Alzheimer's disease (AD) is often underdiagnosed, especially at early stages when symptoms are mild, and patients may benefit from new and recently approved anti-amyloid therapies. An updated patient care pathway may facilitate timely diagnosis and intervention. We conducted a scan of published information and convened an expert panel of health care professionals to gain insights on early AD care pathways. We developed an Early AD Patient Care Pathway as an implementation guide that includes new diagnostic and treatment modalities and addresses needs and opportunities. The Early AD Patient Care Pathway focuses on patient identification, assessment, diagnosis, treatment, and management and monitoring. Operational readiness considerations aid pathway implementation and include evaluating and addressing gaps in program and business planning, technology, education and resources, access and reimbursement, and care coordination. The pathway is adaptable to health system needs and may be further tested and refined for sustainability.
Tau neurofibrillary pathology is a hallmark of Alzheimer's disease (AD) and can be quantified in vivo using tau-selective positron emission tomography (tau PET). Tau PET signal closely correlates with cognitive decline and disease stage, yet the molecular networks underpinning tau accumulation remain incompletely defined.
We performed multi-omics integration of proteomics, transcriptomics, and tau PET standardized uptake value ratios (SUVRs), and clinical assessments data from cognitively normal and cognitively impaired individuals. Using Light Gradient Boosting Machine (LightGBM), two-way orthogonal partial least squares, and network-based approaches, we explored key tau-associated proteomic signatures and constructed protein–protein interaction (PPI) modules. Module activities were quantified by gene set variation analysis and related to tau PET and cognition.
Among 60 regions, 15 tau PET imaging biomarkers were selected based on group differences, LightGBM importance, and cognitive relevance. Fifty key tau-associated proteins were identified and organized into four functional modules. PPI modules 1 (metabolic-cytoskeletal) and 3 (adhesion-nutrient sensing) exhibited strong associations with elevated tau PET uptake across selected cortical and limbic regions, as well as with cognitive impairment.
Distinct modules reflected regional tau PET burden and cognitive outcomes in AD, highlighting convergent disruptions in energy metabolism, cytoskeletal stability, and intercellular signaling.
As Alzheimer's disease (AD) research advances, tau has emerged as both a critical biomarker and a promising therapeutic target, central to understanding disease mechanisms, tracking progression, and guiding treatment development. The Fall 2024 Alzheimer's Association Research Roundtable convened experts from academia, industry, National Institutes of Health (NIH), and the United States Food and Drug Administration (FDA) to explore current progress and future directions in tau-centered diagnostics and therapeutics. Discussions addressed the integration of tau biomarkers into the 2024 Revised Diagnostic Criteria for AD, updates to amyloid and tau positron emission tomography (PET) imaging, and modeling of biomarker trajectories. Presenters highlighted tau-targeting therapeutics including antisense oligonucleotides, monoclonal antibodies, and small molecules, alongside innovations in drug delivery. The interplay between anti-amyloid and anti-tau therapies and strategic design of combination trials were key themes. Regulatory insights facilitated discussions on drug approval pathways. The meeting highlighted the rapid evolution of tau research and emphasized opportunities to improve diagnostics, trial design, and treatment strategies in AD.
Chronic cerebral hypoperfusion (CCH)-induced white matter hyperintensities (WMHs) are a well-established risk factor for cognitive impairment and dementia. While animal and post mortem studies suggest that myelin loss in normal-appearing white matter (NAWM) precedes WMHs, in vivo evidence in human brain remains limited. We aimed to investigate the associations between myelin changes in NAWM, CCH, and cognitive function in patients with moyamoya disease (MMD, a human model of CCH).
We included 58 patients with MMD and 36 healthy controls, and all participants underwent 3.0T magnetic resonance imaging (MRI) with T1-weighted, T2-weighted, and arterial spin labeling (ASL) sequences. Myelin was assessed by the T1-weighted/T2-weighted ratio (rT1/T2), and cerebral blood flow (CBF) in each arterial region was measured by ASL. Cognitive function was evaluated using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA).
Patients exhibited decreased rT1/T2 at lower percentiles (P5 and P10) and increased rT1/T2 at higher percentiles (P75, P90, and P95) in NAWM (false discovery rate [FDR]-corrected p < 0.005), along with reduced CBF in the region of anterior circulation (FDR-corrected p < 0.05). Voxel-based analysis of NAWM showed region-specific decreases and increases in rT1/T2 in MMD. The percentile ranges (P90-P10 and P95-P5) of rT1/T2 showed high accuracy in differentiating patients from controls (accuracy: 88% to 90%). Multivariate analysis further revealed that in patients, both P5 and P10 of rT1/T2 were significantly associated with reduced CBF in the anterior circulation region (standardized β = 0.318, p = 0.016 and standardized β = 0.267, p = 0.043), and P5 of rT1/T2 significantly correlated with MMSE and MoCA (standardized β = 0.332, p = 0.004 and standardized β = 0.260, p = 0.011).
Our study provides in vivo evidence that CCH induces both myelin loss and potential plastic adaptations in NAWM, with severe myelin loss being associated with cognitive decline.
We tested the hypothesis that increased middle cerebral artery velocity (MCA velocity) during complex motor (overground walking) and cognitive tasks (e.g., dual task) is associated with cognitive performance in older adults with varying levels of cognitive ability.
Fifty-six participants (19 females, 75 ± 7 years old) completed a seated single task that assessed working memory performance; a walking single task, assessing overground walking gait speed; and a dual task, combining both. Continuous MCA velocity was collected, and participants completed a Montreal Cognitive Assessment (MoCA).
Higher MCA velocity was associated with faster gait speed, better working memory performance, and greater MoCA scores (all p < 0.05). Participants with lower MoCA scores had lower MCA velocity (p = 0.052), slower gait speed (p = 0.035), and lower working memory performance (p = 0.016) than people with higher MoCA scores. The hyperemic response of MCA velocity from single task walking to the dual task with increased cognitive load significantly contributed to MoCA scores (p = 0.017).
The functional response of cerebral blood flow with these tests suggests vascular properties may be considered a biomarker indicative of subclinical cognitive function during walking tasks.
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