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Background: Studies relating adiposity to cognition in the elderly show conflicting results, which may be explained by the choice of adiposity measures. Thus, we studied the longitudinal associations of different adiposity measures, fat mass by bioelectrical impedance analysis, body mass index (BMI) and waist circumference (WC), with cognitive performance in the Cardiovascular Health Study. Methods: Cognitive performance was assessed with the modified Mini-Mental State Examination, the Digit Symbol Substitution Test, and a composite of both. We used linear mixed models to estimate rates of change in cognitive function scores associated with adiposity measured at baseline. Results: The final sample was comprised of 2,681 women (57.9%) and 1,949 men (42.1%) aged 73 ± 5.2 and 73.9 ± 5.6 years, respectively. Adiposity was associated with slower cognitive decline in most analyses. Results were similar for fat mass, BMI and WC. Higher fat-free mass was also related to slower cognitive decline. Results were similar in analyses excluding persons with cancer, smokers, and persons with short follow-up, poor self-reported health, or persons with cardiovascular disease. Conclusions: Higher adiposity and higher fat-free mass in the elderly was related to better cognitive performance. This finding was not explained by confounding by preexisting conditions.

Background: Randomized controlled efficacy trials (RCTs), the scientific gold standard, are required for regulatory approval of Alzheimer’s disease (AD) interventions, yet provide limited information regarding real-world therapeutic effectiveness. Objective: To compare the nature of evidence regarding the combination of approved AD treatments from RCTs versus long-term observational controlled studies (LTOCs). Methods: Comparisons of strengths, limitations, and evidence level for monotherapy [cholinesterase inhibitor (ChEI) or memantine] and combination therapy (ChEI + memantine) in RCTs versus LTOCs. Results: RCTs examined highly selected populations over months. LTOCs collected data across multiple AD stages in large populations over many years. RCTs and LTOCs show similar patterns favoring combination over monotherapy over placebo/no treatment. Long-term combination therapy compared to monotherapy reduced cognitive and functional decline and delayed time to nursing home admission. Persistent treatment was associated with slower decline. While LTOCs used control groups, adjusted for multiple covariates, had higher external validity, and favorable ethical, practical and cost considerations, their limitations included potential selection bias due to lack of placebo comparisons and randomization. Conclusions: Naturalistic LTOCs provide complementary long-term level II evidence to complement level I evidence from short-term RCTs regarding therapeutic effectiveness in AD that may otherwise be unobtainable. A coordinated strategy/consortium to pool LTOC data from multiple centers to estimate long-term comparative effectiveness, risks/benefits, and costs of AD treatments is needed.

Background: Therapeutic endpoints based on reduced clinical worsening represent clinically relevant and realistic goals for patients suffering from progressive neurodegenerative disorders such as Alzheimer’s disease (AD). Methods: Data from 906 patients (388 receiving placebo; 518 receiving donepezil) with mild-to-moderate AD [Mini-Mental State Examination (MMSE) score 10–27] were pooled from 3 randomized, double-blind placebo-controlled studies. Clinical worsening was defined as decline in (1) cognition (MMSE), (2) cognition and global ratings (Clinician’s Interview-Based Impression of Change plus Caregiver Input/Gottfries-Bråne-Steen scale) or (3) cognition, global ratings and function (various functional measures). Results: At week 24, lower percentages of donepezil-treated patients than placebo patients met the criteria for clinical worsening, regardless of the definition. The odds of declining were significantly reduced for donepezil-treated versus placebo patients (p < 0.0001; all definitions). Among patients meeting criteria for clinical worsening, mean declines in MMSE scores were greater for placebo than donepezil-treated patients. Conclusion: In this population, donepezil treatment was associated with reduced odds of clinical worsening of AD symptoms. Moreover, patients worsening on donepezil were likely to experience less cognitive decline than expected if left untreated. This suggests that AD patients showing clinical worsening on donepezil may still derive benefits compared with placebo/untreated patients.

Background: The Cardiovascular Health Cognition Study has evaluated the determinants of dementia among 3,608 participants that had a magnetic resonance imaging (MRI) of the brain in 1991 and were followed to 1998–1999. Methods: There were 480 incident dementia cases, 330 (69%) were classified as Alzheimer’s disease (AD). Results: In univariate analysis, low scores on the Modified Mini-Mental State Examination (3MSE) and on the Digit Symbol Substitution Test as well as declines in scores over time prior to the development of dementia were significant predictors of dementia. A high ventricular grade on the MRI (atrophy) as well as high white matter grade, a number of brain infarcts on the MRI were all determinants of dementia. Apolipoprotein E Ε4 (ApoE-4) was also a powerful predictor of dementia. In a multivariate Cox proportional hazards model controlling for race, gender and grade, the hazard ratios for age (1.1), 3MSE score (0.9), ventricular size (1.4), white matter grade (1.8), presence of large infarcts >3 mm (1.3) and ApoE-4 (2.1) were significant predictors of dementia. The combination of an ApoE-4 genotype, 3MSE score Conclusions: Measures of cognition, ApoE-4 and MRI of the brain are strong predictors of both dementia and of AD.

Objective: To describe a methodology to evaluate dementia and frequency of different types of dementia and prevalence of the Cardiovascular Health Study (CHS). Methods: The CHS is a longitudinal study of cardiovascular disease among community-dwelling individuals over the age of 65. Of the 5,888 participants in the original study, 3,608 had a magnetic resonance imaging (MRI) of the brain in 1991, and formed the cohort for the dementia study. The CHS included yearly measures of cognitive function and, from 1998 to 2000, participants were evaluated for dementia by detailed neurological, and neuropsychological examinations. The possible cases of dementia and mild cognitive impairment (MCI) were adjudicated by a review committee of neurologists and psychiatrists. Results: There were 480 cases of (13.3%) incident dementia in the total sample, 227 (6.3%) prevalent dementia, 577 (16.0%) MCI, and 2,318 (64.4%) normal. The adjudication committee classified 69% of the incident dementia as Alzheimer’s disease (AD), 11% as vascular dementia (VaD), 16% as both, and 4% as other types. There was a substantial agreement between pre- and postMRI diagnosis of types of dementia. The frequency of dementia within the CHS cohort which survived to the end of the study in 1998–1999, was 13.5% for white men, 14.5% for white women, 22.2% for black men and 23.4% for black women. Conclusion: The CHS has developed a methodology for longitudinal studies of dementia in large cohorts and represents the largest study of dementia including cognitive testing, MRI and genetic markers.

We examined the relationship between unawareness of cognitive deficits and psychiatric and neuropsychological manifestations in 181 patients with probable Alzheimer's disease (AD). Patients unaware of their cognitive deficits were more cognitively impaired, as measured by the Mini-Mental State Examination, and had a specific defect in 'frontal/executive' functions. The presence of major depression, delusions and hallucinations was no more likely among patients who were aware of their cognitive impairment than among those who were not. These findings have important implications for the understanding of anosognosia and deficit awareness in dementia.

The presence of cerebral amyloid angiopathy (CAA) in capillaries and arterioles of the cerebral and cerebellar cortex of Alzheimer's disease (AD) patients may provide an opportunity to study the clinical significance of these vascular changes in AD. We reviewed the clinical and pathological features of 40 patients with AD without other CNS disease. The sections were examined by the red Congo method under a polarized light for the presence of CAA. Twenty-two (55%) had AD + CAA. CAA was seen most frequently and was of greater severity in occipital and frontal gray matter. We concluded that it is not possible to differentiate between AD patients with CAA and those without CAA in terms of demographic characteristics and neurological and psychiatric symptomatology.