Characterizing brain tau and cognitive decline along the amyloid timeline in Alzheimer's disease.

Recent longitudinal PET imaging studies have established methods to estimate the age at which amyloid becomes abnormal at the level of the individual. Here we recontextualized amyloid levels into the temporal domain to better understand the downstream Alzheimer's disease processes of tau neurofibrillary tangle (NFT) accumulation and cognitive decline. This cohort study included a total of 601 individuals from the Wisconsin Registry for Alzheimer's Prevention and Wisconsin Alzheimer's Disease Research Center that underwent amyloid and tau PET, longitudinal neuropsychological assessments and met clinical criteria for three clinical diagnosis groups: cognitively unimpaired (n = 537); mild cognitive impairment (n = 48); or dementia (n = 16). Cortical 11C-Pittsburgh compound B (PiB) distribution volume ratio (DVR) and sampled iterative local approximation were used to estimate amyloid positive (A+; global PiB DVR > 1.16 equivalent to 17.1 centiloids) onset age and years of A+ duration at tau PET (i.e. amyloid chronicity). Tau PET burden was quantified using 18F-MK-6240 standardized uptake value ratios (70-90 min, inferior cerebellar grey matter reference region). Whole-brain and region-specific approaches were used to examine tau PET binding along the amyloid timeline and across the Alzheimer's disease clinical continuum. Voxel-wise 18F-MK-6240 analyses revealed that with each decade of A+, the spatial extent of measurable tau spread (i.e. progressed) from regions associated with early to late NFT tau stages. Regional analyses indicated that tau burden in the entorhinal cortex was detectable, on average, within 10 years of A+ onset. Additionally, the entorhinal cortex was the region most sensitive to early amyloid pathology and clinical impairment in this predominantly preclinical sample. Among initially cognitively unimpaired (n = 472) individuals with longitudinal cognitive follow-up, mixed effects models showed significant linear and non-linear interactions of A+ duration and entorhinal tau on cognitive decline, suggesting a synergistic effect whereby greater A+ duration, together with a higher entorhinal tau burden, increases the likelihood of cognitive decline beyond their separable effects. Overall, the amyloid time framework enabled a spatiotemporal characterization of tau deposition patterns across the Alzheimer's disease continuum. This approach, which examined cross-sectional tau PET data along the amyloid timeline to make longitudinal disease course inferences, demonstrated that A+ duration explains a considerable amount of variability in the magnitude and topography of tau spread, which largely recapitulated NFT staging observed in human neuropathological studies. By anchoring disease progression to the onset of amyloid, this study provides a temporal disease context, which may help inform disease prognosis and timing windows for anti-amyloid therapies.

Longitudinal plasma phosphorylated-tau217 and other related biomarkers in a non-demented Alzheimer's risk-enhanced sample.

INTRODUCTION: Understanding longitudinal change in key plasma biomarkers will aid in detecting presymptomatic Alzheimer's disease (AD). METHODS: Serial plasma samples from 424 Wisconsin Registry for Alzheimer's Prevention participants were analyzed for phosphorylated-tau217 (p-tau217; ALZpath) and other AD biomarkers, to study longitudinal trajectories in relation to disease, health factors, and cognitive decline. Of the participants, 18.6% with known amyloid status were amyloid positive (A+); 97.2% were cognitively unimpaired (CU). RESULTS: In the CU, amyloid-negative (A-) subset, plasma p-tau217 levels increased modestly with age but were unaffected by body mass index and kidney function. In the whole sample, average p-tau217 change rates were higher in those who were A+ (e.g., simple slopes(se) for A+ and A- at age 60 were 0.232(0.028) and 0.038(0.013))). High baseline p-tau217 levels predicted faster preclinical cognitive decline. DISCUSSION: p-tau217 stands out among markers for its strong association with disease and cognitive decline, indicating its potential for early AD detection and monitoring progression. HIGHLIGHTS: Phosphorylated-tau217 (p-tau217) trajectories were significantly different in people who were known to be amyloid positive. Subtle age-related trajectories were seen for all the plasma markers in amyloid-negative cognitively unimpaired. Kidney function and body mass index were not associated with plasma p-tau217 trajectories. Higher plasma p-tau217 was associated with faster preclinical cognitive decline.

Longitudinal normative standards for cognitive tests and composites using harmonized data from two Wisconsin AD-risk-enriched cohorts.

INTRODUCTION: Published norms are typically cross-sectional and often are not sensitive to preclinical cognitive changes due to dementia. We developed and validated demographically adjusted cross-sectional and longitudinal normative standards using harmonized outcomes from two Alzheimer's disease (AD) risk-enriched cohorts. METHODS: Data from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center were combined. Quantile regression was used to develop unconditional (cross-sectional) and conditional (longitudinal) normative standards for 18 outcomes using data from cognitively unimpaired participants (N = 1390; mean follow-up = 9.25 years). Validity analyses (N = 2456) examined relationships between percentile scores (centiles), consensus-based cognitive statuses, and AD biomarker levels. RESULTS: Unconditional and conditional centiles were lower in those with consensus-based impairment or biomarker positivity. Similarly, quantitative biomarker levels were higher in those whose centiles suggested decline. DISCUSSION: This study presents normative standards for cognitive measures sensitive to pre-clinical changes. Future directions will investigate potential clinical applications of longitudinal normative standards. HIGHLIGHTS: Quantile regression was used to construct longitudinal norms for cognitive tests. Poorer percentile scores were related to concurrent diagnosis and Alzheimer's disease biomarkers. A ShinyApp was built to display test scores and norms and flag low performance.

Association of neighborhood disadvantage with cognitive function and cortical disorganization in an unimpaired cohort.

Objective: Neighborhood disadvantage is associated with worse health and cognitive outcomes. Morphological similarity network (MSN) is a promising approach to elucidate cortical network patterns underlying complex cognitive functions. We hypothesized that MSNs could capture intricate changes in cortical patterns related to neighborhood disadvantage and cognitive function, potentially explaining some of the risk for later life cognitive impairment among individuals who live in disadvantaged contexts. Methods: This cross-sectional study included cognitively unimpaired participants (n=524, age=62.96±8.377, gender (M:F)=181:343, ADI(L:H) =450,74) from the Wisconsin Alzheimer's Disease Research Center or Wisconsin Registry for Alzheimer's Prevention. Neighborhood disadvantage status was obtained using the Area Deprivation Index (ADI). Cognitive performance was assessed through six tests evaluating memory, executive functioning, and the modified preclinical Alzheimer's cognitive composite (mPACC). Morphological Similarity Networks (MSN) were constructed for each participant based on the similarity in distribution of cortical thickness of brain regions, followed by computation of local and global network features. We used linear regression to examine ADI associations with cognitive scores and MSN features. The mediating effect of MSN features on the relationship between ADI and cognitive performance was statistically assessed. Results: Neighborhood disadvantage showed negative association with category fluency, implicit learning speed, story recall and mPACC scores, indicating worse cognitive function among those living in more disadvantaged neighborhoods. Local network features of frontal and temporal brain regions differed based on ADI status. Centrality of left lateral orbitofrontal region showed a partial mediating effect between association of neighborhood disadvantage and story recall performance. Conclusion: Our findings suggest differences in local cortical organization by neighborhood disadvantage, which also partially mediated the relationship between ADI and cognitive performance, providing a possible network-based mechanism to, in-part, explain the risk for poor cognitive functioning associated with disadvantaged neighborhoods. Future work will examine the exposure to neighborhood disadvantage on structural organization of the brain.

Unraveling diurnal and technical variability in cerebral hemodynamics from neurovascular 4D-Flow MRI.

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.

Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology.

Importance: Phosphorylated tau (p-tau) is a specific blood biomarker for Alzheimer disease (AD) pathology, with p-tau217 considered to have the most utility. However, availability of p-tau217 tests for research and clinical use has been limited. Expanding access to this highly accurate AD biomarker is crucial for wider evaluation and implementation of AD blood tests. Objective: To determine the utility of a novel and commercially available immunoassay for plasma p-tau217 to detect AD pathology and evaluate reference ranges for abnormal amyloid ß (Aß) and longitudinal change across 3 selected cohorts. Design, Setting, and Participants: This cohort study examined data from 3 single-center observational cohorts: cross-sectional and longitudinal data from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort (visits October 2017-August 2021) and Wisconsin Registry for Alzheimer's Prevention (WRAP) cohort (visits February 2007-November 2020) and cross-sectional data from the Sant Pau Initiative on Neurodegeneration (SPIN) cohort (baseline visits March 2009-November 2021). Participants included individuals with and without cognitive impairment grouped by amyloid and tau (AT) status using PET or CSF biomarkers. Data were analyzed from February to June 2023. Exposures: Magnetic resonance imaging, Aß positron emission tomography (PET), tau PET, cerebrospinal fluid (CSF) biomarkers (Aß42/40 and p-tau immunoassays), and plasma p-tau217 (ALZpath pTau217 assay). Main Outcomes and Measures: Accuracy of plasma p-tau217 in detecting abnormal amyloid and tau pathology, longitudinal p-tau217 change according to baseline pathology status. Results: The study included 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%] and 282 males [35.9%]). High accuracy was observed in identifying elevated Aß (area under the curve [AUC], 0.92-0.96; 95% CI, 0.89-0.99) and tau pathology (AUC, 0.93-0.97; 95% CI, 0.84-0.99) across all cohorts. These accuracies were comparable with CSF biomarkers in determining abnormal PET signal. The detection of abnormal Aß pathology using a 3-range reference yielded reproducible results and reduced confirmatory testing by approximately 80%. Longitudinally, plasma p-tau217 values showed an annual increase only in Aß-positive individuals, with the highest increase observed in those with tau positivity. Conclusions and Relevance: This study found that a commercially available plasma p-tau217 immunoassay accurately identified biological AD, comparable with results using CSF biomarkers, with reproducible cut-offs across cohorts. It detected longitudinal changes, including at the preclinical stage.

Diagnostic accuracy of the plasma ALZpath pTau217 immunoassay to identify Alzheimer's disease pathology.

Importance: Phosphorylated tau (pTau) is a specific blood biomarker for Alzheimer's disease (AD) pathology, with pTau217 considered to have the most utility. However, availability of pTau217 tests for research and clinical use has been limited. Expanding access to this highly accurate AD biomarker is crucial for wider evaluation and implementation of AD blood tests. Objective: To determine the utility of a novel and commercially available Single molecule array (Simoa) for plasma pTau217 (ALZpath) to detect AD pathology. To evaluate references ranges for abnormal Aß across three selected cohorts. Design Setting Participants: Three single-centre observational cohorts were involved in the study: Translational Biomarkers in Aging and Dementia (TRIAD), Wisconsin Registry for Alzheimer's Prevention (WRAP), and Sant Pau Initiative on Neurodegeneration (SPIN). MRI, Aß-PET, and tau-PET data were available for TRIAD and WRAP, while CSF biomarkers were additionally measured in a subset of TRIAD and SPIN. Plasma measurements of pTau181, pTau217 (ALZpath), pTau231, Aß42/40, GFAP, and NfL, were available for all cohorts. Longitudinal blood biomarker data spanning 3 years for TRIAD and 8 years for WRAP were included. Exposures: MRI, Aß-PET, tau-PET, CSF biomarkers (Aß42/40 and pTau immunoassays) and plasma pTau217 (ALZpath Simoa). Main Outcomes and Measures: The accuracy of plasma pTau217 for detecting abnormal amyloid and tau pathology. Longitudinal pTau217 change according to baseline pathology status. Results: The study included 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%]) were included in the study. High accuracy was observed in identifying elevated Aß (AUC, 0.92-0.96; 95%CI 0.89-0.99) and tau pathology (AUC, 0.93-0.97; 95%CI 0.84-0.99) across all cohorts. These accuracies were significantly higher than other plasma biomarker combinations and comparable to CSF biomarkers. The detection of abnormal Aß pathology using binary or three-range references yielded reproducible results. Longitudinally, plasma pTau217 showed an annual increase only in Aß-positive individuals, with the highest increase observed in those with tau-positivity. Conclusions and Relevance: The ALZpath plasma pTau217 Simoa assay accurately identifies biological AD, comparable to CSF biomarkers, with reproducible cut-offs across cohorts. It detects longitudinal changes, including at the preclinical stage, and is the first widely available, accessible, and scalable blood test for pTau217 detection.