Catherine M. Roe

APOE predicts amyloid‐beta but not tau Alzheimer pathology in cognitively normal aging

To examine interactions of apolipoprotein E (APOE) genotype with age and with in vivo measures of preclinical Alzheimer disease (AD) in cognitively normal aging.

Neuropathology of nondemented aging: Presumptive evidence for preclinical Alzheimer disease

OBJECTIVE To determine the frequency and possible cognitive effect of histological Alzheimers disease (AD) in autopsied older nondemented individuals. DESIGN Senile plaques (SPs) and neurofibrillary tangles (NFTs) were assessed quantitatively in 97 cases from 7 Alzheimers Disease Centers (ADCs). Neuropathological diagnoses of AD (npAD) were also made with four sets of criteria. Adjusted linear mixed models tested differences between participants with and without npAD on the quantitative neuropathology measures and psychometric test scores prior to death. Spearman rank-order correlations between AD lesions and psychometric scores at last assessment were calculated for cases with pathology in particular regions. SETTING Washington University Alzheimers Disease Research Center. PARTICIPANTS Ninety-seven nondemented participants who were age 60 years or older at death (mean=84 years). RESULTS About 40% of nondemented individuals met at least some level of criteria for npAD; when strict criteria were used, about 20% of cases had npAD. Substantial overlap of Braak neurofibrillary stages occurred between npAD and no-npAD cases. Although there was no measurable cognitive impairment prior to death for either the no-npAD or npAD groups, cognitive function in nondemented aging appears to be degraded by the presence of NFTs and SPs. CONCLUSIONS Neuropathological processes related to AD in persons without dementia appear to be associated with subtle cognitive dysfunction and may represent a preclinical stage of the illness. By age 80-85 years, many nondemented older adults have substantial AD pathology.

Pittsburgh Compound B Imaging and Prediction of Progression From Cognitive Normality to Symptomatic Alzheimer Disease

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 Alzheimers 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.

The AD8 A brief informant interview to detect dementia

Background: Brief measures that accurately discriminate normal cognitive aging from very mild dementia are lacking. Cognitive tests often are insensitive to very mild dementia. Informant-based measures may be more sensitive in detecting early dementia. Objective: To identify informant-reported clinical variables that differentiate cognitively normal individuals from those with very mild dementia. Methods: A 55-item battery of informant queries regarding an individuals cognitive status was derived from a semistructured interview and a consensus panel of dementia experts. The battery was evaluated with informants for 189 consecutive participants of a longitudinal study of memory and aging and compared with an independently obtained Clinical Dementia Rating (CDR) score for the participant. Multiple regression and receiver operator characteristic curves assessed subsets of the items to discriminate between CDR 0 (no dementia) and CDR 0.5 (very mild dementia). Results: The final version (AD8) querying memory, orientation, judgment, and function was administered to an additional sample of 112 CDR 0 and 68 CDR 0.5 participants. Using a cut-off of two items endorsed, the area under the curve was 0.834, suggesting good to excellent discrimination, sensitivity was 74%, and specificity was 86% (prevalence of 0.38 for very mild dementia). Inclusion of 56 additional individuals with mild to severe dementia (increasing dementia prevalence to 0.53) increased sensitivity to 85%. Conclusions: The AD8 is a brief, sensitive measure that reliably differentiates between nondemented and demented individuals. Use of the AD8 in conjunction with a brief assessment of the participant could improve diagnostic accuracy in general practice.

Cerebrospinal fluid tau and ptau181 increase with cortical amyloid deposition in cognitively normal individuals: Implications for future clinical trials of Alzheimer's disease

Alzheimers disease (AD) pathology is estimated to develop many years before detectable cognitive decline. Fluid and imaging biomarkers may identify people in early symptomatic and even preclinical stages, possibly when potential treatments can best preserve cognitive function. We previously reported that cerebrospinal fluid (CSF) levels of amyloid‐β42 (Aβ42) serve as an excellent marker for brain amyloid as detected by the amyloid tracer, Pittsburgh compound B (PIB). Using data from 189 cognitively normal participants, we now report a positive linear relationship between CSF tau/ptau181 (primary constituents of neurofibrillary tangles) with the amount of cortical amyloid. We observe a strong inverse relationship of cortical PIB binding with CSF Aβ42 but not for plasma Aβ species. Some individuals have low CSF Aβ42 but no cortical PIB binding. Together, these data suggest that changes in brain Aβ42 metabolism and amyloid formation are early pathogenic events in AD, and that significant disruptions in CSF tau metabolism likely occur after Aβ42 initially aggregates and increases as amyloid accumulates. These findings have important implications for preclinical AD diagnosis and treatment.

Education and Alzheimer disease without dementia: Support for the cognitive reserve hypothesis

Background: Individuals with no cognitive impairment during life but with neuropathologic Alzheimer disease (AD) may represent cases of presymptomatic, or unrecognized early symptomatic, AD. The cognitive reserve hypothesis suggests that at a particular level of AD pathology, highly educated individuals are less likely to manifest clinical symptoms of dementia vs less-educated individuals. Objective: To investigate whether education can help explain a clinical diagnosis of no dementia within 1 year of death among individuals with neuropathologic diagnoses of AD. Methods: Samples of participants (age 65+ years at last clinical assessment) meeting each of three neuropathologic criteria for AD were constructed using data from the National Alzheimers Coordinating Center Minimum and Neuropathology Data Sets. Generalized linear mixed models (using the logit link function) were used in each sample to examine whether years of education was associated with dementia within 1 year of death, adjusting for other relevant variables. Results: Twelve percent of individuals meeting Khachaturian (122/1,009), 19% meeting low, intermediate, or high likelihood for National Institute on Aging/Reagan Institute (320/1,704), and 14% meeting possible, probable, or definite Consortium to Establish a Registry for Alzheimers Disease (265/1,835) neuropathologic criteria for AD were nondemented at their final clinical assessment. Persons with more education were less likely to have a dementia diagnosis in each sample. Conclusions: Regardless of the neuropathologic criteria used, education is predictive of dementia status among individuals with neuropathologic Alzheimer disease. These results support the theory that individuals with greater cognitive reserve, as reflected in years of education, are better able to cope with AD brain pathology without observable deficits in cognition.

YKL-40: A Novel Prognostic Fluid Biomarker for Preclinical Alzheimer's Disease

BACKGROUND Disease-modifying therapies for Alzheimers disease (AD) would be most effective during the preclinical stage (pathology present, cognition intact) before significant neuronal loss occurs. Therefore, biomarkers that detect AD pathology in its early stages and predict dementia onset and progression will be invaluable for patient care and efficient clinical trial design. METHODS AD-associated changes in cerebrospinal fluid (CSF) were measured using two-dimensional difference gel electrophoresis and liquid chromatography tandem mass spectrometry. Subsequently, CSF YKL-40 was measured by enzyme-linked immunosorbent assay in the discovery cohort (n = 47), validation cohort (n = 292) with paired plasma samples (n = 237), frontotemporal lobar degeneration (n=9) [corrected], and progressive supranuclear palsy (PSP; n = 6). Immunohistochemistry was performed to identify source(s) of YKL-40 in human AD brain. RESULTS Discovery and validation cohorts, showed higher mean CSF YKL-40 in very mild and mild AD-type dementia (Clinical Dementia Rating [CDR] 0.5 and 1) versus control subjects (CDR 0) and PSP subjects. Importantly, CSF YKL-40/Aβ42 ratio predicted risk of developing cognitive impairment (CDR 0 to CDR > 0 conversion), as well as the best CSF biomarkers identified to date, tau/Aβ42 and p-tau 181/Aβ42. Mean plasma YKL-40 was higher in CDR 0.5 and 1 versus CDR 0, and correlated with CSF levels. YKL-40 immunoreactivity labeled astrocytes near a subset of amyloid plaques, implicating YKL-40 in the neuroinflammatory response to Aβ deposition. CONCLUSIONS These data demonstrate that YKL-40, a putative indicator of neuroinflammation, is elevated in AD and, together with Aβ42, has potential prognostic utility as a biomarker for preclinical AD.

LONGITUDINAL DRIVING PERFORMANCE IN EARLY-STAGE DEMENTIA OF THE ALZHEIMER TYPE

Objectives: To longitudinally assess on‐road driving performance in healthy older adults and those with early‐stage dementia of the Alzheimer type (DAT).

Validity and reliability of the AD8 informant interview in dementia

Objective: To establish the validity, reliability, and discriminative properties of the AD8, a brief informant interview to detect dementia, in a clinic sample. Methods: We evaluated 255 patient–informant dyads. We compared the number of endorsed AD8 items with an independently derived Clinical Dementia Rating (CDR) and with performance on neuropsychological tests. Construct and concurrent validity, test–retest, interrater and intermodal reliability, and internal consistency of the AD8 were determined. Receiver operator characteristic curves were used to assess the discriminative properties of the AD8. Results: Concurrent validity was strong with AD8 scores correlating with the CDR (r = 0.75, 95% CI 0.63 to 0.88). Construct validity testing showed strong correlation between AD8 scores, CDR domains, and performance on neuropsychological tests. The Cronbach alpha of the AD8 was 0.84 (95% CI 0.80 to 0.87), suggesting excellent internal consistency. The AD8 demonstrated good intrarater reliability and stability (weighted kappa = 0.67, 95% CI 0.59 to 0.75). Both in-person and phone administration showed equal reliability (weighted kappa = 0.65, 95% CI 0.57 to 0.73). Interrater reliability was very good (Intraclass correlation coefficient = 0.80, 95% CI 0.55 to 0.92). The area under the curve was 0.92 (95% CI 0.88 to 0.95), suggesting excellent discrimination between nondemented individuals and those with cognitive impairment regardless of etiology. Conclusion: The AD8 is a brief, sensitive measure that validly and reliably differentiates between nondemented and demented individuals. It can be used as a general screening device to detect cognitive change regardless of etiology and with different types of informants.

Cancer linked to Alzheimer disease but not vascular dementia

Objective: To investigate whether cancer is associated with Alzheimer disease (AD) and vascular dementia (VaD). Methods: Cox proportional hazards models were used to test associations between prevalent dementia and risk of future cancer hospitalization, and associations between prevalent cancer and risk of subsequent dementia. Participants in the Cardiovascular Health Study–Cognition Substudy, a prospective cohort study, aged 65 years or older (n = 3,020) were followed a mean of 5.4 years for dementia and 8.3 years for cancer. Results: The presence of any AD (pure AD + mixed AD/VaD; hazard ratio [HR] = 0.41, 95% confidence interval [CI] = 0.20–0.84) and pure AD (HR = 0.31, 95% CI = 0.12–0.86) was associated with a reduced risk of future cancer hospitalization, adjusted for demographic factors, smoking, obesity, and physical activity. No significant associations were found between dementia at baseline and rate of cancer hospitalizations for participants with diagnoses of VaD. Prevalent cancer was associated with reduced risk of any AD (HR = 0.72; 95% CI = 0.52–0.997) and pure AD (HR = 0.57; 95% CI = 0.36–0.90) among white subjects after adjustment for demographics, number of APOE ε4 alleles, hypertension, diabetes, and coronary heart disease; the opposite association was found among minorities, but the sample size was too small to provide stable estimates. No significant association was found between cancer and subsequent development of VaD. Conclusions: In white older adults, prevalent Alzheimer disease (AD) was longitudinally associated with a reduced risk of cancer, and a history of cancer was associated with a reduced risk of AD. Together with other work showing associations between cancer and Parkinson disease, these findings suggest the possibility that cancer is linked to neurodegeneration.