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1.  Cognitive Decline in Prodromal Alzheimer's Disease and Mild Cognitive Impairment 
Archives of neurology  2011;68(3):351-356.
Objective
To characterize the course of cognitive decline during the prodromal phase of Alzheimer's disease.
Design
Longitudinal cohort study with up to 16 years of observation.
Participants
Older persons from two projects underwent annual clinical evaluations that included cognitive function testing and clinical classification of mild cognitive impairment, dementia, and Alzheimer's disease. At baseline, there were 2,071 individuals without dementia and 1,511 without cognitive impairment.
Main Outcome Measures
Change in previously established composite measures of global cognition and specific cognitive domains assessed in mixed-effects models that allow rate of decline to shift at specific points.
Results
During follow-up, 462 persons developed Alzheimer's disease (20 with dementia solely due to another condition were excluded). Five to six years before the diagnosis, rate of global cognitive decline sharply accelerated by more than 15-fold. The acceleration in decline occurred slightly earlier for semantic memory (76 months before diagnosis) and working memory (75 months) than other cognitive functions. Mild cognitive impairment was also preceded by years of cognitive decline which began earlier (80 months before diagnosis) and proceeded more rapidly (annual loss of 0.102 unit) in the amnestic than nonamnestic (62 months, 0.072 unit) subtype.
Conclusion
Dementia due to Alzheimer's disease is preceded by about five to six years of accelerated decline in multiple cognitive functions. By contrast, little decline is evident in persons not developing Alzheimer's disease.
doi:10.1001/archneurol.2011.31
PMCID: PMC3100533  PMID: 21403020
2.  Meta-Analysis confirms CR1, CLU, and PICALM as Alzheimer’s disease risk loci and reveals interactions with APOE genotypes 
Archives of neurology  2010;67(12):1473-1484.
Objectives
To determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer’s disease (AD) and whether risk for AD associated with these genes is influenced by APOE genotypes.
Design
Association study of AD and CLU, PICALM, CR1 and APOE genotypes.
Setting
Academic research institutions in the United States, Canada, and Israel.
Participants
7,070 AD cases, 3,055 with autopsies, and 8,169 elderly cognitively normal controls, 1,092 with autopsies from 12 different studies, including Caucasians, African Americans, Israeli-Arabs, and Caribbean Hispanics.
Results
Unadjusted, CLU [odds ratio (OR) = 0.91, 95% confidence interval (CI) = 0.85 – 0.96 for single nucleotide polymorphism (SNP) rs11136000], CR1 (OR = 1.14, CI = 1.07 – 1.22, SNP rs3818361), and PICALM (OR = 0.89, CI = 0.84 – 0.94, SNP rs3851179) were associated with AD in Caucasians. None were significantly associated with AD in the other ethnic groups. APOE ε4 was significantly associated with AD (ORs from 1.80 to 9.05) in all but one small Caucasian cohort and in the Arab cohort. Adjusting for age, sex, and the presence of at least one APOE ε4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, APOE ε4 (+/−), and an interaction term showed significant interaction between APOE ε4 (+/−) and PICALM.
Conclusions
We confirm in a completely independent dataset that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE ε4-positive subject. Thus, APOE and PICALM synergistically interact.
doi:10.1001/archneurol.2010.201
PMCID: PMC3048805  PMID: 20697030
3.  Telephone Assessment of Cognitive Function in the Late Onset Alzheimer’s Disease Family Study 
Archives of neurology  2010;67(7):855-861.
Context
Administration of cognitive test batteries by telephone has been shown to be a valid and cost-effective means of assessing cognition, but it remains relatively uncommon in epidemiological research.
Objective
To develop composite cognitive measures and assess how much of the variability in their scores is associated with mode of test administration (i.e., in person or by telephone).
Design
Cross-sectional cohort study
Setting
Late Onset of Alzheimer’s Disease Family Study conducted at 18 centers across the United States.
Participants
A total of 1,584 persons, 368 with dementia, from 646 families.
Main Outcome Measures
Scores on composite measures of memory and cognitive function derived from a battery of 7 performance tests administered in person (69%) or by telephone (31%) by examiners who underwent a structured performance-based training program with annual recertification.
Results
Based in part on the results of a factor analysis of the 7 tests, we developed summary measures of working memory, declarative memory, episodic memory, semantic memory, and global cognition. In linear regression analyses, mode of test administration accounted for less than 2% of the variance in the measures. In mixed-effects models, variability in cognitive scores due to center was small relative to variability due to differences between individuals and families.
Conclusions
In epidemiologic research on aging and AD, assessment of cognition by telephone has little effect on performance and provides operational flexibility and a means of reducing costs and missing data.
doi:10.1001/archneurol.2010.129
PMCID: PMC2971664  PMID: 20625093
Alzheimer’s disease; dementia; memory; cognition
4.  The Association of Magnetic Resonance Imaging Measures With Cognitive Function in a Biracial Population Sample 
Archives of neurology  2010;67(4):475-482.
Background
White matter hyperintensity volume (WMHV), cerebral infarcts, and total brain volume (TBV) are associated with cognitive function, but few studies have examined these associations in the general population or whether they differ by race.
Objective
To examine the association of WMHV, cerebral infarcts, and TBV with global cognition and cognition in 5 separate domains in a biracial population sample.
Setting
A biracial community population of Chicago, Illinois.
Design
Cross-sectional population study.
Participants
The study population comprised 575 participants from the Chicago Health and Aging Project (CHAP).
Main Outcome Measures
Volumetric magnetic resonance imaging (MRI) measures of WMHV, TBV, and cerebral infarcts and detailed neuropsychological testing assessments of global cognition and 5 cognitive domains.
Results
Overall and among those without dementia, cognition was inversely associated with WMHV and number of infarcts but was positively associated with TBV. When all 3 measures were simultaneously added to the model, the association of global cognition with WMHV and TBV remained significant and unchanged but was no longer significant with infarcts. Among subjects without dementia, all 3 MRI measures were associated with performance in multiple cognitive domains, specifically perceptual speed. However, among subjects with dementia, only TBV was associated with cognition and performance in multiple cognitive systems. Race did not significantly modify any of these associations.
Conclusions
In this biracial general population sample, the associations of MRI measures with cognition differed according to clinical status of subjects (stronger among subjects without dementia) and were not modified by race. These associations did not affect all cognitive domains equally but were more consistent with impairments in perceptual speed.
doi:10.1001/archneurol.2010.42
PMCID: PMC2947487  PMID: 20385915
5.  Association of Muscle Strength with the Risk of Alzheimer’s Disease and the Rate of Cognitive Decline in Community-Dwelling Older Persons 
Archives of neurology  2009;66(11):1339-1344.
Objective
Loss of muscle strength is common and associated with a variety of adverse health outcomes in old age, but few studies have examined the association of muscle strength with the risk of Alzheimer’s disease (AD) or mild cognitive impairment (MCI). We tested the hypothesis that muscle strength is associated with incident AD and MCI.
Design
Prospective, observational cohort study.
Setting
Retirement communities across the Chicago metropolitan area.
Participants
More than 900 community-based older persons without dementia at the baseline evaluation and in whom strength was measured in nine muscle groups in both arms and legs as well as in the axial muscles and summarized into a composite measure of muscle strength.
Main Outcome Measures
Incident AD, MCI and rate of change in global cognitive function.
Results
During a mean follow-up of 3.6 years, 138 persons developed AD. In a proportional hazards model adjusted for age, sex, and education, each 1 unit increase in muscle strength at baseline was associated with about a 43% decrease in the risk of AD (HR, 0.57; 95% CI, 0.41,0.79). The association of muscle strength with AD persisted even after adjustment for several covariates, including body mass index, physical activity, pulmonary function, vascular risk factors, vascular diseases and apolipoprotein E4 status. Further, in a mixed-effects model adjusted for age, sex, education, and baseline level of global cognition, increased muscle strength was associated with a slower rate of decline in global cognitive function (p<0.001). Finally, muscle strength was associated with a decreased risk of MCI, the precursor to AD (HR, 0.67; 95% CI, 0.54, 0.84).
Conclusion
These findings suggest a link between muscle strength, AD and cognitive decline in older persons.
doi:10.1001/archneurol.2009.240
PMCID: PMC2838435  PMID: 19901164

Results 1-5 (5)