Journals
2025 EN
Shirzadi Zahra · Schultz Aaron P. · Loghmani Nazila
+14 more
Abstract INTRODUCTION Increased white matter hyperintensity (WMH) volume is a common but non‐specific finding in AD. This study investigates the effect of baseline WMH volume and APO E ε4 on magnetic resonance imaging (MRI)‐visible hemorrhagic lesion emergence. METHODS We included A4 participants with 0/1 hemorrhagic lesion at baseline and >1 post‐baseline MRI. We examined age, sex, amyloid, WMH, APOE ε4, and cardiovascular risk as predictors of whether people would accrue ≥2 hemorrhagic lesions by their last MRI. RESULTS Among 1097 individuals with 0/1 baseline lesion, 120 had at least two hemorrhagic lesions on their last MRI. Elevated baseline WMH (odds ratio [OR] = 2.3, p = 0.002) and APOE ɛ4/ɛ4 (OR = 4.8, p < 0.001) independently predicted membership to this group. Both hetero‐ and homozygous APOE ɛ4 carriers with low WMH volume had a low risk of accumulating hemorrhagic lesions. DISCUSSION These results support the independent consideration of WMH and APOE ɛ4 in the natural history of hemorrhagic lesion accumulation and suggest that individuals with low WMH volume have a low short‐term risk, irrespective of APOE genotype. Trial Registration : NCT02008357 Highlights Elevated baseline white matter lesion volume is related to the risk of ARIA‐H emergence. The effects of white matter lesion volume and APOE ɛ4 on ARIA‐H are independent. APOE ɛ4 carriers with low white matter lesion volume had a low risk of ARIA‐H emergence.
Journals
2025 EN
Dodge Hiroko H. · Chen Liu · Wu ChaoYi
+4 more
Abstract INTRODUCTION Plasma biomarkers are increasingly used as surrogate outcomes in clinical trials for Alzheimer's disease and related dementias (ADRD) due to their non‐invasive nature. In early‐phase trials designed to evaluate mechanisms of action and biological efficacy, assessing pre–post changes in plasma biomarkers within the same individuals – using a single‐arm placebo lead‐in design – offers a potentially cost‐effective alternative to parallel‐group designs by minimizing between‐subject variability. However, plasma biomarkers are also subject to within‐individual variability, which can obscure true treatment effects. METHODS One strategy to address this limitation is to collect repeated measures during each study period. This approach can improve measurement precision, enhance the signal‐to‐noise ratio, and increase statistical power, even with modest sample sizes. RESULTS We propose an innovative early‐phase trial design, Single‐arm Lead‐In with Multiple measures (SLIM), which incorporates repeated biomarker assessments over a short follow‐up period. DISCUSSION Using simulation studies, we demonstrate that the SLIM design can substantially reduce required sample sizes. Highlights SLIM involves repeated biomarker assessments during both the lead‐in and post‐treatment periods. It minimizes between‐subject variability and improves the precision of within‐subject estimates. It is well suited for early‐phase, short‐duration trials. It is not suitable for cognitive tests or other outcomes prone to practice or placebo effects. SLIM design can be an alternative to the traditional parallel design by reducing required sample sizes, thereby lowering the recruitment burden.
Journals
2025 EN
Chan Diane · Weck Gabrielle · Jackson Brennan L.
+22 more
Abstract INTRODUCTION We evaluated the long‐term effects of daily 40 Hz (gamma frequency) audiovisual stimulation on cognition and biomarkers in five patients with mild Alzheimer's disease (AD). METHODS Over 2 years, patients received 1‐h daily stimulation. Electroencephalography (EEG) was used to assess neural entrainment; magnetic resonance imaging (MRI) measured brain volumes; actigraphy monitored activity patterns; neuropsychological tests evaluated cognition; and S‐PLEX assay measured plasma pTau217. RESULTS No adverse events occurred over the study period. Three female patients with late‐onset AD (LOAD) retained strong EEG entrainment and showed less decline in Mini‐Mental State Examination (MMSE), Clinical Dementia Rating (CDR), and Functional Assessment Scale (FAS) scores compared to matched controls from National Alzheimer's Coordinating Center (NACC), Alzheimer's Disease Neuroimaging Initiative (ADNI), and Longitudinal Early‐Onset Alzheimer's Disease Study (LEADS). Plasma samples were available for only two of five participants – both with LOAD – and both showed pTau217 reductions of 47% and 19%. DISCUSSION These findings suggest that long‐term 40 Hz audiovisual stimulation is safe, feasible, and may offer cognitive and biomarker benefits in some individuals with mild AD, supporting further investigation. CLINICAL TRIAL REGISTRATION INFORMATION ClinicalTrials.gov (NCT04055376). Highlights Five mild Alzheimer's disease (AD) patients safely used daily 40 Hz audiovisual stimulation for 2 years. Late‐onset AD (LOAD) patients showed increased 40 Hz electroencephalography (EEG) power and improved cognitive scores. National Alzheimer's Coordinating Center (NACC) data enhanced early‐phase analysis and support precision medicine in AD studies. Plasma pTau217 declined in 2 LOAD patients after 2 years of daily use. This small pilot is the first to link long‐term 40 Hz therapy to AD biomarker change.
Journals
2025 EN
Oomens Julie E. · Biber Sarah A. · Albert Marilyn
+59 more
Abstract INTRODUCTION The Consortium for Clarity in Alzheimer's disease related dementias (ADRD) Research Through Imaging (CLARiTI) is a study that aims to collect standardized imaging and plasma biomarkers on 2000 Clinical Core participants enrolled across all Alzheimer's Disease Research Centers (ADRC) sites. We sought to summarize the known heterogeneity across centers regarding scientific focus and initial enrollment plans for CLARiTI. METHODS We developed and distributed a survey capturing information on the 36 CLARiTI site's theme/expertise, recruitment plans, and the intersection of CLARiTI with other ADRC imaging efforts. RESULTS Anticipated CLARiTI enrollees spanned 11 different categories of suspected etiologies underlying impairment. A wide range of risk factors were endorsed across sites regarding the enrollment of unimpaired individuals. Variability also existed regarding site‐level strategies in enrollment into CLARiTI versus other imaging efforts. DISCUSSION We anticipate that the 2000 individuals that will enroll into CLARiTI will reflect the clinical heterogeneity already in place across the ADRC network. Highlights The ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) will leverage and contribute to the existing Alzheimer's Disease Research Centers (ADRC) program by supporting standardized imaging and plasma collection across all centers. We summarize the variation in scientific focus and enrollment plans across ADRC sites participating in CLARiTI. The anticipated CLARiTI cohort will reflect the clinical heterogeneity that already exists across the ADRC network. CLARiTI will contribute to scientific goals related to the detection of multi‐etiological signatures relevant for Alzheimer's disease and related disorders (ADRDs).
Journals
2025 EN
Dyck Christopher H. · Sperling Reisa · Johnson Keith
+7 more
Abstract INTRODUCTION In Clarity AD, lecanemab reduced markers of amyloid in early symptomatic Alzheimer's disease and slowed cognitive and functional decline at 18 months. Herein, we report 36‐month data from the ongoing open‐label extension (OLE). METHODS Clarity AD is an 18‐month, randomized study (Core), with an OLE where participants received open‐label lecanemab. Clinical and health‐related quality‐of‐life (HRQoL) outcomes were evaluated overall and by examining “delayed‐start” and “early‐start” cohorts. Low pathology (i.e., low baseline amyloid or tau) subgroups were analyzed. RESULTS ARIA rates were low after 6 months and not associated with long‐term progression. Across clinical and HRQoL endpoints, lecanemab‐treated participants continued to benefit through 36 months. Separation between early and delayed start was maintained between 18 and 36 months. The low pathology subgroup showed stability or improvement over 18–36 months. DISCUSSION Benefit continued to accrue with ongoing lecanemab treatment through 36 months. Results in the low pathology subgroup support early initiation of lecanemab treatment. Highlights This research evaluated the long‐term efficacy, safety, and HRQoL results from an ongoing extension of the phase 3 Clarity AD, which included open‐label lecanemab treatment for up to 36 months. Overall, the results show participants continue to accrue a lecanemab treatment benefit up to 36 months and highlight the importance of continued long‐term lecanemab treatment. Results presented in our paper demonstrate that lecanemab continued suppression of amyloid plaque levels and significantly slowed clinical decline on multiple measures of cognition, function, and quality of life in early AD at 18 months and continued for 36 months to date. No new safety signals were observed with continued lecanemab treatment. After the first 6 months, ARIA rates were low and similar to ARIA rates on placebo, with no association between ARIA occurrence and accelerated long‐term clinical progression. Taken together with existing data, these results provide a clear rationale and a demonstration of the disease modification effects of long‐term lecanemab therapy.
Journals
2025 EN
Balogun Wasiu G. · Zeng Xuemei · TrianaBaltzer Gallen
+12 more
Abstract INTRODUCTION Cross‐cohort validation studies for plasma phosphorylated tau (p‐tau) 217 are limited. We evaluated the Janssen plasma p‐tau217+ assay and proposed a cutpoint value in three independent community‐based cohorts. METHODS We included n = 441 participants (age = 70.3 ± 7.3) from three independent community‐based cohorts with amyloid‐beta–positron emission tomography (Aβ‐PET), tau‐PET, clinical, and cognitive information. RESULTS The cohorts had low pre‐test probability (%Aβ positivity = 14.9–24.7) and were predominantly cognitively normal (> 73%). Plasma p‐tau217+ had high accuracy for abnormal Aβ PET (areas under the curve [AUCs] = 81‐86%), good correlation with Aβ‐PET burden (0.336‐0.397) that was highest in the cohort with the most Aβ‐PET‐positive participants, and the biomarker concentrations were highest in the joint Aβ‐PET and tau‐PET positive group. Negative predictive value (NPV) was high across cohorts (≤93%) but positive predictive value (PPV) was consistently poor (< 57%). Sensitivity and specificity averaged 75% and 84%, respectively. A combined cohort cutpoint of 0.05pg/ml gave AUC = 84.5%, NPV = 94%, PPV = 50%, sensitivity = 75%, and specificity = 84%. DISCUSSION Plasma p‐tau217+ can rule out Aβ pathophysiology due to Alzheimer's disease at the population level. Cohort‐level %Aβ‐PET positivity influences accuracies. Highlights Plasma phosphorylated tau (p‐tau) 217 assays have demonstrated potential to identify older adults with brain amyloid pathology due to Alzheimer's disease. Community‐based studies are crucial for accessing the clinical validity of fluid biomarkers and their real‐world applicability. We evaluated the Janssen plasma p‐tau217+ assay in three community‐based cohorts. Janssen plasma p‐tau217+ identified amyloid‐beta abnormalities across three diverse cohorts of community‐dwelling older adults. High NPV indicates p‐tau217+ as a good tool for initial screening to enrich for high‐risk individuals particularly for cohort studies and clinical trial participation.
Journals
2025 EN
Tambo Willians · Powell Keren · Wadolowski Steven
+7 more
Abstract INTRODUCTION Neuropeptide dysregulation and microvascular injury are involved in pathogenesis of vascular cognitive impairment (VCI); however, the underlying etiology of this pathological axis remains unclear. METHODS We investigated pathological mediators across varying severities of VCI in a rat model of chronic cerebral hypoperfusion (CCH). Proteomic analysis guided the evaluation of neuropeptide and non‐neuropeptide markers associated with vascular and non‐vascular dysfunction, which were correlated with cognitive function to determine their role in VCI. RESULTS Proteomic analysis revealed vasomotor dysfunction as the primary pathological pathway in VCI. Microvascular vasoconstriction was the earliest and most persistent event, initiating a cascade of both microvascular and non‐vascular dysfunction. Dysregulation of vasoactive neuropeptides was identified as the key driver of this process. Calcitonin gene‐related peptide (CGRP) supplementation effectively prevented vasoconstriction, and improved cognitive function in CCH. DISCUSSION This study suggests dysregulation of vasoactive neuropeptides plays a central role in CCH pathomechanism, with microvascular vasoconstriction acting as the primary mediator. Highlights Neuropeptides are the primary drivers of dominant pathomechanisms underlying chronic cerebral hypoperfusion (CCH). Early vasoactive neuropeptide dysregulation is a key driver of cognitive decline. Microvascular dysfunction precedes classical non‐vascular pathologies in CCH. Capillary constriction precedes and drives amyloid accumulation in CCH. CGRP mitigates microvascular constriction, enhancing cognitive function in VCI.
Journals
2025 EN
Wu ChaoYi · Chen Liu · Fatima Hadia
+5 more
Abstract INTRODUCTION Accurate identification of individuals at risk for cognitive decline is critical for treatment planning and trial enrichment strategies. We evaluated the combined utility of plasma phosphorylated tau at threonine 217 (p‐tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in predicting domain‐specific cognitive decline. METHODS Participants ( n = 523; 40.9% cognitively unimpaired [CU]; 59.1% mild cognitive impairment [MCI]) were from the Massachusetts Alzheimer's Disease Research Center. Cognition was assessed using the National Alzheimer's Coordinating Center Uniform Data Set. Participants were classified as high(+)/low(−) for each biomarker using Gaussian mixture models. RESULTS Among all participants, high p‐tau217 alone [p‐tau217(+)NfL(–)GFAP(–)] was associated with a steeper decline in episodic/semantic memory and processing speed compared to the all‐low group ( p ≤ 0.02). With the addition of high GFAP [p‐tau217(+)NfL(–)GFAP(+)], steeper decline extended to most cognitive domains, including global cognition and executive function, compared to the all‐low group. In CU, faster decline in global cognition and executive function was seen when all biomarkers were elevated ([p‐tau217(+)NfL(+)GFAP(+)]; p ≤ 0.04). DISCUSSION Combined plasma biomarkers predict decline in cognitive domains vulnerable to early disease. Highlights High phosphorylated tau at threonine 217 (p‐tau217) alone was associated with declines in semantic/episodic memory, whereas its combination with elevated glial fibrillary acidic protein (GFAP) predicted declines in a wider range of cognitive domains. Elevated neurofilament light chain (NfL) amplifies the cognitive decline already driven by p‐tau217 and GFAP. In cognitively unimpaired individuals, subtle domain‐specific cognitive declines can be detected when both core and non‐core Alzheimer's disease biomarkers are used. Our finding highlights the importance of focusing on vulnerable cognitive domains during early disease where global cognition may appear stable but specific impairments can be masked within composite scores.
Journals
2025 EN
Goniotaki Despoina · Hausherr Maximilian · Lynham Steven
+8 more
Abstract INTRODUCTION Tauopathies involve progressive accumulation of abnormal tau species that disrupt the autophagy‐lysosomal pathway (ALP), critical for degrading intracellular macromolecules and aggregates, leading to toxicity and cell death. This study examines how overexpression of the N‐terminally truncated Tau35 protein affects proteolytic pathways, including autophagy and endo‐lysosomal processes. METHODS Using the Tau35 mouse model and SH‐SY5Y human neuroblastoma cells stably expressing Tau35 or full‐length tau, we assessed protein degradation and lysosomal function via Western blotting, proteomics of lysosome‐enriched brain fractions, cathepsin activity assays, endocytosis/proteolysis assays, and live‐cell imaging using LysoTracker. RESULTS We identified early endo‐lysosomal alterations associated with Tau35 expression, including increased endocytosis, disrupted autophagic flux, proteolytic impairment, and lysosomal motility defects. DISCUSSION These findings extend previous research by elucidating Tau35‐induced dysfunction in intracellular degradation systems and offer mechanistic insight into tauopathy progression. This work provides a foundation for developing targeted therapies to restore acidification, proteostasis, and lysosomal function in tauopathies. HighlightsTau35, an N‐terminally truncated tau fragment, disrupts proteolytic pathways : We show that Tau35 overexpression leads to significant alterations in autophagy and endo‐lysosomal function. Endo‐lysosomal dysfunction is an early pathological event : Our findings demonstrate early‐stage increases in endocytosis, impaired proteolytic activity, altered autophagic flux, and disrupted lysosomal motility in Tau35‐expressing models. In vivo and in vitro models confirm consistent pathogenic signatures : Parallel studies in a Tau35 mouse model and SH‐SY5Y cells reveal converging cellular and molecular dysfunctions. Lysosome‐enriched proteomics reveals novel pathway alterations : Proteomic profiling of lysosomal fractions identifies Tau35‐specific protein dysregulation contributing to disease pathology. Mechanistic insights into tauopathy progression : These results provide a mechanistic understanding of how truncated tau species contribute to neuronal dysfunction, offering a rationale for targeting endo‐lysosomal pathways in therapeutic development.
Journals
2025 EN
Njamnshi Wepnyu Yembe · Chiotis Konstantinos · Tsoy Elena
+51 more
Abstract INTRODUCTION Brief digital cognitive measures may be a valuable and scalable alternative to traditional tests for improving early detection and disease monitoring in patients with early‐onset Alzheimer's disease (EOAD). METHODS We examined the convergent, diagnostic, and neuroanatomical validity of Tablet‐based Cognitive Assessment Tool (TabCAT) tests in the multisite Longitudinal Early‐Onset Alzheimer's Disease Study. Four hundred seventy‐five participants from 16 sites (83 cognitively unimpaired participants, 146 individuals diagnosed with mild cognitive impairment [MCI], and 246 with mild dementia) underwent TabCAT testing, including two executive/attentional tasks (Match and Flanker) and two visuospatial tasks (Line Length and Line Orientation). RESULTS TabCAT tests showed good convergent validity with traditional pen‐and‐paper tests. Match was the most accurate TabCAT test in differentiating among clinical groups (controls vs. MCI vs. dementia) and predicting amyloid positron emission tomography (PET) positivity in clinically impaired participants. TabCAT tests were associated with regional tau PET patterns. DISCUSSION TabCAT digital measures have promise for frontline identification of patients with EOAD. Highlights Four hundred seventy‐five participants from 16 US sites underwent tablet‐based cognitive assessment. Digital tests assessed executive function and visuospatial abilities. Digital tests correlated with traditional pen‐and‐paper cognitive tests. Match (test of executive function) differentiated clinical groups. Digital tests were associated with amyloid positron emission tomography (PET) status and regional tau PET patterns.