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INTRODUCTION: Fluid biomarkers capable of specifically tracking tau tangle pathology in vivo are greatly needed. METHODS: We measured cerebrospinal fluid (CSF) and plasma concentrations of N‐terminal tau fragments (NTA‐tau), using a novel immunoassay (NTA) in the TRIAD cohort, consisting of 272 individuals assessed with amyloid beta (Aβ) positron emission tomography (PET), tau PET, magnetic resonance imaging (MRI) and cognitive assessments. RESULTS: CSF and plasma NTA‐tau concentrations were specifically increased in cognitively impaired Aβ‐positive groups. CSF and plasma NTA‐tau concentrations displayed stronger correlations with tau PET than with Aβ PET and MRI, both in global uptake and at the voxel level. Regression models demonstrated that both CSF and plasma NTA‐tau are preferentially associated with tau pathology. Moreover, plasma NTA‐tau was associated with longitudinal tau PET accumulation across the aging and Alzheimer's disease (AD) spectrum. DISCUSSION: NTA‐tau is a biomarker closely associated with in vivo tau deposition in the AD continuum and has potential as a tau tangle biomarker in clinical settings and trials. Highlights: An assay for detecting N‐terminal tau fragments (NTA‐tau) in plasma and CSF was evaluated.NTA‐tau is more closely associated with tau PET than amyloid PET or neurodegeneration.NTA‐tau can successfully track in vivo tau deposition across the AD continuum.Plasma NTA‐tau increased over time only in cognitively impaired amyloid‐β positive individuals. [ABSTRACT FROM AUTHOR]

Introduction: Synaptic loss is closely associated with tau aggregation and microglia activation in later stages of Alzheimer's disease (AD). However, synaptic damage happens early in AD at the very early stages of tau accumulation. It remains unclear whether microglia activation independently causes synaptic cleavage before tau aggregation appears. Methods: We investigated 104 participants across the AD continuum by measuring 14-3-3 zeta/delta ( ζ / δ ) as a cerebrospinal fluid biomarker for synaptic degradation, and fluid and imaging biomarkers of tau, amyloidosis, astrogliosis, neurodegeneration, and inflammation. We performed correlation analyses in cognitively unimpaired and impaired participants and used structural equation models to estimate the impact of microglia activation on synaptic injury in different disease stages. Results: 14-3-3 ζ / δ was increased in participants with amyloid pathology at the early stages of tau aggregation before hippocampal volume loss was detectable. 14-3-3 ζ / δ correlated with amyloidosis and tau load in all participants but only with biomarkers of neurodegeneration and memory deficits in cognitively unimpaired participants. This early synaptic damage was independently mediated by sTREM2. At later disease stages, tau and astrogliosis additionally mediated synaptic loss. Conclusions: Our results advertise that sTREM2 is mediating synaptic injury at the early stages of tau accumulation, underlining the importance of microglia activation for AD disease propagation. [ABSTRACT FROM AUTHOR]

For many years Alzheimer's disease (AD) was associated with the dementia stage of the disease, the tail end of a pathophysiological process that lasts approximately two decades. Whereas early disease staging assessments focused on progressive deterioration of clinical functioning, brain imaging with positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarker studies highlighted the long preclinical phase of AD in which a cascade of detectable biological abnormalities precede cognitive decline. The recent proliferation of imaging and fluid biomarkers of AD pathophysiology provide an opportunity for the identification of several biological stages in the preclinical phase of AD. We discuss the use of clinical and biomarker information in past, present, and future staging of AD. We highlight potential applications of PET, CSF, and plasma biomarkers for staging AD severity in vivo. Disease staging uses important points in the disease course to measure disease severity, evaluate clinical outcomes, and guide patient management. Staging of Alzheimer's disease (AD) has evolved from clinically defined stages based on symptomatic severity to integrated information on several biomarkers. Currently, staging of AD involves the identification of AD using biomarkers, with clinical outcomes designating disease severity. Staging of preclinical AD is possible using imaging biomarkers optimized to detect stage-specific pathological changes. Furthermore, phosphorylated tau (pTau) panels in which multiple pTau epitopes are evaluated from a single sample (plasma or CSF) may be useful for determining the extent of pathological tau hyperphosphorylation. Staging of AD using biomarkers will allow the identification of the optimal time-window in which specific therapeutic interventions will be most effective. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid neurofilament light and plasma neurofilament light concentrations are elevated in patients with mild cognitive impairment and Alzheimer's disease. We investigated the clinical relevance of increased neurofilament light concentrations in mild cognitive impairment and Alzheimer's disease patients. In this study, 244 subjects were divided into cognitively normal control (n = 67), stable mild cognitive impairment (n = 52), progressive mild cognitive impairment (n = 68), and Alzheimer's disease (n = 57). Linear regression examined the relationships between neurofilament light levels in cerebrospinal fluid or plasma and the diagnostic group. The relationships between neurofilament light and other biomarkers were assessed by Spearman correlation. Linear mixed-effects models were used to test cerebrospinal fluid and plasma neurofilament light as predictors of Alzheimer's disease characteristics, including cognition, cortical glucose metabolism, and brain structure. Cerebrospinal fluid and plasma neurofilament light levels were significantly elevated in Alzheimer's disease. Still, the correlations between neurofilament light and other cerebrospinal fluid biomarkers within the diagnostic groups were often not statistically significant. In addition, the diagnostic accuracy of cerebrospinal fluid and plasma neurofilament light for progressive mild cognitive impairment and Alzheimer's disease was almost the same as that of cerebrospinal fluid total tau (T-tau). It is phosphorylated tau (Ptau) and high cerebrospinal fluid. Neurofilament light predicted conversion from mild cognitive impairment to Alzheimer's disease. A high neurofilament light is related to poor cognition, low cerebral metabolism, hippocampal atrophy, and ventricular enlargement caused by Alzheimer's disease. Our work further identifies cerebrospinal fluid neurofilament light and plasma neurofilament light as biomarkers of axonal degeneration in patients with mild cognitive impairment and Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid (CSF) measurements of neurogranin (Ng) have emerged as a promising biomarker for cognitive decline in mild cognitive impairment (MCI) and Alzheimer's disease (AD). The apolipoprotein E ε4 (APOE ε4) allele is by far the most consistent genetic risk factor for AD. However, it is not known whether the pathophysiological roles of Ng in MCI or AD are related to APOE ε4. We stratified 250 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database into cognitively normal (CN) ε4 negative (CN ε4−), CN ε4 positive (CN ε4+), MCI ε4 negative (MCI ε4−), MCI ε4 positive (MCI ε4+), AD ε4 negative (AD ε4−), and AD ε4 positive (AD ε4+). CSF Ng levels were significantly increased in APOE ε4 carriers compared to APOE ε4 non-carriers with MCI. In addition, CSF Ng identified MCI ε4+ versus CN ε4−, but not MCI ε4− versus CN ε4−. Similarly, CSF Ng negatively correlated with Mini-Mental State Examination (MMSE) scores at baseline in the MCI ε4+ group. Our findings support the use of CSF Ng as a biomarker of synaptic pathology for AD. We propose that the roles of CSF Ng in the pathophysiology of MCI may be related to APOE ε4. [ABSTRACT FROM AUTHOR]

Objectives: To study the frequency of suicidal ideation and its association with clinical and neurobiological correlates among cognitively intact autosomal dominant Alzheimer's disease (ADAD) at-risk individuals.Methods/design: In a cross-sectional study of 183 ADAD at-risk individuals (91 mutation carriers and 92 noncarriers), we compared the frequency of suicidal ideation among carriers and noncarriers. Linear mixed-effects models with family-level random effects evaluated the relationships between geriatric depression scale (GDS), neuropsychiatric inventory-questionnaire (NPI-Q), and suicidal ideation scores among all ADAD at-risk individuals. An interaction term was added to the regression models to evaluate the interactions of suicidal ideation and mutation status on neuropsychiatric symptoms.Results: Twenty-six (14.20%) ADAD at-risk individuals (13 [14.28%] carriers and 13 [14.13%] noncarriers) had suicidal ideation. The frequency of suicidal ideation did not differ between carriers and noncarriers. Suicidal ideation was associated with higher GDS among all ADAD at-risk individuals. When stratified into mutation carrier status, noncarriers with suicidal ideation had higher GDS than carriers. There was no statistically significant association between suicidal ideation and NPI-Q among ADAD at-risk individuals. Awareness of mutation status, neuropsychological performances, and cerebrospinal fluid AD biomarkers were not associated with suicidal ideation among carriers and noncarriers.Conclusions: Suicidal ideation is common among cognitively intact ADAD at-risk individuals. While ADAD at-risk individuals with suicidal ideation have greater depressive symptoms, noncarriers with suicidal ideation have higher GDS scores than carriers. Interestingly, awareness of the mutation status was not associated with suicidal ideation in our study. Early identification of suicidal thoughts can facilitate timely interventions to prevent suicidal behaviours. Keywords autosomal dominant Alzheimer's diseasedominantly inherited Alzheimer's networkneuropsychiatric symptomssuicidal ideation. [ABSTRACT FROM AUTHOR]

Understanding whether vascular risk factors (VRFs) synergistically potentiate Alzheimer's disease (AD) progression is important in the context of emerging treatments for preclinical AD. In a group of 503 cognitively unimpaired individuals, we tested whether VRF burden interacts with AD pathophysiology to accelerate neurodegeneration and cognitive decline. Baseline VRF burden was calculated considering medical data and AD pathophysiology was assessed based on cerebrospinal fluid (CSF) amyloid-β 1–42 (Aβ 1–42) and tau phosphorylated at threonine 181 (p-tau 181). Neurodegeneration was assessed with plasma neurofilament light (NfL) and global cognition with the modified version of the Preclinical Alzheimer's Cognitive Composite. The mean (SD) age of participants was 72.9 (6.1) years, and 220 (43.7%) were men. Linear mixed-effects models revealed that an elevated VRF burden synergistically interacted with AD pathophysiology to drive longitudinal plasma NfL increase and cognitive decline. Additionally, VRF burden was not associated with CSF Aβ 1–42 or p-tau 181 changes over time. Our results suggest that VRF burden and AD pathophysiology are independent processes; however, they synergistically lead to neurodegeneration and cognitive deterioration. In preclinical stages, the combination of therapies targeting VRFs and AD pathophysiology might potentiate treatment outcomes. • VRF burden potentiates longitudinal plasma NfL increase in preclinical AD. • VRF burden potentiates cognitive decline in preclinical AD, particularly affecting memory. • VRF burden does not influence longitudinal changes in CSF Aβ and tau biomarkers. • Therapies targeting VRFs and AD pathophysiology may enhance trial outcomes. • Plasma NfL is a potential surrogate in trials targeting VRFs and AD pathophysiology. [ABSTRACT FROM AUTHOR]