Electronic health records to test multimorbidity influences to plasma biomarker interpretation for Alzheimer's disease.

Objective: Plasma biomarkers of Alzheimer's disease (AD) pathology are frequently tested in specialized research settings, limiting generalizability of findings. Using electronic health records and banked plasma, we evaluated plasma biomarkers - phosphorylated tau 217 (p-tau), β-amyloid 1-42/1-40 (Aβ/Aβ) and p-tau/Aβ - in a real-world, diverse clinical population with multimorbidities.

Methods: Participants (n=617; 44% Black/African American; 41% female) were selected from the University of Pennsylvania Medicine BioBank with plasma assayed using Fujirebio Lumipulse.

Comparison of plasma p-tau217/Aβ42, p-tau217, and Aβ42/Aβ40 biomarkers by race to detect Alzheimer's disease.

Introduction: In clinically and racially diverse training and test sets, we evaluated and validated Alzheimer's disease (AD) plasma biomarkers: phosphorylated tau-217 (p-tau217), amyloid beta 1-42/1-40 (Aβ42/Aβ40), and p-tau217/Aβ42.

Methods: Inclusion criteria were available plasma, race (people who self-identified as Black/African American [pBlack] or White [pWhite]), cognitive status (normal, mild cognitive impairment [MCI], dementia), and F-florbetaben or F-florbetapir positron emission tomography (PET) data. In the training set (n = 289; 28% pBlack), we used receiver-operating characteristic (ROC) analysis to calculate two cut points (0.

Tau-Clinical Mismatch Identifies Individuals with Co-Pathology and Predicts Clinical Trajectory.

Importance: The heterogeneous course of Alzheimer's disease makes it difficult to predict individuals' cognitive trajectories, which is particularly important in the era of disease modifying therapy. Identifying individuals more likely to have co-pathology and differing disease courses using clinically practical tools remains a critical gap.

Objective: To evaluate tau-clinical mismatch for identifying resilient and vulnerable individuals and compare levels of co-pathology and clinical trajectories between groups.

Multimorbidity in dementia: Current perspectives and future challenges.

Multimorbidity-the co-occurrence of two or more chronic health conditions-affects > 86% of people with dementia. It is associated with cognitive and functional decline, reduced health-related quality of life, increased health-care use, and higher mortality. The relationship between multimorbidity and dementia is potentially bidirectional; conditions such as hypertension and diabetes increase the risk of developing dementia, and cognitive impairment can complicate their management.

Tau burden is best captured by magnitude and extent: Tau-MaX as a measure of global tau.

Introduction: Tau burden consists of both spatial spread and local accumulation, but no study has combined these measures into a single metric to capture overall global tau burden. Here we investigate a new measure combining magnitude and extent-Tau-MaX-as a marker of Alzheimer's disease (AD) severity.

Methods: A total of 1077 F-flortaucipir positron emission tomography scans were analyzed using Gaussian mixture models to identify tau+ regions and quantify magnitude of accumulation.

Choroidal evaluation of FTLD-Tau and biomarker-determined Alzheimer's disease.

Frontotemporal lobar degeneration with tauopathy (FTLD-Tau) can present clinically similar to Alzheimer's disease but lacks a biomarker. Alzheimer's disease has been associated with choroidal thinning compared to controls. We compared the choroid of 25 probable FTLD-Tau (pFTLD-Tau) patients (42 eyes), 26 biomarker-determined probable Alzheimer's disease neuropathologic change (pADNC) patients (49 eyes), and 53 normal controls (80 eyes).

Societal Gender Norms and Their Influence on Late Life Cognition.

Introduction: This study assesses the influence of normative gender effects on cognitive outcomes of cognitively unimpaired older adults. The results help to understand how sex/gender identity operates as a structural determinant of AD outcomes and informs future research that is more inclusive of gender-diverse identities.

Methods: We analyze data from 216 adults aged 65 and older who completed survey questions from the Aging Gender Index (AGI), which pertain to often gendered experiences of American men and women, which relate to education, employment experiences, and relationship characteristics.

Retinal imaging and tissue analysis for frontotemporal degeneration: recent advances and challenges for biomarker development.

Frontotemporal degeneration (FTD) is a group of neurodegenerative disorders affecting behaviour, language and executive functions. FTD is a common cause of early-onset dementia, but there are no FDA-approved treatments or established biomarkers for diagnosing and tracking these conditions, making early and accurate diagnosis challenging during life. Recent advances in retinal imaging, particularly through technologies like optical coherence tomography (OCT), have emerged as promising tools for identifying potential biomarkers for FTD and related neurodegenerative diseases.

Neighborhood deprivation moderates prognosis in behavioral-variant frontotemporal degeneration.

Introduction: Neighborhood deprivation has been associated with shorter survival, cognitive impairment and neurodegeneration in aging and Alzheimer's disease. However, the association of neighborhood deprivation with disease progression in behavioral-variant frontotemporal degeneration (bvFTD) is unknown.

Methods: We examined associations between tertiles of neighborhood deprivation, using the Area Deprivation Index (ADI), and survival in 311 individuals clinically diagnosed with bvFTD from the Penn Frontotemporal Degeneration (FTD) Center.

Tau Burden is Best Captured by Magnitude and Extent: Tau-MaX as a Measure of Global Tau.

Tau exhibits change in both spatial extent and density of pathology along the Alzheimer's disease (AD) spectrum with each aspect contributing to the overall burden of pathological tau. Nevertheless, studies using Tau PET have measured either magnitude using standardized uptake value ratios (SUVRs) or extent using number of Tau+ regions. We hypothesized that combining these two dimensions into a single measure of Magnitude and eXtent, Tau-MaX, would provide improved quantification of global tau burden as well as allowing for a region-agnostic measure of global tau burden that does not require a pre-specified region of interest (ROI) or meta-ROI.

Posterior hippocampal sparing in Lewy body disorders with Alzheimer's copathology: An in vivo MRI study.

Background: Lewy body disorders (LBD), encompassing Parkinson disease (PD), PD dementia (PDD), and dementia with Lewy bodies (DLB), are characterized by alpha-synuclein pathology but often are accompanied by Alzheimer's disease (AD) neuropathological change (ADNC). The medial temporal lobe (MTL) is a primary locus of tau accumulation and associated neurodegeneration in AD. However, it is unclear the extent to which AD copathology in LBD (LBD/AD+) contributes to MTL-specific patterns of degeneration.

ADNI Biomarker Core: A review of progress since 2004 and future challenges.

Background: We describe the Alzheimer's Disease Neuroimaging Initiative (ADNI) Biomarker Core major activities from October 2004 to March 2024, including biobanking ADNI cerebrospinal fluid (CSF), plasma, and serum biofluid samples, biofluid analyses for Alzheimer's disease (AD) biomarkers in the Biomarker Core and various non-ADNI laboratories, and continuous assessments of pre-analytics.

Results: Validated immunoassay and mass spectrometry-based assays were performed in CSF with a shift to plasma, a more accessible biofluid, as qualified assays became available. Performance comparisons across different CSF and plasma AD biomarker measurement platforms have enriched substantially the ADNI participant database enabling method performance determinations for AD pathology detection and longitudinal assessments of disease progression.

Cytoarchitectonic gradients of laminar degeneration in behavioral variant frontotemporal dementia.

Behavioral variant frontotemporal dementia (bvFTD) is a clinical syndrome primarily caused by either tau (bvFTD-tau) or TDP-43 (bvFTD-TDP) proteinopathies. We previously found lower cortical layers and dorsolateral regions accumulate greater tau than TDP-43 pathology; however, patterns of laminar neurodegeneration across diverse cytoarchitecture in bvFTD is understudied. We hypothesized that bvFTD-tau and bvFTD-TDP have distinct laminar distributions of pyramidal neurodegeneration along cortical gradients, a topologic order of cytoarchitectonic subregions based on increasing pyramidal density and laminar differentiation.

Pathologic and cognitive correlates of plasma biomarkers in neurodegenerative disease.

Introduction: We investigate pathological correlates of plasma phosphorylated tau 181 (p-tau), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) across a clinically diverse spectrum of neurodegenerative disease, including normal cognition (NormCog) and impaired cognition (ImpCog).

Methods: Participants were NormCog (n = 132) and ImpCog (n = 461), with confirmed β-amyloid (Aβ+/-) status (cerebrospinal fluid, positron emission tomography, autopsy) and single molecule array plasma measurements. Logistic regression and receiver operating characteristic (ROC) area under the curve (AUC) tested how combining plasma analytes discriminated Aβ+ from Aβ-.

Automatic classification of AD pathology in FTD phenotypes using natural speech.

Introduction: Screening for Alzheimer's disease neuropathologic change (ADNC) in individuals with atypical presentations is challenging but essential for clinical management. We trained automatic speech-based classifiers to distinguish frontotemporal dementia (FTD) patients with ADNC from those with frontotemporal lobar degeneration (FTLD).

Methods: We trained automatic classifiers with 99 speech features from 1 minute speech samples of 179 participants (ADNC = 36, FTLD = 60, healthy controls [HC] = 89).

Greater white matter degeneration and lower structural connectivity in non-amnestic vs. amnestic Alzheimer's disease.

Introduction: Multimodal evidence indicates Alzheimer's disease (AD) is characterized by early white matter (WM) changes that precede overt cognitive impairment. WM changes have overwhelmingly been investigated in typical, amnestic mild cognitive impairment and AD; fewer studies have addressed WM change in atypical, non-amnestic syndromes. We hypothesized each non-amnestic AD syndrome would exhibit WM differences from amnestic and other non-amnestic syndromes.

Evaluation of ATN Framework and Biofluid Markers to Predict Cognitive Decline in Early Parkinson Disease.

Background And Objectives: In Parkinson disease (PD), Alzheimer disease (AD) copathology is common and clinically relevant. However, the longitudinal progression of AD CSF biomarkers-β-amyloid 1-42 (Aβ), phosphorylated tau 181 (p-tau), and total tau (t-tau)-in PD is poorly understood and may be distinct from clinical AD. Moreover, it is unclear whether CSF p-tau and serum neurofilament light (NfL) have added prognostic utility in PD, when combined with CSF Aβ.

Tau maturation in the clinicopathological spectrum of Lewy body and Alzheimer's disease.

Objective: Alzheimer's disease neuropathologic change and alpha-synucleinopathy commonly co-exist and contribute to the clinical heterogeneity of dementia. Here, we examined tau epitopes marking various stages of tangle maturation to test the hypotheses that tau maturation is more strongly associated with beta-amyloid compared to alpha-synuclein, and within the context of mixed pathology, mature tau is linked to Alzheimer's disease clinical phenotype and negatively associated with Lewy body dementia.

Methods: We used digital histology to measure percent area-occupied by pathology in cortical regions among individuals with pure Alzheimer's disease neuropathologic change, pure alpha-synucleinopathy, and a co-pathology group with both Alzheimer's and alpha-synuclein pathologic diagnoses.

Changes in Digital Speech Measures in Asymptomatic Carriers of Pathogenic Variants Associated With Frontotemporal Degeneration.

Background And Objectives: Clinical trials developing therapeutics for frontotemporal degeneration (FTD) focus on pathogenic variant carriers at preclinical stages. Objective, quantitative clinical assessment tools are needed to track stability and delayed disease onset. Natural speech can serve as an accessible, cost-effective assessment tool.

Comparison of category and letter fluency tasks through automated analysis.

Introduction: Category and letter fluency tasks are commonly used neuropsychological tasks to evaluate lexical retrieval.

Methods: This study used validated automated methods, which allow for more expansive investigation, to analyze speech production of both category ("Animal") and letter ("F") fluency tasks produced by healthy participants ( = 36) on an online platform. Recordings were transcribed and analyzed through automated pipelines, which utilized natural language processing and automatic acoustic processing tools.

Alzheimer Disease Biomarkers: Moving from CSF to Plasma for Reliable Detection of Amyloid and tau Pathology.

Background: Development of validated biomarkers to detect early Alzheimer disease (AD) neuropathology is needed for therapeutic AD trials. Abnormal concentrations of "core" AD biomarkers, cerebrospinal fluid (CSF) amyloid beta1-42, total tau, and phosphorylated tau correlate well with neuroimaging biomarkers and autopsy findings. Nevertheless, given the limitations of established CSF and neuroimaging biomarkers, accelerated development of blood-based AD biomarkers is underway.