 2356 had at least 1 follow-up evaluation (10 591 person-years of observation)., Main Outcome Measure: Dementia and Alzheimer disease diagnoses were based on standard criteria. Age-specific incidence rates were calculated using a person-years approach with Poisson distribution confidence intervals. Cox proportional hazards model analysis was used to examine other factors., Results: Two hundred fifteen cases of dementia and 151 cases of AD were diagnosed. Incidence rates for dementia and AD increase across the 5-year age groups; AD rates rise from 2.8 per 1000 person-years (age group, 65-69 years) to 56.1 per 1000 person-years in the older than 90-year age group. The rates nearly triple from the 75-to-79-year and 80-to-84-year age groups, but the relative increase is much less thereafter. Sex was not associated with AD onset. Educational level (>15 years vs <12 years) was associated with a decreased risk of AD; however, the association was also dependent on the baseline cognitive screening test score., Conclusions: Our dementia and AD incidence rates are consistent with recent US and European cohort studies, providing clinicians and researchers new information concerning the reproducibility of incidence estimates across settings. Increased risk was associated with age and the apolipoprotein E genotype; also with a low baseline cognitive screening test score. Educational level was inversely associated with the risk of dementia and positively associated with the baseline cognitive test score; thus, detection of AD by the screening test could also be influenced by educational level.

Background: Hippocampal sclerosis (HS) is a neuropathologic finding characterized by neuronal loss and gliosis in the CA-1 and subiculum of the hippocampus. Previous studies of HS have shown that this is a common postmortem finding in elderly subjects with dementia. However, these studies were from selected samples and therefore are not necessarily representative of patients seen in the general medical community., Objectives: To examine the clinical and pathologic characteristics of HS in a community-based case series of dementia and to compare these characteristics with those observed in subjects with Alzheimer disease (AD) from the same study sample., Methods: One hundred thirty-four autopsy cases were available from a community-based registry of dementia. Sixteen cases (12%) had a postmortem diagnosis of HS. Thirty-two comparison control cases with a neuropathologic diagnosis of AD were selected from the same files. Each case of HS was reviewed for HS neuropathologic features, including severity, distribution, and additional pathologic processes. Blinded review of clinical characteristics for the HS and control groups was performed to assess risk factors., Results: There was a wide range of severity and distribution of HS lesions between cases and substantial variability in lesion severity and age within individual cases. Serial neuropsychologic and behavioral assessments revealed similar clinical features and rates of dementia progression between HS and AD groups. Of all neuropsychologic tests performed at enrollment, only enhanced performance on Trails A differentiated the HS from the AD group (64 seconds, 0 errors vs 114 seconds, 0.6 errors; P< or = .05). The number of AD cases with at least 1 apolipoprotein epsilon 4 allele was significantly greater than the HS cases (61% vs 31%; chi(2) = 3.81, P< or = .05). Although medical record review indicated higher frequencies of clinical stroke and neuroradiologic white matter abnormalities in the HS group, risk factors for vascular disease and neuropathologic evidence of cerebrovascular disease did not differ between the groups., Conclusions: Our results suggest that HS is a frequent pathologic finding in community-based dementia. Individuals with HS have similar initial symptoms and rates of dementia progression to those with AD and therefore are frequently misclassified as having AD. Our clinical and pathologic findings suggest that HS has characteristics of a progressive disorder although the underlying cause remains elusive.

Limbic-predominant age-related TDP-43 encephalopathy (LATE) affects approximately one-third of older individuals and is associated with cognitive impairment. However, there is a highly incomplete understanding of the genetic determinants of LATE neuropathologic changes (LATE-NC) in diverse populations. The defining neuropathologic feature of LATE-NC is TDP-43 proteinopathy, often with comorbid hippocampal sclerosis (HS). In terms of genetic risk factors, LATE-NC and/or HS are associated with single nucleotide variants (SNVs) in 3 genes-TMEM106B (rs1990622), GRN (rs5848), and ABCC9 (rs1914361 and rs701478). We evaluated these 3 genes in convenience samples of individuals of African ancestry. The allele frequencies of the LATE-associated alleles were significantly different between persons of primarily African (versus European) ancestry: In persons of African ancestry, the risk-associated alleles for TMEM106B and ABCC9 were less frequent, whereas the risk allele in GRN was more frequent. We performed an exploratory analysis of data from African-American subjects processed by the Alzheimer's Disease Genomics Consortium, with a subset of African-American participants (n = 166) having corroborating neuropathologic data through the National Alzheimer's Coordinating Center (NACC). In this limited-size sample, the ABCC9/rs1914361 SNV was associated with HS pathology. More work is required concerning the genetic factors influencing non-Alzheimer disease pathology such as LATE-NC in diverse cohorts.

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Alzheimer's disease (AD) and other dementias are likely preceded by a protracted preclinical state. Thus, identification of biomarkers that signal potential points of intervention during this prodromal phase (during which patients are largely able to compensate for their cognitive deficits) is of paramount importance. Insulin is a pancreatic hormone with potent central nervous system effects, and insulin dysregulation has been implicated in the pathogenesis of both AD and vascular dementia. The aim of the current study was to determine whether circulating insulin differs as a function of mild cognitive impairment (MCI) diagnosis, and whether this relationship is mediated by sex and apolipoprotein E (APOE) genotype. A sample of 549 nondemented participants aged 65 and over from the Adult Changes in Thought community-based cohort underwent cognitive testing and blood draw to determine fasting levels of plasma insulin. Subjects were categorized as having normal cognitive functioning, amnestic MCI, or nonamnestic MCI. Results showed that the relationship between insulin and diagnostic category is moderated by sex, such that men with nonamnestic or amnestic MCI have higher fasting plasma insulin than cognitively normal men, while women with amnestic MCI have lower fasting plasma insulin than cognitively normal women. Exploratory analyses suggest that APOE ℇ4 genotype may further influence the relationship between sex and insulin. Future research will help determine whether insulin dysregulation results in differential effects on vascular function and AD pathology as a function of sex and/or APOE genotype. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the association between dynamic measures of renal function ascertained over time and onset of dementia. Design Prospective community cohort study. Setting Group Health, Seattle, Washington. Participants Two thousand nine hundred sixty-eight adults aged 65 and older followed for the development of dementia over a median of 6.0 years (interquartile range 3.1-10.1 years). Measurements Time-varying measures of renal function were constructed based on 49,340 serum creatinine measurements and included average estimated glomerular filtration rate (eGFR), eGFR trajectory, and variability in eGFR around this trajectory over 5-year exposure windows. The association between these three eGFR exposure measures and risk of dementia was estimated using a Cox regression model adjusted for other participant characteristics. Time-varying measures of urine protein by dipstick were also adjusted for in sensitivity analyses. Results Participants with a lower eGFR had a higher incidence of dementia, but this did not reach statistical significance in adjusted analyses (omnibus P = .14). There were trends toward a higher adjusted incidence of dementia in participants with positive eGFR trajectories (omnibus P = .07) and greater variability in eGFR (omnibus P = .04) over time. The results of sensitivity analyses, including those in which time-varying measures of proteinuria were included, were consistent with those of the primary analysis. Conclusion In a community cohort of older adults followed for a median of 6 years, strong associations were not found between measures of kidney disease severity and progression and incident dementia. [ABSTRACT FROM AUTHOR]

Mild cognitive impairment (MCI) is proposed to be a prodrome to dementia in some older adults. However, the presentation of MCI in the community can differ substantially from clinic-based samples. The aim of the current study is to demonstrate the effects of different operational definitions of MCI on prevalence estimates in community-dwelling older adults. A consecutive series of 200 participants aged 65 and over from the Adult Changes in Thought (ACT) community-based cohort were approached to undergo comprehensive neuropsychological and medical evaluation; 159 were included in the final analyses. Nondemented subjects were categorized using various diagnostic criteria for MCI. In a novel approach, neuropsychological test scores were evaluated using an individualized benchmark as a point of test comparison, as well as traditional methods that entail comparison to age-based normative data. Diagnostic criteria were further subdivided by severity of impairment (1.0 vs. 1.5 standard deviations [sd] below the benchmark) and extent of impairment (based on a single test or an average of tests within a cognitive domain). MCI prevalence rates in the sample were highly dependent on these diagnostic factors, and varied from 11% to 92% of the sample. Older groups tended to show higher prevalence rates, although this was not the case across all diagnostic schemes. The use of an individualized benchmark, less severe impairment cutoff, and impairment on only a single test all produced higher rates of MCI. Longitudinal follow-up will determine whether varying diagnostic criteria improves sensitivity and specificity of the MCI diagnosis as a predictor for dementia. [ABSTRACT FROM AUTHOR]

Objectives: To assess the reliability and interobserver agreement of stroke identification on neuroimaging in patients presenting with dementia. Design: Comparison study between neurologists, radiology reports, and autopsy. Setting: Dementia registry within a health maintenance organization. Participants: Dementia patients with computed tomography (CT) scans obtained near the time of diagnosis and postmortem neuropathological examinations (N=99). Measurements: Three neurologists independently read CT scans for the presence and locations of strokes. Radiology reports from these scans were reviewed. The results from neurologists, radiologists, and autopsies were compared. Results: The positive predictive value for CT-observed strokes compared with their presence on autopsy was 0.44 to 0.49, regardless of the specialty of the observer. Strokes were present at autopsy in 46 of 99 cases. Agreement between neurologists on the presence of strokes was fair to moderate (kappa=0.27–0.56). Less agreement was found between neurologists and radiologists (kappa=0.00–0.11). Results improved slightly when each case was evaluated as any stroke present versus no stroke on imaging (kappa=0.34–0.75) or for the presence of multiple strokes (kappa=0.17–0.69). Conclusion: There is only fair to moderate agreement between observers regarding the identification of strokes on CT scans in patients presenting with dementia. Furthermore, strokes identified on imaging were present on pathology only half the time. [ABSTRACT FROM AUTHOR]

Head injury and apolipoprotein E (APOE)-epsilon 4 (e4) genotype have each been associated with increased risk of Alzheimer's disease. If APOE-e4 affects neuronal viability and branching, and if response to head injury differs in e4 patients, then the association between head injury and Alzheimer's disease may vary with the presence of the e4 allele. The authors examined this association in a case-control study conducted between 1987 and 1995 among enrollees of the Group Health Cooperative of Puget Sound, a health maintenance organization in Seattle, Washington. Proxy informants reported prior head injury with loss of consciousness for 32 of 349 patients with probable Alzheimer's disease and for 16 of 342 control subjects of similar age and sex who had been randomly selected from the same population (odds ratio (OR) = 2.1, 95% confidence interval (CI) 1.1–3.8). Elevated risk was observed among men (OR = 4.2, 95% CI 1.5–11.5) but not among women (OR = 1.1, 95% CI 0.5=2.6). No significant variation in the head injury-Alzheimer's disease risk relation by APOE-e4 genotype was found among 230 cases and 309 controls (OR = 3.1 (95% CI 0.7–14.6) for persons with at least one e4 allele and OR = 2.0 (95% CI 0.8–5.2) for those without e4). Neither age, education, race, type of proxy informant, nor duration of relationship with the proxy confounded the association. Head injury with loss of consciousness, although uncommon in this sample, was associated with increased risk of Alzheimer's disease. APOE-e4 was an independent risk factor which neither modified nor confounded the association. Susceptibility to Alzheimer's disease as conferred by APOE-e4 does not appear to increase the risk associated with head injury. Am J Epidemiol 1997;146:373–84. [ABSTRACT FROM AUTHOR]

The article reports that the American Geriatrics Society (AGS) released a revised list of treatments and tests to question and discuss when working with older adults. Topics mentioned include new proof on lung cancer screenings, the importance of avoiding medications other than metformin when pursuing moderate blood-glucose control in older patients with diabetes, and AGS's advice not to use physical restraints to deal with behavioral symptoms in hospitalized older adults with delirium.