Comparison of two plasma p-tau217 assays to detect and monitor Alzheimer's pathology.

BACKGROUND: Blood-based biomarkers of Alzheimer's disease (AD) have become increasingly important as scalable tools for diagnosis and determining clinical trial eligibility. P-tau217 is the most promising due to its excellent sensitivity and specificity for AD-related pathological changes. METHODS: We compared the performance of two commercially available plasma p-tau217 assays (ALZpath p-tau217 and Janssen p-tau217+) in 294 individuals cross-sectionally. Correlations with amyloid PET and tau PET were assessed, and Receiver Operating Characteristic (ROC) analyses evaluated both p-tau217 assays for identifying AD pathology. FINDINGS: Both plasma p-tau217 assays were strongly associated with amyloid and tau PET. Furthermore, both plasma p-tau217 assays identified individuals with AD vs other neurodegenerative diseases (ALZpath AUC = 0.95; Janssen AUC = 0.96). Additionally, plasma p-tau217 concentrations rose with AD severity and their annual changes correlated with tau PET annual change. INTERPRETATION: Both p-tau217 assays had excellent diagnostic performance for AD. Our study supports the future clinical use of commercially-available assays for p-tau217. FUNDING: This research is supported by the Weston Brain Institute, Canadian Institutes of Health Research (CIHR), Canadian Consortium on Neurodegeneration in Aging, the Alzheimer's Association, Brain Canada Foundation, the Fonds de Recherche du Québec - Santé and the Colin J. Adair Charitable Foundation.

Decreased Electroencephalography Global Field Synchronization in Slow-Frequency Bands Characterizes Synaptic Dysfunction in Amnestic Subtypes of Mild Cognitive Impairment.

Background: Mild cognitive impairment (MCI) is highly prevalent in a memory clinic setting and is heterogeneous regarding its clinical presentation, underlying pathophysiology, and prognosis. The most prevalent subtypes are single-domain amnestic MCI (sd-aMCI), considered to be a prodromal phase of Alzheimer's disease (AD), and multidomain amnestic MCI (md-aMCI), which is associated with multiple etiologies. Since synaptic loss and dysfunction are the closest pathoanatomical correlates of AD-related cognitive impairment, we aimed to characterize it in patients with sd-aMCI and md-aMCI by means of resting-state electroencephalography (EEG) global field power (GFP), global field synchronization (GFS), and novel cerebrospinal fluid (CSF) synaptic biomarkers. Methods: We included 52 patients with sd-aMCI (66.9 ± 7.3 years, 52% women) and 30 with md-aMCI (63.1 ± 7.1 years, 53% women). All patients underwent a detailed clinical assessment, resting-state EEG recordings and quantitative analysis (GFP and GFS in delta, theta, alpha, and beta bands), and analysis of CSF biomarkers of synaptic dysfunction, neurodegeneration, and AD-related pathology. Cognitive subtyping was based on a comprehensive neuropsychological examination. The Mini-Mental State Examination (MMSE) was used as an estimation of global cognitive performance. EEG and CSF biomarkers were included in a multivariate model together with MMSE and demographic variables, to investigate differences between sd-aMCI and md-aMCI. Results: Patients with sd-aMCI had higher CSF phosphorylated tau, total tau and neurogranin levels, and lower values in GFS delta and theta. No differences were observed in GFP. The multivariate model showed that the most important synaptic measures for group separation were GFS theta, followed by GFS delta, GFP theta, CSF neurogranin, and GFP beta. Conclusion: Patients with sd-aMCI when compared with those with md-aMCI have a neurophysiological and biochemical profile of synaptic damage, neurodegeneration, and amyloid pathology closer to that described in patients with AD. The most prominent signature in sd-aMCI was a decreased global synchronization in slow-frequency bands indicating that functional connectivity in slow frequencies is more specifically related to early effects of AD-specific molecular pathology.

Blood Biomarkers for Alzheimer's Disease in Down Syndrome.

Epidemiological evidence suggests that by the age of 40 years, all individuals with Down syndrome (DS) have Alzheimer's disease (AD) neuropathology. Clinical diagnosis of dementia by cognitive assessment is complex in these patients due to the pre-existing and varying intellectual disability, which may mask subtle declines in cognitive functioning. Cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers, although accurate, are expensive, invasive, and particularly challenging in such a vulnerable population. The advances in ultra-sensitive detection methods have highlighted blood biomarkers as a valuable and realistic tool for AD diagnosis. Studies with DS patients have proven the potential blood-based biomarkers for sporadic AD (amyloid-ß, tau, phosphorylated tau, and neurofilament light chain) to be useful in this population. In addition, biomarkers related to other pathologies that could aggravate dementia progression-such as inflammatory dysregulation, energetic imbalance, or oxidative stress-have been explored. This review serves to provide a brief overview of the main findings from the limited neuroimaging and CSF studies, outline the current state of blood biomarkers to diagnose AD in patients with DS, discuss possible past limitations of the research, and suggest considerations for developing and validating blood-based biomarkers in the future.