Day, Gregory S

Abstract INTRODUCTION Monoclonal anti‐amyloid therapies are now accessible, but how these treatments influence changes within the brain is still not clear. We investigated overall and regional change in amyloid removal, glucose metabolism, and atrophy in trial participants with dominantly inherited Alzheimer's disease (DIAD). METHODS In the DIAN‐TU‐001 trial, 92 carriers received gantenerumab or placebo and underwent serial neuroimaging assessments including [ 11 C]‐Pittsburgh compound‐B (PiB) positron emission tomography (PET), [ 18 F]‐fluoro‐2‐deoxyglucose (FDG) PET, and magnetic resonance imaging (MRI). RESULTS Gantenerumab significantly reduced PiB‐PET uptake overall and in most regions and showed no changes in FDG‐PET or MRI measures. Drug effects were associated with baseline PiB‐PET uptake, and the largest effects occurred in medial regions. DISCUSSION Treated DIAD participants, and especially those with higher amyloid burden, showed a decrease in PiB‐PET uptake, which was more pronounced in the basal ganglia and medial frontal structures. These results may inform patient response and future drug trial design. Highlights Gantenerumab unevenly decreased Aβ burden as measured by PiB‐PET across brain regions. The strongest decrease in PiB‐PET uptake was in basal ganglia and medial frontal structures. Variable drug effect on Aβ was partly due to the amount of burden present before treatment. There was no regional effect on FDG‐PET metabolism or MRI volumetrics after 4 years.

Abstract INTRODUCTION When cerebrospinal fluid (CSF) and positron emission tomography (PET) measurements for amyloid‐beta‐peptide (Aβ) related pathology are discordant, therapeutic decision‐making becomes uncertain. METHODS Using data from patients with mild cognitive impairment ( n = 541) from the Alzheimer's Disease Neuroimaging Initiative, we examined baseline characteristics and longitudinal clinical outcomes in persons grouped according to normal/abnormal Aβ via concurrent CSF and PET determinations using standard cutpoints. RESULTS Discordant groups for brain Aβ status (CSF+/PET− and CSF−/PET+) each represented about 5% of the mild cognitive impairment (MCI) population. Longitudinally, neither discordant group declined more than the CSF−/PET− group on either a memory measure or the Clinical Dementia Rating Sum of Boxes scores over a median 4 years of observation, while the CSF+/PET+ group exhibited worsening on both measures. DISCUSSION In contrast to the clinical decline observed in the CSF+/PET+ group, persons with MCI and CSF+/PET− or CSF−/PET+ brain amyloid patterns did not exhibit incipient decline. Highlights Discrepant abnormal cerebrospinal fluid (CSF) and positron emission tomography (PET) brain amyloid indicators are uncommon in mild cognitive impairment (MCI). CSF‐PET discrepant persons with MCI tend to have less abnormal values initially. CSF‐PET discrepant persons with MCI have a benign prognosis at 4 years.

Abstract Objective To compare iron deposition in the substantia nigra (SN) as measured with quantitative susceptibility mapping (QSM) on antemortem magnetic resonance imaging (MRI) between individuals with and without Lewy‐related pathology at autopsy. Methods We performed a retrospective cohort study including 54 participants who underwent autopsy and antemortem MRI with QSM. Cases were classified as Lewy body disease (LBD)‐present (n = 13) if they had Lewy‐related pathology and LBD‐absent (n = 41) if they did not have Lewy‐related pathology. QSM was calculated for the whole SN and the two subregions: pars compacta (SNc) and pars reticulata (SNr). Nonparametric Wilcoxon rank‐sum tests were used to compare SN QSM values between LBD‐present and LBD‐absent cases. Area under the receiver operating characteristic (ROC) curve (AUC) analyses tested the accuracy of SN QSM values to distinguish the two groups. Associations of QSM values in the SN and its subregions with clinical features were tested with Spearman's correlations. Results The LBD‐present group had higher QSM values in the SNc ( P = 0.008) than the LBD‐absent group with no differences in SNr. QSM values of the SNc distinguished LBD‐present and LBD‐absent cases with good accuracy (AUC = 0.74) and correlated with the presence of parkinsonism and parkinsonism severity. Conclusions This study provides neuropathological confirmation of the utility of SNc QSM as an in vivo biomarker of Lewy‐related pathology. Imaging evidence of abnormal iron deposition in the SNc could potentially serve as a biomarker for inclusion in emerging research frameworks aimed at defining individuals with LBD based on their biological characteristics. Ultimately, this could facilitate more precise diagnoses and guide treatment strategies in LBD. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Objective To determine the clinical features that identify patients with suspected rapidly progressive dementia (RPD) who will develop RPD. Methods Patients with suspected RPD were enrolled and followed at Mayo Clinic (Jacksonville, FL; January 2020 to October 2023) and Washington University (Saint Louis, MO; June 2016 to December 2019). Two dementia specialists independently reviewed clinical data and assigned diagnoses. Patients were diagnosed with RPD if they developed dementia within 1 year or incapacitation within 2 years of symptom onset. The associations between clinical features and causes and outcomes were explored via univariate and multivariate comparisons. Results Of 248 patients with suspected RPD, 185 (74.6%) met criteria for RPD. Patients with RPD were older (62.6 ± 14.5 vs 55.2 ± 18.1 years; p < 0.001), and more frequently diagnosed with Alzheimer's disease or related dementias (OR 3.13, 95% CI 1.40, 7.31) or Creutzfeldt–Jakob disease (OR 4.67, 95% CI 1.38, 15.75). Visual agnosia (15/183; 8.2%), substantial brain atrophy (27/182; 14.8%), and periodic epileptiform discharges (11/151; 7.3%) were exclusively detected in patients with RPD. After controlling for age, intensive care unit admission (OR 4.77, 95% CI 1.61, 14.12), lack of seizures (OR 2.47, 95% CI 1.15, 5.31), abnormal brain magnetic resonance imaging (OR 2.01, 95% CI 0.997, 4.05), and cerebrospinal fluid white blood cell count ≤5 cells/mm 3 (OR 3.30, 95% CI 1.60, 6.82) were also independently associated with RPD. Patients with RPD were more likely to die or develop severe dementia (mean time to outcome, 36.1 months; 95% CI 31.2–41.0). Interpretation Selected clinical features may identify patients with suspected RPD who are likely to continue to decline. Early recognition of these features may improve diagnostic accuracy and inform prognosis. ANN NEUROL 2025;98:764–776

Abstract INTRODUCTION Plasma biomarkers of Alzheimer's disease (AD) represent accessible alternatives to positron emission tomography (PET) and cerebrospinal fluid (CSF)‐based biomarkers in well‐characterized cohorts. It remains to be determined whether performance is maintained in outpatient clinics comprised of patients with multiple causes of cognitive impairment. METHODS Plasma phosphorylated tau217 (p‐tau217) and amyloid beta (Aβ) 42/40 were measured in 509 patients evaluated in a tertiary‐care memory clinic. Biomarker performance was compared across diagnoses, referencing established cutpoints for positive and negative biomarkers. RESULTS Plasma p‐tau217 distinguished patients with diagnoses of symptomatic AD with 95% sensitivity and 82% specificity. Integration of Aβ42 measurements (p‐tau217/Aβ42) incrementally improved specificity (86%). Plasma p‐tau217 and p‐tau217/Aβ42 concentrations closely associated with established CSF biomarkers of AD (area under the curve [AUC]: 0.94 and 0.96, respectively). Reduced kidney function associated with elevated plasma p‐tau217 and p‐tau217/Aβ42 concentrations in patients without AD (referencing CSF biomarkers). DISCUSSION Plasma p‐tau217 and p‐tau217/Aβ42 concentrations demonstrated robust diagnostic performance in a heterogeneous clinical cohort; interpretation requires consideration of kidney function. Highlights Plasma phosphorylated tau217 (p‐tau217) reliably identified clinic patients with Alzheimer's disease. A two‐cutpoint strategy yielded definitive results in 86% of patients. Integration of plasma amyloid beta (Aβ; p‐tau217/Aβ42) minimally improved diagnostic performance. Plasma p‐tau217 levels were increased in patients with kidney dysfunction.

AbstractINTRODUCTIONThis study investigated the role of the ubiquitin–proteasome system (UPS) in dominantly inherited Alzheimer's disease (DIAD) by examining cerebrospinal fluid (CSF) levels of UPS proteins.METHODThe SOMAscan assay was used to detect changes in UPS proteins in mutation carriers (MCs) relative to disease progression; imaging and CSF biomarkers of amyloid, tau, and neurodegeneration measures; and Clinical Dementia Rating scale.RESULTSSubtle increases in specific ubiquitin enzymes were detected in MCs up to two decades before symptom onset, with more pronounced elevations in UPS‐activating enzymes near symptom onset. Significant correlations were found between UPS proteins and Alzheimer's disease (AD) biomarkers, especially between autophagy markers and late‐stage tau biomarkers, microglia, and axonal degeneration.DISCUSSIONThe rise in UPS proteins alongside tau‐related markers suggests UPS involvement in tau neurofibrillary tangles. Elevated CSF UPS proteins in DIAD MCs may serve as indicators of disease progression, and may support the UPS as a therapeutic target in AD.Highlights This study investigates the ubiquitin‐proteasome system (UPS) in Dominantly Inherited Alzheimer's Disease (DIAD), highlighting early molecular changes linked to disease progression. Using SOMAscan proteomics, we identified significant UPS protein alterations in cerebrospinal fluid of mutation carriers, notably up to 20 years before clinical symptom onset. Correlations between UPS protein levels and Alzheimer's biomarkers, particularly tau and neurodegeneration markers, suggest a strong association between UPS dysregulation and tau pathology in DIAD. Dynamic UPS changes align with A/T biological staging: UPS proteins were shown to increase across Aβ/tau (A/T) groups, with largest increases in the A+/T+ group, reinforcing their role in late‐stage tau pathology and disease progression. These findings underscore the potential of UPS proteins as early biomarkers for Alzheimer's disease progression and as novel therapeutic targets, especially in tau‐pathology‐driven neurodegeneration. This work contributes to understanding AD pathogenesis, by emphasizing the importance of protein quality control systems and by offering avenues for future biomarker discovery and therapeutic development in Alzheimer's disease.

Abstract INTRODUCTION β‐synuclein is a promising blood marker to track synaptic degeneration in Alzheimer's disease (AD) but changes in preclinical AD are unclear. METHODS We investigated serum β‐synuclein in 69 cognitively unimpaired mutation non‐carriers, 78 cognitively unimpaired AD mutation carriers (asymptomatic AD), and 31 symptomatic mutation carriers from the Dominantly Inherited Alzheimer Network. RESULTS β‐synuclein levels were already higher in asymptomatic AD mutation carriers compared to non‐carriers and highest in symptomatic carriers. Longitudinal trajectories and correlation analyses indicated that β‐synuclein levels start to rise after amyloid deposition preceding axonal degeneration, brain atrophy and hypometabolism, and cognitive decline. β‐synuclein levels were associated with cognitive impairment and gradually increased with declining cognition. DISCUSSION Our study supports the use of blood β‐synuclein to track synaptic changes in preclinical AD and as a surrogate marker for cognitive impairment which might be used in early diagnosis and to support patient selection and monitoring of treatment effects in clinical trials. Highlights Blood β‐synuclein levels were already higher in asymptomatic Alzheimer's disease (AD) mutation carriers. Blood β‐synuclein levels were highest in symptomatic AD mutation carriers. Blood β‐synuclein levels start to rise 11 years before symptom onset. Rise of β‐synuclein precedes axonal degeneration, brain atrophy, and cognitive decline. β‐synuclein levels gradually increased with declining cognition.