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Background: Cross-sectional studies suggest that the cognitive impact of Alzheimer disease pathology varies depending on education and brain size., Objective: To evaluate the combination of cerebrospinal fluid biomarkers of β-amyloid(42) (Aβ(42)), tau, and phosphorylated tau (ptau(181)) with education and normalized whole-brain volume (nWBV) to predict incident cognitive impairment., Design: Longitudinal cohort study., Setting: Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University, St Louis, Missouri., Participants: A convenience sample of 197 individuals 50 years and older with normal cognition (Clinical Dementia Rating of 0) at baseline observed for a mean of 3.3 years., Main Outcome Measure: Time to Clinical Dementia Rating ≥ 0.5., Results: Three-factor interactions among the baseline biomarker values, education, and nWBV were found for Cox proportional hazards regression models testing tau (P = .02) and ptau (P = .008). In those with lower tau values, nWBV (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.31-0.91; P = .02), but not education, was related to time to cognitive impairment. For participants with higher tau values, education interacted with nWBV to predict incident impairment (P = .01). For individuals with lower ptau values, there was no effect of education or nWBV. Education interacted with nWBV to predict incident cognitive impairment in those with higher ptau values (P = .02)., Conclusion: In individuals with normal cognition and higher levels of cerebrospinal fluid tau and ptau at baseline, time to incident cognitive impairment is moderated by education and brain volume as predicted by the cognitive/brain reserve hypothesis.

Objective: To determine whether preclinical Alzheimer disease (AD), as detected by the amyloid-imaging agent Pittsburgh Compound B (PiB) in cognitively normal older adults, is associated with risk of symptomatic AD., Design: A longitudinal cohort study of cognitively normal older adults assessed with positron emission tomography (PET) to determine the mean cortical binding potential for PiB and followed up with annual clinical and cognitive assessments for progression to very mild dementia of the Alzheimer type (DAT)., Setting: The Alzheimer's Disease Research Center, Washington University, St Louis, Missouri., Participants: One hundred fifty-nine participants with a mean age of 71.5 years with a Clinical Dementia Rating (CDR) of 0 on a PET PiB scan at baseline., Main Outcome Measure: Progression from CDR 0 to CDR 0.5 status (very mild dementia)., Results: Twenty-three participants progressed to CDR 0.5 at follow-up assessment (range, 1-5 assessments after PET PiB). Of these, 9 also were diagnosed with DAT. Higher mean cortical binding potential values for PiB (hazard ratio, 4.85; 95% confidence interval, 1.22-19.01; P = .02) and age (hazard ratio, 1.14; 95% confidence interval, 1.02-1.28; P = .03) predicted progression to CDR 0.5 DAT. The CDR 0.5 DAT group showed decline in 3 cognitive domains (episodic memory, semantic memory, and visuospatial performance) and had volume loss in the parahippocampal gyrus (includes entorhinal cortex) compared with individuals who remained at CDR 0., Conclusion: Preclinical AD as detected by PET PiB is not benign, as it is associated with progression to symptomatic AD.

Background: Cerebrospinal fluid (CSF) levels of Abeta peptide 1-42 (Abeta 42), tau, and phosphorylated tau (ptau) are potential biomarkers of Alzheimer disease., Objective: To determine whether Abeta 42, tau, and ptau predict the rate of cognitive change in individuals with very mild dementia of the Alzheimer type (DAT)., Design: Retrospective analysis of CSF biomarkers and clinical data., Setting: An academic Alzheimer disease research center., Participants: Research volunteers in a longitudinal study of aging and cognition. Participants (n = 49) had a clinical diagnosis of very mild DAT with a Clinical Dementia Rating (CDR) of 0.5 at the time of lumbar puncture. All the participants had at least 1 follow-up assessment (mean [SD] follow-up, 3.5 [1.8] years)., Main Outcome Measures: Baseline CSF levels of Abeta 42, Abeta 40, tau, and ptau at threonine 181 (ptau181) and the rate of dementia progression as measured using the CDR sum of boxes (CDR-SB) score and psychometric performance., Results: The rate of dementia progression was significantly more rapid in individuals with lower baseline CSF Abeta 42 levels, higher tau or ptau181 levels, or high tau: Abeta 42 ratios. For example, the annual change in the CDR-SB score was 1.1 for the lowest 2 tertiles of Abeta 42 values and 0.3 for the highest tertile of Abeta 42 values., Conclusions: In individuals with very mild DAT, lower CSF Abeta 42 levels, high tau or ptau181 levels, or high tau:Abeta 42 ratios quantitatively predict more rapid progression of cognitive deficits and dementia. Biomarkers of CSF may be useful prognostically and to identify individuals who are more likely to progress for participation in therapeutic clinical trials.

Objective: To evaluate the cognitive reserve hypothesis by examining whether individuals of greater educational attainment have better cognitive function than individuals with less education in the presence of elevated fibrillar brain amyloid levels., Design, Setting, and Participants: Uptake of carbon 11-labeled Pittsburgh Compound B ([(11)C]PiB) was measured for participants assessed between August 15, 2003, and January 8, 2008, at the Washington University Alzheimer's Disease Research Center and diagnosed either as nondemented (n = 161) or with dementia of the Alzheimer type (n = 37). Multiple regression was used to determine whether [(11)C]PiB uptake interacted with level of educational attainment to predict cognitive function., Main Outcome Measures: Scores on the Clinical Dementia Rating sum of boxes, Mini-Mental State Examination, and Short Blessed Test and individual measures from a psychometric battery., Results: Uptake of [(11)C]PiB interacted with years of education in predicting scores on the Clinical Dementia Rating sum of boxes (P = .003), the Mini-Mental State Examination (P < .001), the Short Blessed Test (P = .03), and a measure of verbal abstract reasoning and conceptualization (P = .02) such that performance on these measures increased with increasing education for participants with elevated PiB uptake. Education was unrelated to global cognitive functioning scores among those with lower PiB uptake., Conclusion: The results support the hypothesis that cognitive reserve influences the association between Alzheimer disease pathological burden and cognition.

Background: Data from neuropathologic studies of the frequency of Alzheimer disease (AD) among African American persons conflict as to whether the neuropathologic phenotype of AD is identical in African American and white persons., Objectives: To examine clinical and neuropathologic phenotypes of AD in African American individuals and to compare AD and vascular burdens between African American and white persons., Design, Setting, and Patients: Ten African American decedents who underwent brain autopsy at the Washington University Alzheimer's Disease Research Center were matched for age, sex, and Clinical Dementia Rating with 10 white decedents between January 1, 1990, and January 1, 2000. The presence and degree of neurofibrillary tangles, senile plaques, Lewy bodies, cerebral infarcts, and cerebral amyloid angiopathy were determined., Results: All 20 individuals had a neuropathologic diagnosis of AD. There were no group differences in the presence or number of infarcts, plaques, tangles, Lewy bodies, or amyloid angiopathy., Conclusion: In this small sample, we found no substantive differences in the neuropathology of AD among African American and white individuals.

Background: Depression can interfere with the normal expression of cognitive abilities in adults of all ages, but it is unclear if depression in demented people, which is common, is associated with reduced cognitive performance beyond the effect of the dementia itself., Objective: To determine if depression adds to the cognitive deficit in dementia., Design: Performance on psychometric tests of memory and other cognitive function was correlated with the number of depressive features reported by the individual and by a knowledgeable collateral source, as well as the judgment of a research clinician as to whether the person was depressed., Setting: An Alzheimer disease research center., Participants: The convenience sample included individuals with very mild (Clinical Dementia Rating, 0.5; n = 167 [mean age, 76.03 years]) or mild (Clinical Dementia Rating, 1; n = 155 [mean age, 78.41 years]) Alzheimer disease who were enrolled in ongoing longitudinal studies at the center., Main Outcome Measures: Psychometric measures of memory and cognition., Results: Depression was present in 15% of the very mild and 24% of the mild dementia groups. There was no relation between the clinicians' diagnoses of depression and psychometric scores. Little relation was found between performance on the cognitive tests and the number of depressive features (maximum, 9) reported by the individual or collateral source. The few statistically significant (P<.05) correlations were modest (< or =0.21)., Conclusion: Depression does not worsen cognitive test performance beyond the effect of dementia.

Objective: To examine the earliest cognitive changes associated with the onset of dementia as well as changes associated with normal aging., Design: Longitudinal evaluation of participants with annual clinical and psychometric examinations for up to 15 1/2 years., Setting and Participants: Elderly volunteers (n = 82) enrolled with a Clinical Dementia Rating of 0 (cognitively intact) in longitudinal studies., Interventions: None., Main Outcome Measures: Clinical Dementia Rating and results of a 1 1/2-hour psychometric battery., Results: As estimated with survival analysis, 40% of participants had a Clinical Dementia Rating greater than 0 (cognitive decline) within 12 years of enrollment; 59% of these were judged to have dementia of the Alzheimer type or incipient dementia. Participants with poorer performance on psychometric testing at enrollment were at higher risk for cognitive decline subsequently. The rate of change in psychometric performance before clinically detectable cognitive change occurred was not significantly different between those who eventually developed dementia and those who remained stable, except for performance on the Logical Memory subtest of the Wechsler Memory Scale. When subtle cognitive decline was clinically detected, however, an abrupt deterioration in performance on independently administered psychometric tests was observed., Conclusions: Cognitively healthy elderly people maintain stable cognitive performance when measured longitudinally by both careful clinical evaluation and repeated psychometric testing. This stability is maintained unless and until they develop a dementing illness, at which time a sharp decline in performance is observed.

Objective: The influence of age on performance on clinical and psychometric assessments is examined in groups of nondemented persons and individuals with either very mild or mild dementia of the Alzheimer type (DAT)., Design: Initial clinical and psychometric assessments of persons enrolled in longitudinal studies of DAT and nondemented control subjects., Setting: Alzheimer's Disease Research Center at Washington University, St Louis, Mo., Participants: Volunteer samples of 108 people (44 men, 64 women) with mild DAT, 61 people (30 men, 31 women) with very mild DAT, and 122 healthy nondemented people (45 men, 77 women) were recruited between 1979 and 1991. Age ranged from 54 to 87 years. Persons with confounding medical, neurologic, or psychiatric disorders were excluded. Dementia severity was staged using the Clinical Dementia Rating scale., Main Outcome Measures: Five brief quantitative clinical tests included in the 90-minute clinician administered protocol, as well as 14 tests included in a 2-hour psychometric test battery., Results: Dementia severity affected performance on all measurements. Age did not influence performance on clinical assessments. There was a significant interaction between age and dementia severity on 10 of 14 psychometric measures. In general, older nondemented individuals performed less well than younger nondemented individuals while older mildly demented persons performed about the same as, or slightly better than, their younger counterparts., Conclusions: Age does not affect performance on brief clinical assessment instruments. However, age affects psychometric performance differently in cognitively intact persons when compared with persons with DAT. As a result, psychometric differentiation between cognitively normal and demented individuals is more difficult in older populations.

We report a longitudinal study of 16 subjects originally enrolled in the Washington University (St Louis, Mo) Memory and Aging Project with Clinical Dementia Rating (CDR) of "questionable" dementia (CDR 0.5). A 0.5 rating was intended to characterize subjects in whom mild cognitive impairment due to senile dementia of the Alzheimer type was suspected but was insufficient in degree to warrant a diagnosis of definite dementia. Over an 84-month follow-up period, 11 of the 16 subjects either had Alzheimer's disease verified post mortem or had clinically progressed to a more advanced CDR stage in which the dementia was clearly evident. These results suggest that the CDR 0.5 stage likely represents the incipient clinical manifestation of Alzheimer's disease and that the majority of subjects with CDR 0.5 have "very mild senile dementia of the Alzheimer type." Performance on several standard clinical scales was significantly different when comparing a larger sample of controls (n = 83), subjects with CDR 0.5 (n = 41), and subjects with mild senile dementia of the Alzheimer type (score of 1; n = 68).

To examine the natural history and pathogenesis of parkinsonism in Alzheimer's disease, 44 subjects with clearly established senile dementia of the Alzheimer type were studied during a 66-month period. Sixteen subjects (36%) developed idiopathic parkinsonism, and 12 subjects (27%) developed drug-induced parkinsonism; the chief clinical features of both types were bradykinesia and rigidity, but not resting tremor. The presence of parkinsonism was associated with global (rather than selective) cognitive impairment, as determined by psychometric testing, and with more rapid progression to advanced stages of dementia. The pathological correlates of clinical parkinsonism were heterogeneous in 10 subjects with Alzheimer's disease who were examined post mortem. Coexistent Parkinson's disease was observed in five cases and nonspecific nigral degenerative lesions were present in another three; however, two cases had neither histological changes nor reduced neuronal densities in the substantia nigra. These two cases suggested that extranigral lesions, possibly involving mesocortical dopaminergic pathways, may contribute to the development of parkinsonism in subjects with Alzheimer's disease.