Can integration of Alzheimer's plasma biomarkers with MRI, cardiovascular, genetics, and lifestyle measures improve cognition prediction?

There is increasing interest in Alzheimer's disease related plasma biomarkers due to their accessibility and scalability. We hypothesized that integrating plasma biomarkers with other commonly used and available participant data (MRI, cardiovascular factors, lifestyle, genetics) using machine learning (ML) models can improve individual prediction of cognitive outcomes. Further, our goal was to evaluate the heterogeneity of these predictors across different age strata. This longitudinal study included 1185 participants from the Mayo Clinic Study of Aging who had complete plasma analyte work-up at baseline. We used the Quanterix Simoa immunoassay to measure neurofilament light, Aß1-42 and Aß1-40 (used as Aß42/Aß40 ratio), glial fibrillary acidic protein, and phosphorylated tau 181 (p-tau181). Participants' brain health was evaluated through gray and white matter structural MRIs. The study also considered cardiovascular factors (hyperlipidemia, hypertension, stroke, diabetes, chronic kidney disease), lifestyle factors (area deprivation index, body mass index, cognitive and physical activities), and genetic factors (APOE, single nucleotide polymorphisms, and polygenic risk scores). An ML model was developed to predict cognitive outcomes at baseline and decline (slope). Three models were created: a base model with groups of risk factors as predictors, an enhanced model included socio-demographics, and a final enhanced model by incorporating plasma and socio-demographics into the base models. Models were explained for three age strata: younger than 65 years, 65-80 years, and older than 80 years, and further divided based on amyloid positivity status. Regardless of amyloid status the plasma biomarkers showed comparable performance (R² = 0.15) to MRI (R² = 0.18) and cardiovascular measures (R² = 0.10) when predicting cognitive decline. Inclusion of cardiovascular or MRI measures with plasma in the presence of socio-demographic improved cognitive decline prediction (R² = 0.26 and 0.27). For amyloid positive individuals Aß42/Aß40, glial fibrillary acidic protein and p-tau181 were the top predictors of cognitive decline while Aß42/Aß40 was prominent for amyloid negative participants across all age groups. Socio-demographics explained a large portion of the variance in the amyloid negative individuals while the plasma biomarkers predominantly explained the variance in amyloid positive individuals (21% to 37% from the younger to the older age group). Plasma biomarkers performed similarly to MRI and cardiovascular measures when predicting cognitive outcomes and combining them with either measure resulted in better performance. Top predictors were heterogeneous between cross-sectional and longitudinal cognition models, across age groups, and amyloid status. Multimodal approaches will enhance the usefulness of plasma biomarkers through careful considerations of a study population's socio-demographics, brain and cardiovascular health.

The ADNI4 Digital Study: A novel approach to recruitment, screening, and assessment of participants for AD clinical research.

INTRODUCTION: We evaluated preliminary feasibility of a digital, culturally-informed approach to recruit and screen participants for the Alzheimer's Disease Neuroimaging Initiative (ADNI4). METHODS: Participants were recruited using digital advertising and completed digital surveys (e.g., demographics, medical exclusion criteria, 12-item Everyday Cognition Scale [ECog-12]), Novoic Storyteller speech-based cognitive test). Completion rates and assessment performance were compared between underrepresented populations (URPs: individuals from ethnoculturally minoritized or low education backgrounds) and non-URPs. RESULTS: Of 3099 participants who provided contact information, 654 enrolled in the cohort, and 595 completed at least one assessment. Two hundred forty-seven participants were from URPs. Of those enrolled, 465 met ADNI4 inclusion criteria and 237 evidenced possible cognitive impairment from ECog-12 or Storyteller performance. URPs had lower ECog and Storyteller completion rates. Scores varied by ethnocultural group and educational level. DISCUSSION: Preliminary results demonstrate digital recruitment and screening assessment of an older diverse cohort, including those with possible cognitive impairment, are feasible. Improving engagement and achieving educational diversity are key challenges. HIGHLIGHTS: A total of 654 participants enrolled in a digital cohort to facilitate ADNI4 recruitment. Culturally-informed digital ads aided enrollment of underrepresented populations. From those enrolled, 42% were from underrepresented ethnocultural and educational groups. Digital screening tools indicate > 50% of participants likely cognitively impaired. Completion rates and assessment performance vary by ethnocultural group and education.

A Protocol for the Inclusion of Minoritized Persons in Alzheimer Disease Research From the ADNI3 Diversity Taskforce.

Importance: Black or African American (hereinafter, Black) and Hispanic or Latino/a/x (hereinafter, Latinx) adults are disproportionally affected by Alzheimer disease, but most research studies do not enroll adequate numbers of both of these populations. The Alzheimer's Disease Neuroimaging Initiative-3 (ADNI3) launched a diversity taskforce to pilot a multipronged effort to increase the study inclusion of Black and Latinx older adults. Objective: To describe and evaluate the culturally informed and community-engaged inclusion efforts to increase the screening and enrollment of Black and Latinx older adults in ADNI3. Design, Setting, and Participants: This cross-sectional study used baseline data from a longitudinal, multisite, observational study conducted from January 15, 2021, to July 12, 2022, with no follow-up. The study was conducted at 13 ADNI3 sites in the US. Participants included individuals aged 55 to 90 years without cognitive impairment and those with mild cognitive impairment or Alzheimer disease. Exposures: Efforts included (1) launch of an external advisory board, (2) changes to the study protocol, (3) updates to the digital prescreener, (4) selection and deployment of 13 community-engaged research study sites, (5) development and deployment of local and centralized outreach efforts, and (6) development of a community-science partnership board. Main Outcomes and Measures: Screening and enrollment numbers from centralized and local outreach efforts, digital advertisement metrics, and digital prescreener completion. Results: A total of 91 participants enrolled in the trial via centralized and local outreach efforts, of which 22 (24.2%) identified as Latinx and 55 (60.4%) identified as Black (median [IQR] age, 65.6 [IQR, 61.5-72.5] years; 62 women [68.1%]). This represented a 267.6% increase in the monthly rate of enrollment (before: 1.11 per month; during: 4.08 per month) of underrepresented populations. For the centralized effort, social media advertisements were run between June 1, 2021, and July 31, 2022, which resulted in 2079 completed digital prescreeners, of which 1289 met criteria for subsequent site-level screening. Local efforts were run between June 1, 2021, to July 31, 2022. A total of 151 participants underwent site-level screening (100 from local efforts, 41 from centralized efforts, 10 from other sources). Conclusions and Relevance: In this cross-sectional study of pilot inclusion efforts, a culturally informed, community-engaged approach increased the inclusion of Black and Latinx participants in an Alzheimer disease cohort study.

Optical Coherence Tomography Angiography Retinal Imaging Associations With Burden of Small Vessel Disease and Amyloid Positivity in the Brain.

BACKGROUND: Alzheimer disease (AD) and other dementias are associated with vascular changes and amyloid deposition, which may be reflected as density changes in the retinal capillaries. These changes may can be directly visualized and quantified with optical coherence tomography angiography (OCTA), making OCTA a potential noninvasive preclinical biomarker of small vessel disease and amyloid positivity. Our objective was to investigate the feasibility of retinal imaging metrics as noninvasive biomarkers of small vessel disease and amyloid positivity in the brain. METHODS: We investigated associations between OCTA and neuroimaging and cognitive metrics in 41 participants without dementia from the Mayo Clinic Study of Aging and Alzheimer's Disease Research Center. OCTA metrics included superficial, deep, and full retina capillary density of the fovea, parafovea, and macula as well as the area of the foveal avascular zone (FAZ). Neuroimaging metrics included a high burden of white matter hyperintensity (WMH), presence of cerebral microbleeds (CMB), lacunar infarcts, and amyloid positivity as evidenced on positron emission tomography (PET), whereas cognitive metrics included mini-mental status examination (MMSE) score. We performed generalized estimating equations to account for measurements in each eye while controlling for age and sex to estimate associations between OCTA metrics and neuroimaging and cognitive scores. RESULTS: Associations between OCTA and neuroimaging metrics were restricted to the fovea. OCTA showed decreased capillary density with high burden of WMH in both the superficial (P = 0.003), deep (P = 0.004), and full retina (P = 0.01) in the fovea but not the parafovea or whole macula. Similarly, participants with amyloid PET positivity had significantly decreased capillary density in the superficial fovea (P = 0.027) and deep fovea (P = 0.03) but higher density in the superficial parafovea (P = 0.038). Participants with amyloid PET positivity also had a significantly larger FAZ (P = 0.031), whereas in those with high WMH burden the difference did not reach statistical significance (P = 0.075). There was also a positive association between MMSE and capillary density of the full retina within the fovea (P = 0.037) and in the superficial parafovea (P = 0.046). No associations were found between OCTA metrics and presence of CMB or presence of lacunar infarcts. CONCLUSION: The associations of lower foveal capillary density with cerebral WMH and amyloid positivity suggest that further research is warranted to evaluate for shared mechanisms of disease between small vessel disease and AD pathologies.

The Alzheimer's Disease Neuroimaging Initiative Clinical Core.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) Clinical Core is responsible for coordination of all clinical activities at the ADNI sites, including project management, regulatory oversight, and site management and monitoring, as well as the collection of all clinical data and management of all study data. The Clinical Core is also charged with determining the clinical classifications and criteria for enrollment in evolving AD trials and enabling the ongoing characterization of the cross-sectional features and longitudinal trajectories of the ADNI cohorts with application of these findings to optimal clinical trial designs. More than 2400 individuals have been enrolled in the cohorts since the inception of ADNI, facilitating refinement of our understanding of the AD trajectory and allowing academic and industry investigators to model therapeutic trials across the disease spectrum from the presymptomatic stage through dementia. HIGHLIGHTS: Since 2004, the Alzheimer's Disease Neuroimaging Initiative (ADNI) Clinical Core has overseen the enrollment of > 2400 participants with mild cognitive impairment, mild Alzheimer's disease (AD) dementia, and normal cognition. The longitudinal dataset has elucidated the full cognitive and clinical trajectory of AD from its presymptomatic stage through the onset of dementia. The ADNI data have supported the design of most major trials in the field.

Can white matter hyperintensities based Fazekas visual assessment scales inform about Alzheimer's disease pathology in the population?

BACKGROUND: White matter hyperintensities (WMH) are considered hallmark features of cerebral small vessel disease and have recently been linked to Alzheimer's disease (AD) pathology. Their distinct spatial distributions, namely periventricular versus deep WMH, may differ by underlying age-related and pathobiological processes contributing to cognitive decline. We aimed to identify the spatial patterns of WMH using the 4-scale Fazekas visual assessment and explore their differential association with age, vascular health, AD imaging markers, namely amyloid and tau burden, and cognition. Because our study consisted of scans from GE and Siemens scanners with different resolutions, we also investigated inter-scanner reproducibility and combinability of WMH measurements on imaging. METHODS: We identified 1144 participants from the Mayo Clinic Study of Aging consisting of a population-based sample from Olmsted County, Minnesota with available structural magnetic resonance imaging (MRI), amyloid, and tau positron emission tomography (PET). WMH distribution patterns were assessed on FLAIR-MRI, both 2D axial and 3D, using Fazekas ratings of periventricular and deep WMH severity. We compared the association of periventricular and deep WMH scales with vascular risk factors, amyloid-PET, and tau-PET standardized uptake value ratio, automated WMH volume, and cognition using Pearson partial correlation after adjusting for age. We also evaluated vendor compatibility and reproducibility of the Fazekas scales using intraclass correlations (ICC). RESULTS: Periventricular and deep WMH measurements showed similar correlations with age, cardiometabolic conditions score (vascular risk), and cognition, (p < 0.001). Both periventricular WMH and deep WMH showed weak associations with amyloidosis (R = 0.07, p = < 0.001), and none with tau burden. We found substantial agreement between data from the two scanners for Fazekas measurements (ICC = 0.82 and 0.74). The automated WMH volume had high discriminating power for identifying participants with Fazekas ≥ 2 (area under curve = 0.97) and showed poor correlation with amyloid and tau PET markers similar to the visual grading. CONCLUSION: Our study investigated risk factors underlying WMH spatial patterns and their impact on global cognition, with no discernible differences between periventricular and deep WMH. We observed minimal impact of amyloidosis on WMH severity. These findings, coupled with enhanced inter-scanner reproducibility of WMH data, suggest the combinability of inter-scanner data assessed by harmonized protocols in the context of vascular contributions to cognitive impairment and dementia biomarker research.

Mayo Normative Studies: Amyloid and Neurodegeneration Negative Normative Data for the Auditory Verbal Learning Test and Sex-Specific Sensitivity to Mild Cognitive Impairment/Dementia.

Background: Conventional normative samples include individuals with undetected Alzheimer's disease neuropathology, lowering test sensitivity for cognitive impairment. Objective: We developed Mayo Normative Studies (MNS) norms limited to individuals without elevated amyloid or neurodegeneration (A-N-) for Rey's Auditory Verbal Learning Test (AVLT). We compared these MNS A-N- norms in female, male, and total samples to conventional MNS norms with varying levels of demographic adjustments. Methods: The A-N- sample included 1,059 Mayo Clinic Study of Aging cognitively unimpaired (CU) participants living in Olmsted County, MN, who are predominantly non-Hispanic White. Using a regression-based approach correcting for age, sex, and education, we derived fully-adjusted T-score formulas for AVLT variables. We validated these A-N- norms in two independent samples of CU (n = 261) and mild cognitive impairment (MCI)/dementia participants (n = 392) > 55 years of age. Results: Variability associated with age decreased by almost half in the A-N- norm sample relative to the conventional norm sample. Fully-adjusted MNS A-N- norms showed approximately 7- 9% higher sensitivity to MCI/dementia compared to fully-adjusted MNS conventional norms for trials 1- 5 total and sum of trials. Among women, sensitivity to MCI/dementia increased with each normative data refinement. In contrast, age-adjusted conventional MNS norms showed greatest sensitivity to MCI/dementia in men. Conclusions: A-N- norms show some benefits over conventional normative approaches to MCI/dementia sensitivity, especially for women. We recommend using these MNS A-N- norms alongside MNS conventional norms. Future work is needed to determine if normative samples that are not well characterized clinically show greater benefit from biomarker-refined approaches.

Clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome.

Predominant limbic degeneration has been associated with various underlying aetiologies and an older age, predominant impairment of episodic memory and slow clinical progression. However, the neurological syndrome associated with predominant limbic degeneration is not defined. This endeavour is critical to distinguish such a syndrome from those originating from neocortical degeneration, which may differ in underlying aetiology, disease course and therapeutic needs. We propose a set of clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome that is highly associated with limbic-predominant age-related TDP-43 encephalopathy but also other pathologic entities. The criteria incorporate core, standard and advanced features, including older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of neocortical degeneration and low likelihood of neocortical tau, with degrees of certainty (highest, high, moderate and low). We operationalized this set of criteria using clinical, imaging and biomarker data to validate its associations with clinical and pathologic outcomes. We screened autopsied patients from Mayo Clinic and Alzheimer's Disease Neuroimaging Initiative cohorts and applied the criteria to those with an antemortem predominant amnestic syndrome (Mayo, n = 165; Alzheimer's Disease Neuroimaging Initiative, n = 53) and who had Alzheimer's disease neuropathological change, limbic-predominant age-related TDP-43 encephalopathy or both pathologies at autopsy. These neuropathology-defined groups accounted for 35, 37 and 4% of cases in the Mayo cohort, respectively, and 30, 22 and 9% of cases in the Alzheimer's Disease Neuroimaging Initiative cohort, respectively. The criteria effectively categorized these cases, with Alzheimer's disease having the lowest likelihoods, limbic-predominant age-related TDP-43 encephalopathy patients having the highest likelihoods and patients with both pathologies having intermediate likelihoods. A logistic regression using the criteria features as predictors of TDP-43 achieved a balanced accuracy of 74.6% in the Mayo cohort, and out-of-sample predictions in an external cohort achieved a balanced accuracy of 73.3%. Patients with high likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods. Stratifying patients with both Alzheimer's disease neuropathological change and limbic-predominant age-related TDP-43 encephalopathy from the Mayo cohort according to their likelihoods revealed that those with higher likelihoods had more temporo-limbic degeneration and a slower rate of decline and those with lower likelihoods had more lateral temporo-parietal degeneration and a faster rate of decline. The implementation of criteria for a limbic-predominant amnestic neurodegenerative syndrome has implications to disambiguate the different aetiologies of progressive amnestic presentations in older age and guide diagnosis, prognosis, treatment and clinical trials.

Optimizing cutpoints for clinical interpretation of brain amyloid status using plasma p-tau217 immunoassays.

INTRODUCTION: We aimed to evaluate clinical interpretation cutpoints for two plasma phosphorylated tau (p-tau)217 assays (ALZpath and Lumipulse) as predictors of amyloid status for implementation in clinical practice. METHODS: Clinical performance of plasma p-tau217 against amyloid positron emission tomography status was evaluated in participants with mild cognitive impairment or mild dementia (n = 427). RESULTS: Using a one-cutpoint approach (negative/positive), neither assay achieved ≥ 90% in both sensitivity and specificity. A two-cutpoint approach yielding 92% sensitivity and 96% specificity provided the desired balance of false positives and false negatives, while categorizing 20% and 39% of results as indeterminate for the Lumipulse and ALZpath assays, respectively. DISCUSSION: This study provides a systematic framework for selection of assay-specific cutpoints for clinical use of plasma p-tau217 for determination of amyloid status. Our findings suggest that a two-cutpoint approach may have advantages in optimizing diagnostic accuracy while minimizing potential harm from false positive results. HIGHLIGHTS: Phosphorylated tau (p-tau)217 cutpoints for detection of amyloid pathology were established. A two-cutpoint approach exhibited the best performance for clinical laboratory use. p-tau217 assays differed in the percentage of results categorized as intermediate.

Association of Anxiety and Unspecified Emotional Distress Obtained from a Medical Records Linkage System with Incident Cognitive Outcomes in a Population-Based Setting.

Background: Studies that assess cognition prospectively and study in detail anxiety history in the participants' medical records within the context of brain aging and Alzheimer's disease are limited. Objective: To examine the associations of anxiety and unspecified emotional distress (UED) acquired throughout a person's life with prospectively collected cognitive outcomes. Methods: Mayo Clinic Study of Aging participants who were cognitively unimpaired at baseline were included. Anxiety and UED data were abstracted from the medical record using the Rochester Epidemiology Project (REP) resources and were run separately as predictors in our models. The data were analyzed using Cox proportional hazards models for the outcomes of incident mild cognitive impairment (MCI) and dementia and using linear mixed effects models for the outcomes of global and domain specific cognitive z-scores and included key covariates. Results: The study sample (n = 1,808) had a mean (standard deviation) age of 74.5 (7.3) years and 51.4% were male. Anxiety was associated with increased risk of MCI and dementia and was associated with lower baseline cognitive z-scores and accelerated decline over time in the global, memory, and attention domains. UED was associated with faster decline in all domains except visuospatial but did not show evidence of association with incident cognitive outcomes. These results varied by medication use and timing of anxiety. Conclusions: Anxiety and UED both showed inverse associations with cognition. Utilization of anxiety and UED data from across the life course, as available, from the REP system adds robustness to our results.

Flortaucipir PET uncovers relationships between tau and amyloid-ß in primary age-related tauopathy and Alzheimer's disease.

[18F]-Flortaucipir positron emission tomography (PET) is considered a good biomarker of Alzheimer's disease. However, it is unknown how flortaucipir is associated with the distribution of tau across brain regions and how these associations are influenced by amyloid-ß. It is also unclear whether flortaucipir can detect tau in definite primary age-related tauopathy (PART). We identified 248 individuals at Mayo Clinic who had undergone [18F]-flortaucipir PET during life, had died, and had undergone an autopsy, 239 cases of which also had amyloid-ß PET. We assessed nonlinear relationships between flortaucipir uptake in nine medial temporal and cortical regions, Braak tau stage, and Thal amyloid-ß phase using generalized additive models. We found that flortaucipir uptake was greater with increasing tau stage in all regions. Increased uptake at low tau stages in medial temporal regions was only observed in cases with a high amyloid-ß phase. Flortaucipir uptake linearly increased with the amyloid-ß phase in medial temporal and cortical regions. The highest flortaucipir uptake occurred with high Alzheimer's disease neuropathologic change (ADNC) scores, followed by low-intermediate ADNC scores, then PART, with the entorhinal cortex providing the best differentiation between groups. Flortaucipir PET had limited ability to detect PART, and imaging-defined PART did not correspond with pathologically defined PART. In summary, spatial patterns of flortaucipir mirrored the histopathological tau distribution, were influenced by the amyloid-ß phase, and were useful for distinguishing different ADNC scores and PART.

Speech-language within and between network disruptions in primary progressive aphasia variants.

Primary progressive aphasia (PPA) variants present with distinct disruptions in speech-language functions with little known about the interplay between affected and spared regions within the speech-language network and their interaction with other functional networks. The Neurodegenerative Research Group, Mayo Clinic, recruited 123 patients with PPA (55 logopenic (lvPPA), 44 non-fluent (nfvPPA) and 24 semantic (svPPA)) who were matched to 60 healthy controls. We investigated functional connectivity disruptions between regions within the left-speech-language network (Broca, Wernicke, anterior middle temporal gyrus (aMTG), supplementary motor area (SMA), planum temporale (PT) and parietal operculum (PO)), and disruptions to other networks (visual association, dorsal-attention, frontoparietal and default mode networks (DMN)). Within the speech-language network, multivariate linear regression models showed reduced aMTG-Broca connectivity in all variants, with lvPPA and nfvPPA findings remaining significant after Bonferroni correction. Additional loss in Wernicke-Broca connectivity in nfvPPA, Wernicke-PT connectivity in lvPPA and greater aMTG-PT connectivity in svPPA were also noted. Between-network connectivity findings in all variants showed reduced aMTG-DMN and increased aMTG-dorsal-attention connectivity, with additional disruptions between aMTG-visual association in both lvPPA and svPPA, aMTG-frontoparietal in lvPPA, and Wernicke-DMN breakdown in svPPA. These findings suggest that aMTG connectivity breakdown is a shared feature in all PPA variants, with lvPPA showing more extensive connectivity disruptions with other networks.

Harmonizing tau positron emission tomography in Alzheimer's disease: The CenTauR scale and the joint propagation model.

INTRODUCTION: Tau-positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods of analysis. METHODS: Using head-to-head data from five cohorts with tau PET radiotracers designed to target tau deposition in AD, we tested a joint propagation model (JPM) to harmonize quantification (units termed "CenTauR" [CTR]). JPM is a statistical model that simultaneously models the relationships between head-to-head and anchor point data. JPM was compared to a linear regression approach analogous to the one used in the amyloid PET Centiloid scale. RESULTS: A strong linear relationship was observed between CTR values across brain regions. Using the JPM approach, CTR estimates were similar to, but more accurate than, those derived using the linear regression approach. DISCUSSION: Preliminary findings using the JPM support the development and adoption of a universal scale for tau-PET quantification. HIGHLIGHTS: Tested a novel joint propagation model (JPM) to harmonize quantification of tau PET. Units of common scale are termed "CenTauRs". Tested a Centiloid-like linear regression approach. Using five cohorts with head-to-head tau PET, JPM outperformed linearregressionbased approach. Strong linear relationship was observed between CenTauRs values across brain regions.

Prediction of future cognitive decline among cognitively unimpaired individuals using measures of soluble phosphorylated tau or tau tangle pathology.

Plasma p-tau217 and Tau-PET are strong prognostic biomarkers in Alzheimer's disease (AD), but their relative performance in predicting future cognitive decline among cognitively unimpaired (CU) individuals is unclear. In this head-to-head comparison study including 9 cohorts and 1534 individuals, we found that plasma p-tau217 and medial temporal lobe Tau-PET signal showed similar associations with cognitive decline on a global cognitive composite test (R2 PET=0.32 vs R2 PLASMA=0.32, pdifference=0.812) and with progression to mild cognitive impairment (Hazard ratio[HR]PET=1.56[1.43-1.70] vs HRPLASMA=1.63[1.50-1.77], pdifference=0.627). Combined plasma and PET models were superior to the single biomarker models (R2=0.36, p<0.01). Furthermore, sequential selection using plasma p-tau217 and then Tau-PET reduced the number of participants required for a clinical trial by 94%, compared to a 75% reduction when using plasma p-tau217 alone. We conclude that plasma p-tau217 and Tau-PET showed similar performance for predicting future cognitive decline in CU individuals, and their sequential use (i.e., plasma p-tau217 followed by Tau-PET in a subset with high plasma p-tau217) is useful for screening in clinical trials in preclinical AD.

NODDI in gray matter is a sensitive marker of aging and early AD changes.

INTRODUCTION: Age-related and Alzheimer's disease (AD) dementia-related neurodegeneration impact brain health. While morphometric measures from T1-weighted scans are established biomarkers, they may be less sensitive to earlier changes. Neurite orientation dispersion and density imaging (NODDI), offering biologically meaningful interpretation of tissue microstructure, may be an advanced brain health biomarker. METHODS: We contrasted regional gray matter NODDI and morphometric evaluations concerning their correlation with (1) age, (2) clinical diagnosis stage, and (3) tau pathology as assessed by AV1451 positron emission tomography. RESULTS: Our study hypothesizes that NODDI measures are more sensitive to aging and early AD changes than morphometric measures. One NODDI output, free water fraction (FWF), showed higher sensitivity to age-related changes, generally better effect sizes in separating mild cognitively impaired from cognitively unimpaired participants, and stronger associations with regional tau deposition than morphometric measures. DISCUSSION: These findings underscore NODDI's utility in capturing early neurodegenerative changes and enhancing our understanding of aging and AD. Highlights: Neurite orientation dispersion and density imaging can serve as an effective brain health biomarker for aging and early Alzheimer's disease (AD).Free water fraction has higher sensitivity to normal brain aging.Free water fraction has stronger associations with early AD and regional tau deposition.

Advancing Tau PET Quantification in Alzheimer Disease with Machine Learning: Introducing THETA, a Novel Tau Summary Measure.

Alzheimer disease (AD) exhibits spatially heterogeneous 3- or 4-repeat tau deposition across participants. Our overall goal was to develop an automated method to quantify the heterogeneous burden of tau deposition into a single number that would be clinically useful. Methods: We used tau PET scans from 3 independent cohorts: the Mayo Clinic Study of Aging and Alzheimer's Disease Research Center (Mayo, n = 1,290), the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 831), and the Open Access Series of Imaging Studies (OASIS-3, n = 430). A machine learning binary classification model was trained on Mayo data and validated on ADNI and OASIS-3 with the goal of predicting visual tau positivity (as determined by 3 raters following Food and Drug Administration criteria for 18F-flortaucipir). The machine learning model used region-specific SUV ratios scaled to cerebellar crus uptake. We estimated feature contributions based on an artificial intelligence-explainable method (Shapley additive explanations) and formulated a global tau summary measure, Tau Heterogeneity Evaluation in Alzheimer's Disease (THETA) score, using SUV ratios and Shapley additive explanations for each participant. We compared the performance of THETA with that of commonly used meta-regions of interest (ROIs) using the Mini-Mental State Examination, the Clinical Dementia Rating-Sum of Boxes, clinical diagnosis, and histopathologic staging. Results: The model achieved a balanced accuracy of 95% on the Mayo test set and at least 87% on the validation sets. It classified tau-positive and -negative participants with an AUC of 1.00, 0.96, and 0.94 on the Mayo, ADNI, and OASIS-3 cohorts, respectively. Across all cohorts, THETA showed a better correlation with the Mini-Mental State Examination and the Clinical Dementia Rating-Sum of Boxes (ρ ≥ 0.45, P < 0.05) than did meta-ROIs (ρ < 0.44, P < 0.05) and discriminated between participants who were cognitively unimpaired and those who had mild cognitive impairment with an effect size of 10.09, compared with an effect size of 3.08 for meta-ROIs. Conclusion: Our proposed approach identifies positive tau PET scans and provides a quantitative summary measure, THETA, that effectively captures heterogeneous tau deposition observed in AD. The application of THETA for quantifying tau PET in AD exhibits great potential.

Alzheimer Disease Cerebrospinal Fluid Biomarkers in a Tertiary Neurology Practice.

OBJECTIVE: To evaluate the performance of Alzheimer disease (AD) cerebrospinal fluid (CSF) biomarkers in a tertiary neurology clinic setting with high frequency of non-AD cases, including normal pressure hydrocephalus (NPH). METHODS: There were 534 patients who underwent AD CSF biomarkers (Roche Elecsys Aß42, p-Tau181, total-Tau) from April 1, 2020, through April 23, 2021. A behavioral neurologist blinded to CSF results assigned a clinical diagnosis retrospectively on the basis of consensus criteria, and a neuroradiologist blinded to the diagnosis and CSF studies graded brain magnetic resonance images for indicators of CSF dynamics disorders. Associations between biomarkers, diagnoses, and imaging were assessed by χ2, analysis of covariance, and linear regression methods. RESULTS: Median age at time of testing was 67 years (range, 19 to 96 years), median symptom duration was 2 years (range, 0.4 to 28 years), and median Short Test of Mental Status score was 30 (range, 0 to 38). Clinical diagnoses significantly correlated with different CSF biomarker values (χ2=208.3; P=10e-4). p-Tau181/Aß42 ratios above 0.023 positively correlated with Alzheimer dementia (more than individual measures). This ratio also had the best performance for differentiating Alzheimer dementia from NPH (area under the curve, 0.869). Imaging markers supportive of CSF dynamics disorders correlated with low Aß42, p-Tau181, and total-Tau. CONCLUSION: In a heterogeneous clinical population, abnormal p-Tau181/Aß42 ratios (>0.023) have the strongest association with Alzheimer dementia and probably represent a comorbid AD pathologic component in persons clearly matching non-AD neurodegenerative syndromes. Altered CSF dynamics were associated with lower concentrations of AD CSF biomarkers regardless of clinical diagnosis, but the ratio compensates for these changes. In the appropriate clinical setting, an isolated abnormal Aß42 should prompt consideration of NPH.

Complex relationships of socioeconomic status with vascular and Alzheimer's pathways on cognition.

INTRODUCTION: AD and CVD, which frequently co-occur, are leading causes of age-related cognitive decline. We assessed how demographic factors, socioeconomic status (SES) as indicated by education and occupation, vascular risk factors, and a range of biomarkers associated with both CVD (including white matter hyperintensities [WMH], diffusion MRI abnormalities, infarctions, and microbleeds) and AD (comprising amyloid-PET and tau-PET) collectively influence cognitive function. METHODS: In this cross-sectional population study, structural equation models were utilized to understand these associations in 449 participants (mean age (SD) = 74.5 (8.4) years; 56% male; 7.5% cognitively impaired). RESULTS: (1) Higher SES had a protective effect on cognition with mediation through the vascular pathway. (2) The effect of amyloid directly on cognition and through tau was 11-fold larger than the indirect effect of amyloid on cognition through WMH. (3) There is a significant effect of vascular risk on tau deposition. DISCUSSION: The utilized biomarkers captured the impact of CVD and AD on cognition. The overall effect of vascular risk and SES on these biomarkers are complex and need further investigation.

Gliovascular transcriptional perturbations in Alzheimer's disease reveal molecular mechanisms of blood brain barrier dysfunction.

To uncover molecular changes underlying blood-brain-barrier dysfunction in Alzheimer's disease, we performed single nucleus RNA sequencing in 24 Alzheimer's disease and control brains and focused on vascular and astrocyte clusters as main cell types of blood-brain-barrier gliovascular-unit. The majority of the vascular transcriptional changes were in pericytes. Of the vascular molecular targets predicted to interact with astrocytic ligands, SMAD3, upregulated in Alzheimer's disease pericytes, has the highest number of ligands including VEGFA, downregulated in Alzheimer's disease astrocytes. We validated these findings with external datasets comprising 4,730 pericyte and 150,664 astrocyte nuclei. Blood SMAD3 levels are associated with Alzheimer's disease-related neuroimaging outcomes. We determined inverse relationships between pericytic SMAD3 and astrocytic VEGFA in human iPSC and zebrafish models. Here, we detect vast transcriptome changes in Alzheimer's disease at the gliovascular-unit, prioritize perturbed pericytic SMAD3-astrocytic VEGFA interactions, and validate these in cross-species models to provide a molecular mechanism of blood-brain-barrier disintegrity in Alzheimer's disease.