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Introduction: This study examines the utility of a multipanel of cerebrospinal fluid (CSF) biomarkers complementing Alzheimer's disease (AD) biomarkers in a clinical research sample. We compared biomarkers across groups defined by clinical diagnosis and pTau181/Aβ42 status (+/−) and explored their value in predicting cognition. Methods: CSF biomarkers amyloid beta (Aβ)42, pTau181, tTau, Aβ40, neurogranin, neurofilament light (NfL), α‐synuclein, glial fibrillary acidic protein (GFAP), chitinase‐3‐like protein 1 (YKL‐40), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), S100 calcium binding protein B (S100B), and interleukin 6 (IL6), were measured with the NeuroToolKit (NTK) for 720 adults ages 40 to 93 years (mean age = 63.9 years, standard deviation [SD] = 9.0; 50 with dementia; 54 with mild cognitive impairment [MCI], 616 unimpaired). Results: Neurodegeneration and glial activation biomarkers were elevated in pTau181/Aβ42+ MCI/dementia participants relative to all pTau181/Aβ42‐ participants. Neurodegeneration biomarkers increased with clinical severity among pTau181/Aβ42+ participants and predicted worse cognitive performance. Glial activation biomarkers were unrelated to cognitive performance. Discussion: The NTK contains promising markers that improve the pathophysiological characterization of AD. Neurodegeneration biomarkers beyond tTau improved statistical prediction of cognition and disease stages. [ABSTRACT FROM AUTHOR]

Background: Characterizing longitudinal changes in AD and neurodegeneration related CSF biomarkers in cognitively unimpaired adults is critical to distinguishing typical aging from disease pathology, Yet longitudinal change in established and especially emerging CSF biomarkers are not well characterized. We examined linear age trends in CSF biomarkers for AD (Ab42, pTau), neurodegeneration (NFL, Neurogranin and α‐Synuclein) and glial activation (YKL40, GFAP, sTREM2, S100B) assayed using the Roche NeuroToolKit (NTK), a panel of automated prototype CSF immunoassays. Methods: Analyses were based on a subsample of 146 cognitively unimpaired participants who underwent at least two lumbar punctures (total N=402). Cut‐offs for the ratio of pTau/Ab42 were determined using receiver operating characteristic curve analysis in a larger sample of impaired and unimpaired middle‐aged adults (N=167) treating a positive [C‐11]PiB visual rating as the standard of comparison. CSF analytes, plus ratios Ab42/Ab40 and pTau/Ab42, were fit to linear mixed models with random intercepts and slopes. Biomarker status (pTau/Ab42 +/‐) and covariates (gender, APOE4 status, years education) were entered as fixed effects. We also tested for moderation of age effects by biomarker status. P‐values were adjusted for the false discovery rate. Results: Sample characteristics are shown in Table 1. Twenty participants were AD biomarker positive. We observed small but significant subject‐level variation in slopes for most analytes, including the core AD biomarkers, NFL, neurogranin, YKL40, and S100B. Biomarker status (pTau/Ab42) significantly predicted levels of AD related CSF biomarkers (Table 2), but not levels of neurodegeneration or glial activation related analytes. Ab42/Ab40, but not Ab42, levels significantly decreased over time; all other analytes increased over time with the exception of S100B (Figure 1). Changes in biomarker values over time was not moderated by baseline biomarker status for any of the CSF analytes (not shown). Conclusion: Prior preliminary analyses (recreated in Figure 2) suggested that baseline values for biomarkers of neurodegeneration and glial activation are not related to core AD biomarkers until later in disease pathology. We have added to those findings, showing that among cognitively unimpaired individuals, significant longitudinal changes in both core AD‐related and emerging CSF biomarkers appear to be independent of early signs of joint amyloid and tau pathology. [ABSTRACT FROM AUTHOR]

Objectives: We examined race differences in the DSM-IV clinical significance criterion (CSC), an indicator of depressive role impairment, and its impact on assessment outcomes in older white and black women with diagnosed and subthreshold depression.Design: We conducted a secondary analysis of a community-based interview study, using group comparisons and logistic regression.Setting: Lower-income neighborhoods in a Midwestern city.Participants: 411 community-dwelling depressed and non-depressed women ≥ 65 years (45.3% Black; mean age = 75.2, SD = 7.2) recruited through census tract-based telephone screening.Measurements: SCID interview for DSM-IV to assess major depression and dysthymia; Center for Epidemiologic Studies-Depression Scale to define subthreshold depression (≥16 points); Mini-Mental State Examination, count of medical conditions, activities of daily living, and mental health treatment to assess health factors.Results: Black participants were less likely than Whites to endorse the CSC (11.8% vs. 24.1%; p = .002). There were few race differences in depressive symptom type, severity, or count. Blacks with subthreshold depression endorsed more symptoms, though this comparison was not significant after adjustments. Health factors did not account for race differences in CSC endorsement. Disregarding the CSC-eliminated differences in diagnosis rate, race was a significant predictor of CSC endorsement in a logistic regression.Conclusions: Race differences in CSC endorsement are not due to depressive symptom presentations or health factors. The use of the CSC may lead to underdiagnosis of depression among black older adults. Subthreshold depression among Blacks may be more severe compared to Whites, thus requiring tailored assessment and treatment approaches. [ABSTRACT FROM AUTHOR]

This study investigated differences in retrospective cognitive trajectories between amyloid and tau PET biomarker stratified groups in initially cognitively unimpaired participants sampled from the Wisconsin Registry for Alzheimer's Prevention. One hundred and sixty-seven initially unimpaired individuals (baseline age 59 ± 6 years; 115 females) were stratified by elevated amyloid-β and tau status based on 11C-Pittsburgh compound B (PiB) and 18F-MK-6240 PET imaging. Mixed effects models were used to determine if longitudinal cognitive trajectories based on a composite of cognitive tests including memory and executive function differed between biomarker groups. Secondary analyses investigated group differences for a variety of cross-sectional health and cognitive tests, and associations between 18F-MK-6240, 11C-PiB, and age. A significant group × age interaction was observed with post hoc comparisons indicating that the group with both elevated amyloid and tau pathophysiology were declining approximately three times faster in retrospective cognition compared to those with just one or no elevated biomarkers. This result was robust against various thresholds and medial temporal lobe regions defining elevated tau. Participants were relatively healthy and mostly did not differ between biomarker groups in health factors at the beginning or end of study, or most cognitive measures at study entry. Analyses investigating association between age, MK-6240 and PiB indicated weak associations between age and 18F-MK-6240 in tangle-associated regions, which were negligible after adjusting for 11C-PiB. Strong associations, particularly in entorhinal cortex, hippocampus and amygdala, were observed between 18F-MK-6240 and global 11C-PiB in regions associated with Braak neurofibrillary tangle stages I–VI. These results suggest that the combination of pathological amyloid and tau is detrimental to cognitive decline in preclinical Alzheimer's disease during late middle-age. Within the Alzheimer's disease continuum, middle-age health factors likely do not greatly influence preclinical cognitive decline. Future studies in a larger preclinical sample are needed to determine if and to what extent individual contributions of amyloid and tau affect cognitive decline. 18F-MK-6240 shows promise as a sensitive biomarker for detecting neurofibrillary tangles in preclinical Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: The apolipoprotein E gene (APOE) is the predominant genetic risk factor for late‐onset Alzheimer disease (AD), with three alleles contributing to disease risk and strongly associated with many AD endophenotypes: ε2 (reduced risk), ε3 (reference), and ε4 (increased risk). Researchers often include APOE ε4 carrier status (ε4+/‐) in analyses to account for the genetic effect; however, this does not adequately account for the protective effects of APOE ε2 or the heterogeneous effect of different APOE genotypes (ε2ε2, ε2ε3, ε2ε4, ε3ε3, ε3ε4, and ε4ε4). We hypothesized that accounting for the effect of the full APOE genotype would better recapitulate the influence of APOE in statistical analyses than APOE ε4 status. Method: To generate a weighted risk score for APOE genotype (APOE‐npscore), we log‐transformed the odds ratios from a recent study reporting APOE genetic risk for neuropathology‐confirmed AD. We regressed cerebrospinal fluid (CSF) AD endophenotypes on the APOE‐npscore using data from the Wisconsin Registry for Alzheimer's Prevention (WRAP: 233 cognitively unimpaired (CU), 3 mild cognitive impairment (MCI‐AD)) and Wisconsin Alzheimer's Disease Research Center (WADRC: 287 CU, 42 MCI‐AD, 48 dementia‐AD). In preliminary analyses, APOE‐npscores were tested against CSF amyloid‐beta1‐42 (Aβ42) and phosphorylated tau 181 (pTau181) measured using Elecsys® immunoassays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). Result: After adjusting for sex and age at lumbar puncture, the APOE‐npscore was associated with CSF Aβ42 (β = ‐115.9, p = 5.7e‐17) and pTau181 (β = 2.05, p = 4.7e‐8). APOE ε4 carrier status also associated with CSF Aβ42 (β = ‐238.0, p = 1.9e‐13) and pTau181 (β = 4.25, p = 1.1e‐6); however, models using APOE‐npscore explained 2.4% more variation in CSF Aβ42 and 0.8% more variation in CSF pTau181 than APOE ε4 status. These findings were similar in the subset of cognitively unimpaired participants. Conclusion: Our preliminary results demonstrate the benefit of using a pseudo‐continuous variable like the neuropathology‐based APOE risk score instead of binary APOE ε4 status. The APOE‐npscore allows researchers to use a continuous measure to account for APOE genetic risk for AD that does not collapse important genotype categories. This increases statistical power, avoids modeling issues that result from small cell sizes, and allows for a more nuanced interpretation of the genetic effect in analyses. [ABSTRACT FROM AUTHOR]

Objectives: Prior research has identified numerous genetic (including sex), education, health, and lifestyle factors that predict cognitive decline. Traditional model selection approaches (e.g., backward or stepwise selection) attempt to find one model that best fits the observed data, risking interpretations that only the selected predictors are important. In reality, several predictor combinations may fit similarly well but result in different conclusions (e.g., about size and significance of parameter estimates). In this study, we describe an alternative method, Information-Theoretic (IT) model averaging, and apply it to characterize a set of complex interactions in a longitudinal study on cognitive decline. Methods: Here, we used longitudinal cognitive data from 1256 late–middle aged adults from the Wisconsin Registry for Alzheimer's Prevention study to examine the effects of sex, apolipoprotein E (APOE) ɛ4 allele (non-modifiable factors), and literacy achievement (modifiable) on cognitive decline. For each outcome, we applied IT model averaging to a set of models with different combinations of interactions among sex, APOE, literacy, and age. Results: For a list-learning test, model-averaged results showed better performance for women versus men, with faster decline among men; increased literacy was associated with better performance, particularly among men. APOE had less of an association with cognitive performance in this age range (∼40–70 years). Conclusions: These results illustrate the utility of the IT approach and point to literacy as a potential modifier of cognitive decline. Whether the protective effect of literacy is due to educational attainment or intrinsic verbal intellectual ability is the topic of ongoing work. (JINS , 2019, 25 , 119–133) [ABSTRACT FROM AUTHOR]

Objectives: A major challenge in cognitive aging is differentiating preclinical disease-related cognitive decline from changes associated with normal aging. Neuropsychological test authors typically publish single time-point norms, referred to here as unconditional reference values. However, detecting significant change requires longitudinal, or conditional reference values, created by modeling cognition as a function of prior performance. Our objectives were to create, depict, and examine preliminary validity of unconditional and conditional reference values for ages 4 0 -7 5 years on neuropsychological tests. Method: We used quantile regression to create growth-curve-like models of performance on tests of-memory and executive function using participants from the Wisconsin Registry for Alzheimer's Prevention. Unconditional and conditional models accounted for age, sex, education, and verbal ability/literacy; conditional models also included past performance on and number of prior exposures to the test. Models were then used to estimate individuals' unconditional and conditional percentile ranks for each test. We examined how low performance on each test (operationalized as <7th percentile) related to consensus-conference-determined cognitive statuses and subjective impairment. Results: Participants with low performance were more likely to receive an abnormal cognitive diagnosis at the current visit (but not later visits). Low performance was also linked to subjective and informant reports of worsening memory function. Conclusions: The percentile-based methods and single-test results described here show potential for detecting troublesome within-person cognitive change. Development of reference values for additional cognitive measures, investigation of alternative thresholds for abnormality (including multi-test criteria), and validation in samples with more clinical endpoints are needed. (JINS, 2019, 25, 1-14) [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid (CSF) levels of neurogranin, an index of synaptic degeneration, and neurofilament light chain (NfL), an index of neuroaxonal degradation, are both biomarkers of neurodegeneration in Alzheimer's disease (AD). The presence of APOE is the strongest genetic risk factor for late onset AD and has also been associated with increased CSF neurogranin, a marker of neurodegeneration. To test the association between APOE and CSF biomarkers for neurodegeneration, we used a neuropathology‐based weighted risk score for APOE genotype (APOE‐npscore) and hypothesized that greater AD risk as indexed by the APOE‐npscore would be associated with higher CSF concentrations of neurogranin and NfL. Method: We examined data collected from participants in the Wisconsin Registry for Alzheimer's Prevention (n = 243) (avg age = 65) and Wisconsin Alzheimer's Disease Research Center (n = 411) (avg age = 64) including participants with Dementia (n = 50) Impaired‐Other (n = 8), Mild Cognitive Impairment (MCI) (n = 55), and cognitively unimpaired (n = 545) participants. The CSF biomarkers were measured using the NeuroToolKit panel of robust prototype assays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). Using linear regression, we tested associations between the APOE‐npscore and CSF neurogranin and NfL concentrations, adjusting for age at lumbar puncture (LP) and sex. We also tested for interactions between age at LP or sex and the APOE‐npscore. Results: The APOE‐npscore was significantly associated with CSF neurogranin concentration (β = 3.126, p < 0.01) but not significantly associated with CSF NfL concentration (β = 39.570, p > 0.05). Age at LP was significantly associated (p < 0.001) with CSF neurogranin and NfL concentrations. No significant interactions were found between the APOE‐np score and age at LP or sex in either test. APOE‐npscore, age at LP, and sex accounted for 7% of the variability of CSF neurogranin, and 27% of CSF NfL. Conclusions: The current study lends additional support to the impact of APOE on neurodegeneration, and supports the utility of using the APOE‐npscore to index risk of AD. The effects of APOE were observed on markers of synaptic degeneration, which underscores the importance of synaptic dysfunction in AD. [ABSTRACT FROM AUTHOR]

Neurovascular 4D-Flow MRI enables non-invasive evaluation of cerebral hemodynamics including measures of cerebral blood flow (CBF), vessel pulsatility index (PI), and cerebral pulse wave velocity (PWV). 4D-Flow measures have been linked to various neurovascular disorders including small vessel disease and Alzheimer's disease; however, physiological and technical sources of variability are not well established. Here, we characterized sources of diurnal physiological and technical variability in cerebral hemodynamics using 4D-Flow in a retrospective study of cognitively unimpaired older adults (N = 750) and a prospective study of younger adults (N = 10). Younger participants underwent repeated MRI sessions at 7am, 4 pm, and 10 pm. In the older cohort, having an MRI earlier on the day was significantly associated with higher CBF and lower PI. In prospective experiments, time of day significantly explained variability in CBF and PI; however, not in PWV. Test-retest experiments showed high CBF intra-session repeatability (repeatability coefficient (RPC) =7.2%), compared to lower diurnal repeatability (RPC = 40%). PI and PWV displayed similar intra-session and diurnal variability (PI intra-session RPC = 22%, RPC = 24% 7am vs 4 pm; PWV intra-session RPC = 17%, RPC = 21% 7am vs 4 pm). Overall, CBF measures showed low technical variability, supporting diurnal variability is from physiology. PI and PWV showed higher technical variability but less diurnal variability. [ABSTRACT FROM AUTHOR]

Introduction: We developed the Alzheimer's Biomarker Survey to assess willingness to enroll in biomarker studies that disclose results and anticipated reactions to an elevated biomarker result. Methods: Participants included cognitively unimpaired adults enrolled in longitudinal AD studies (n = 334, mean age = 64.8 ± 7.7, 44% non-Hispanic Black or African American). Exploratory and confirmatory factor analyses determined the latent structure comprising anticipated reactions to learning AD biomarker results. Measurement invariance was tested across racial groups. Results: Two models comprising behavior change and psychological impact fit well for the total sample and the two racial groups. The 2-factor behavior change model assessed constructs of planning and dementia risk-reduction. The 3-factor psychological impact model assessed constructs of distress, cognitive symptoms, and stigma. Both models exhibited measurement invariance across racial groups. Discussion: The 28-item Anticipated Reactions to AD Biomarker Disclosure scale is a reliable and valid measure of anticipated reactions when communicating AD biomarker results to research participants. [ABSTRACT FROM AUTHOR]

Neuropsychological measures sensitive to decline in the preclinical phase of Alzheimer's disease are needed. We previously demonstrated that higher amyloid-beta (Aβ) assessed by positron emission tomography in adults without cognitive impairment was associated with recall of fewer proper names in Logical Memory story recall. The current study investigated the association between proper names and cerebrospinal fluid biomarkers (Aβ 42/40 , phosphorylated tau 181 [pTau 181 ], neurofilament light) in 223 participants from the Wisconsin Registry for Alzheimer's Prevention. We assessed associations between biomarkers and delayed Logical Memory total score and proper names using binary logistic regressions. Sensitivity analyses used multinomial logistic regression and stratified biomarker groups. Lower Logical Memory total score and proper names scores from the most recent visit were associated with biomarker positivity. Relatedly, there was a 27% decreased risk of being classified Aβ 42/40 +/pTau 181 + for each additional proper name recalled. A linear mixed effects model found that longitudinal change in proper names recall was predicted by biomarker status. These results demonstrate a novel relationship between proper names and Alzheimer's disease-cerebrospinal fluid pathology. [ABSTRACT FROM AUTHOR]

Background Insulin resistance (IR) increases Alzheimer's disease (AD) risk. IR is related to greater amyloid burden post-mortem and increased deposition within areas affected by early AD. No studies have examined if IR is associated with an in vivo index of amyloid in the human brain in late middle-aged participants at risk for AD. Methods Asymptomatic, late middle-aged adults (N = 186) from the Wisconsin Registry for Alzheimer's Prevention underwent [C-11]Pittsburgh compound B (PiB) positron emission tomography. The cross-sectional design tested the interaction between insulin resistance and glycemic status on PiB distribution volume ratio in three regions of interest (frontal, parietal, and temporal). Results In participants with normoglycemia but not hyperglycemia, higher insulin resistance corresponded to higher PiB uptake in frontal and temporal areas, reflecting increased amyloid deposition. Conclusions This is the first human study to demonstrate that insulin resistance may contribute to amyloid deposition in brain regions affected by AD. [ABSTRACT FROM AUTHOR]