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SARS-CoV-2 infection can damage the nervous system with multiple neurological manifestations described. However, there is limited understanding of the mechanisms underlying COVID-19 neurological injury. This is a cross-sectional exploratory prospective biomarker cohort study of 21 patients with COVID-19 neurological syndromes (Guillain-Barre Syndrome [GBS], encephalitis, encephalopathy, acute disseminated encephalomyelitis [ADEM], intracranial hypertension, and central pain syndrome) and 23 healthy COVID-19 negative controls. We measured cerebrospinal fluid (CSF) and serum biomarkers of amyloid processing, neuronal injury (neurofilament light), astrocyte activation (GFAp), and neuroinflammation (tissue necrosis factor [TNF] ɑ, interleukin [IL]-6, IL-1β, IL-8). Patients with COVID-19 neurological syndromes had significantly reduced CSF soluble amyloid precursor protein (sAPP)-ɑ (p = 0.004) and sAPPβ (p = 0.03) as well as amyloid β (Aβ) 40 (p = 5.2 × 10

Objective To investigate the relationship between the topography of amyloid‐β plaques, tau neurofibrillary tangles, and the overlap between the two, with cognitive dysfunction in individuals without dementia. Methods We evaluated 154 individuals who were assessed with amyloid‐β PET with [18F]AZD4694, tau‐PET with [18F]MK6240, structural MRI, and neuropsychological testing. We also evaluated an independent cohort of 240 individuals who were assessed with amyloid‐β PET with [18F]Florbetapir, tau‐PET with [18F]Flortaucipir, structural MRI, and neuropsychological testing. Using the VoxelStats toolbox, we conducted voxel‐wise linear regressions between amyloid‐PET, tau‐PET, and their interaction with cognitive function, correcting for age, sex, and years of education. Results In both cohorts, we observed that tau‐PET standardized uptake value ratio in medial temporal lobes was associated with clinical dementia rating Sum of Boxes (CDR‐SoB) scores independently of local amyloid‐PET uptake (FWE corrected at p

Microglial activation and tau accumulation propagate together in patients with Alzheimer's disease, suggesting an interaction that determines disease progression. Compelling experimental evidence suggests that microglial activation is involved in the spread of tau tangles over the neocortex in Alzheimer's disease (AD). We tested the hypothesis that the spatial propagation of microglial activation and tau accumulation colocalize in a Braak-like pattern in the living human brain. We studied 130 individuals across the aging and AD clinical spectrum with positron emission tomography brain imaging for microglial activation ([C-11]PBR28), amyloid-beta (A beta) ([F-18]AZD4694) and tau ([F-18]MK-6240) pathologies. We further assessed microglial triggering receptor expressed on myeloid cells 2 (TREM2) cerebrospinal fluid (CSF) concentrations and brain gene expression patterns. We found that [C-11]PBR28 correlated with CSF soluble TREM2 and showed regional distribution resembling TREM2 gene expression. Network analysis revealed that microglial activation and tau correlated hierarchically with each other following Braak-like stages. Regression analysis revealed that the longitudinal tau propagation pathways depended on the baseline microglia network rather than the tau network circuits. The co-occurrence of A beta, tau and microglia abnormalities was the strongest predictor of cognitive impairment in our study population. Our findings support a model where an interaction between A beta and activated microglia sets the pace for tau spread across Braak stages.

Quantile regression models have become a widely used statistical tool in genetics and in the omics fields because they can provide a rich description of the predictors’ effects on an outcome without imposing stringent parametric assumptions on the outcome-predictors relationship. This work considers the problem of selecting grouped variables in high-dimensional linear quantile regression models. We introduce a group penalized pseudo quantile regression (GPQR) framework with both group-lasso and group non-convex penalties. We approximate the quantile regression check function using a pseudo-quantile check function. Then, using the majorization–minimization principle, we derive a simple and computationally efficient group-wise descent algorithm to solve group penalized quantile regression. We establish the convergence rate property of our algorithm with the group-Lasso penalty and illustrate the GPQR approach performance using simulations in high-dimensional settings. Furthermore, we demonstrate the use of the GPQR method in a gene-based association analysis of data from the Alzheimer’s Disease Neuroimaging Initiative study and in an epigenetic analysis of DNA methylation data.

Introduction This study investigated the diagnostic and disease‐monitoring potential of plasma biomarkers in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia and cognitively unimpaired (CU) individuals. Methods Plasma was analyzed using Simoa assays from 99 CU, 107 MCI, and 103 AD dementia participants. Results Phosphorylated‐tau181 (P‐tau181), neurofilament light, amyloid‐β (Aβ42/40), Total‐tau and Glial fibrillary acidic protein were altered in AD dementia but P‐tau181 significantly outperformed all biomarkers in differentiating AD dementia from CU (area under the curve [AUC] = 0.91). P‐tau181 was increased in MCI converters compared to non‐converters. Higher P‐tau181 was associated with steeper cognitive decline and gray matter loss in temporal regions. Longitudinal change of P‐tau181 was strongly associated with gray matter loss in the full sample and with Aβ measures in CU individuals. Discussion P‐tau181 detected AD at MCI and dementia stages and was strongly associated with cognitive decline and gray matter loss. These findings highlight the potential value of plasma P‐tau181 as a non‐invasive and cost‐effective diagnostic and prognostic biomarker in AD.

Neurofilament light (NfL) is a marker of neuroaxonal injury, a prominent feature of Alzheimer’s disease. It remains uncertain, however, how it relates to amyloid and tau pathology or neurodegeneration across the Alzheimer’s disease continuum. The aim of this study was to investigate how plasma NfL relates to amyloid and tau PET and MRI measures of brain atrophy in participants with and without cognitive impairment. We retrospectively examined the association between plasma NfL and MRI measures of grey/white matter volumes in the Alzheimer’s Disease Neuroimaging Initiative [ADNI: n = 1149; 382 cognitively unimpaired control subjects and 767 cognitively impaired participants (mild cognitive impairment n = 420, Alzheimer’s disease dementia n = 347)]. Longitudinal plasma NfL was measured using single molecule array (Simoa) technology. Cross-sectional associations between plasma NfL and PET amyloid and tau measures were independently assessed in two cohorts: ADNI [n = 198; 110 cognitively unimpaired, 88 cognitively impaired (MCI n = 67, Alzheimer’s disease dementia n = 21), data accessed October 2018]; and Translational Biomarkers in Aging and Dementia [TRIAD, n = 116; 74 cognitively unimpaired, 42 cognitively impaired (MCI n = 16, Alzheimer’s disease dementia n = 26), data obtained November 2017 to January 2019]. Associations between plasma NfL and imaging-derived measures were examined voxel-wise using linear regression (cross-sectional) and linear mixed effect models (longitudinal). Cross-sectional analyses in both cohorts showed that plasma NfL was associated with PET findings in brain regions typically affected by Alzheimer’s disease; associations were specific to amyloid PET in cognitively unimpaired and tau PET in cognitively impaired (P

ObjectiveTo determine the associations between amyloid-PET, tau-PET, and atrophy with the behavioral/dysexecutive presentation of Alzheimer disease (AD), how these differ from amnestic AD, and how they correlate to clinical symptoms.MethodsWe assessed 15 patients with behavioral/dysexecutive AD recruited from a tertiary care memory clinic, all of whom had biologically defined AD. They were compared with 25 patients with disease severity– and age-matched amnestic AD and a group of 131 cognitively unimpaired (CU) elderly individuals. All participants were evaluated with amyloid-PET with [18F]AZD4694, tau-PET with [18F]MK6240, MRI, and neuropsychological testing.ResultsVoxelwise contrasts identified patterns of frontal cortical tau aggregation in behavioral/dysexecutive AD, with peaks in medial prefrontal, anterior cingulate, and frontal insular cortices in contrast to amnestic AD. No differences were observed in the distribution of amyloid-PET or atrophy as determined by voxel-based morphometry. Voxelwise area under the receiver operating characteristic curve analyses revealed that tau-PET uptake in the medial prefrontal, anterior cingulate, and frontal insular cortices were best able to differentiate between behavioral/dysexecutive and amnestic AD (area under the curve 0.87). Voxelwise regressions demonstrated relationships between frontal cortical tau load and degree of executive dysfunction.ConclusionsOur results provide evidence of frontal cortical involvement of tau pathology in behavioral/dysexecutive AD and highlight the need for consensus clinical criteria in this syndrome.

Amyloid-β deposition into plaques is a pathological hallmark of Alzheimer’s disease (AD) appearing years before the onset of symptoms. Although cerebral amyloid-β deposition occurs on a continuum, dichotomization into positive and negative groups has advantages for diagnosis, clinical management and population enrichment for clinical trials. 18F-AZD4694 (also known as 18F-NAV4694) is an amyloid-β imaging ligand with high affinity for amyloid-β plaques. Despite being employed in multiple academic centers, no studies have assessed a quantitative cut-off for amyloid-β positivity using 18F-AZD4694 PET. Methods: We assessed 176 individuals [young adults (n = 22), cognitively unimpaired elderly (n = 89), and cognitively impaired (n = 65)] who underwent amyloid-β PET with 18F-AZD4694, lumbar puncture, structural MRI, and genotyping for APOEe4. 18F-AZD4694 values were normalized using the cerebellar grey matter as a reference region. We compared five methods for deriving a quantitative threshold for 18F-AZD4694 PET positivity: comparison with young controls SUVRs values, Receiver Operating Characteristic (ROC) curves based on clinical classification of CU elderly vs AD dementia, ROC curves based on visual Aβ+/Aβ- classification, Gaussian Mixture Modeling and comparison with cerebrospinal fluid measures of amyloid-β, specifically the Aβ42/Aβ40 ratio. Results: We observed good convergence between four methods ROC curves based on visual classification (optimal cut point: 1.55 SUVR), ROC curves based on clinical classification (optimal cut point: 1.56 SUVR) Gaussian Mixture Modeling (optimal cut point: 1.55 SUVR) and comparison with CSF measures of amyloid-β (optimal cut point: 1.51 SUVR). Means and 2 standard deviations from young controls resulted in a lower threshold (1.33 SUVR) that did not agree with the other methods and labeled the majority of elderly individuals as Aβ+. Conclusion: Good convergence was obtained between a number of methods for determining an optimal cut-off for 18F-AZD4694 PET positivity. Despite conceptual and analytical idiosyncrasies linked with dichotomization of continuous variables, an 18F-AZD4694 threshold of 1.55 SUVR had reliable discriminative accuracy. While clinical use of amyloid-PET currently is made by visual inspection of scans, quantitative thresholds may be helpful to arbitrate disagreement among raters or in borderline cases.

Braak stages of tau neurofibrillary tangle accumulation have been incorporated in the criteria for the neuropathological diagnosis of Alzheimer’s disease. It is expected that Braak staging using brain imaging can stratify living individuals according to their individual patterns of tau deposition, which may prove crucial for clinical trials and practice. However, previous studies using the first-generation tau PET agents have shown a low sensitivity to detect tau pathology in areas corresponding to early Braak histopathological stages (∼20% of cognitively unimpaired elderly with tau deposition in regions corresponding to Braak I–II), in contrast to ∼80–90% reported in post-mortem cohorts. Here, we tested whether the novel high affinity tau tangles tracer 18F-MK-6240 can better identify individuals in the early stages of tau accumulation. To this end, we studied 301 individuals (30 cognitively unimpaired young, 138 cognitively unimpaired elderly, 67 with mild cognitive impairment, 54 with Alzheimer’s disease dementia, and 12 with frontotemporal dementia) with amyloid-β 18F-NAV4694, tau 18F-MK-6240, MRI, and clinical assessments. 18F-MK-6240 standardized uptake value ratio images were acquired at 90–110 min after the tracer injection. 18F-MK-6240 discriminated Alzheimer’s disease dementia from mild cognitive impairment and frontotemporal dementia with high accuracy (∼85–100%). 18F-MK-6240 recapitulated topographical patterns consistent with the six hierarchical stages proposed by Braak in 98% of our population. Cognition and amyloid-β status explained most of the Braak stages variance (P

Neurofilament light chain (NFL) measurement has been gaining strong support as a clinically useful neuronal injury biomarker for various neurodegenerative conditions. However, in Alzheimer’s disease (AD), its reflection on regional neuronal injury in the context of amyloid pathology remains unclear. This study included 83 cognitively normal (CN), 160 mild cognitive impairment (MCI), and 73 AD subjects who were further classified based on amyloid-beta (Aβ) status as positive or negative (Aβ+ vs Aβ−). In addition, 13 rats (5 wild type and 8 McGill-R-Thy1-APP transgenic (Tg)) were examined. In the clinical study, reduced precuneus/posterior cingulate cortex and hippocampal grey matter density were significantly associated with increased NFL concentrations in cerebrospinal fluid (CSF) or plasma in MCI Aβ+ and AD Aβ+. Moreover, AD Aβ+ showed a significant association between the reduced grey matter density in the AD-vulnerable regions and increased NFL concentrations in CSF or plasma. Congruently, Tg rats recapitulated and validated the association between CSF NFL and grey matter density in the parietotemporal cortex, entorhinal cortex, and hippocampus in the presence of amyloid pathology. In conclusion, reduced grey matter density and elevated NFL concentrations in CSF and plasma are associated in AD-vulnerable regions in the presence of amyloid positivity in the AD clinical spectrum and amyloid Tg rat model. These findings further support the NFL as a neuronal injury biomarker in the research framework of AD biomarker classification and for the evaluation of therapeutic efficacy in clinical trials.

CSF and PET biomarkers of amyloid β and tau accurately detect Alzheimer's disease pathology, but the invasiveness, high cost, and poor availability of these detection methods restrict their widespread use as clinical diagnostic tools. CSF tau phosphorylated at threonine 181 (p-tau181) is a highly specific biomarker for Alzheimer's disease pathology. We aimed to assess whether blood p-tau181 could be used as a biomarker for Alzheimer's disease and for prediction of cognitive decline and hippocampal atrophy.We developed and validated an ultrasensitive blood immunoassay for p-tau181. Assay performance was evaluated in four clinic-based prospective cohorts. The discovery cohort comprised patients with Alzheimer's disease and age-matched controls. Two validation cohorts (TRIAD and BioFINDER-2) included cognitively unimpaired older adults (mean age 63-69 years), participants with mild cognitive impairment (MCI), Alzheimer's disease, and frontotemporal dementia. In addition, TRIAD included healthy young adults (mean age 23 years) and BioFINDER-2 included patients with other neurodegenerative disorders. The primary care cohort, which recruited participants in Montreal, Canada, comprised control participants from the community without a diagnosis of a neurological condition and patients referred from primary care physicians of the Canadian National Health Service for specialist care. Concentrations of plasma p-tau181 were compared with established CSF and PET biomarkers and longitudinal measurements using Spearman correlation, area under the curve (AUC), and linear regression analyses.We studied 37 individuals in the discovery cohort, 226 in the first validation cohort (TRIAD), 763 in the second validation cohort (BioFINDER-2), and 105 in the primary care cohort (n=1131 individuals). In all cohorts, plasma p-tau181 showed gradual increases along the Alzheimer's disease continuum, from the lowest concentrations in amyloid β-negative young adults and cognitively unimpaired older adults, through higher concentrations in the amyloid β-positive cognitively unimpaired older adults and MCI groups, to the highest concentrations in the amyloid β-positive MCI and Alzheimer's disease groups (p0·001, Alzheimer's disease vs all other groups). Plasma p-tau181 distinguished Alzheimer's disease dementia from amyloid β-negative young adults (AUC=99·40%) and cognitively unimpaired older adults (AUC=90·21-98·24% across cohorts), as well as other neurodegenerative disorders, including frontotemporal dementia (AUC=82·76-100% across cohorts), vascular dementia (AUC=92·13%), progressive supranuclear palsy or corticobasal syndrome (AUC=88·47%), and Parkinson's disease or multiple systems atrophy (AUC=81·90%). Plasma p-tau181 was associated with PET-measured cerebral tau (AUC=83·08-93·11% across cohorts) and amyloid β (AUC=76·14-88·09% across cohorts) pathologies, and 1-year cognitive decline (p=0·0015) and hippocampal atrophy (p=0·015). In the primary care cohort, plasma p-tau181 discriminated Alzheimer's disease from young adults (AUC=100%) and cognitively unimpaired older adults (AUC=84·44%), but not from MCI (AUC=55·00%).Blood p-tau181 can predict tau and amyloid β pathologies, differentiate Alzheimer's disease from other neurodegenerative disorders, and identify Alzheimer's disease across the clinical continuum. Blood p-tau181 could be used as a simple, accessible, and scalable test for screening and diagnosis of Alzheimer's disease.Alzheimer Drug Discovery Foundation, European Research Council, Swedish Research Council, Swedish Alzheimer Foundation, Swedish Dementia Foundation, Alzheimer Society Research Program.

APOEε4 is the most well-established genetic risk factor for sporadic Alzheimer’s disease and is associated with cerebral amyloid-β. However, the association between APOEε4 and tau pathology, the other major proteinopathy of Alzheimer’s disease, has been controversial. Here, we sought to determine whether the relationship between APOEε4 and tau pathology is determined by local interactions with amyloid-β. We examined three independent samples of cognitively unimpaired, mild cognitive impairment and Alzheimer’s disease subjects: (1) 211 participants who underwent tau-PET with [18F]MK6240 and amyloid-PET with [18F]AZD4694, (2) 264 individuals who underwent tau-PET with [18F]Flortaucipir and amyloid-PET with [18F]Florbetapir and (3) 487 individuals who underwent lumbar puncture and amyloid-PET with [18F]Florbetapir. Using a novel analytical framework, we applied voxel-wise regression models to assess the interactive effect of APOEε4 and amyloid-β on tau load, independently of age and clinical diagnosis. We found that the interaction effect between APOEε4 and amyloid-β, rather than the sum of their independent effects, was related to increased tau load in Alzheimer’s disease-vulnerable regions. The interaction between one APOEε4 allele and amyloid-β was related to increased tau load, while the interaction between amyloid-β and two APOEε4 alleles was related to a more widespread pattern of tau aggregation. Our results contribute to an emerging framework in which the elevated risk of developing dementia conferred by APOEε4 genotype involves mechanisms associated with both amyloid-β and tau aggregation. These results may have implications for future disease-modifying therapeutic trials targeting amyloid or tau pathologies.

Background: Changes in soluble amyloid-beta (Aβ) levels in cerebrospinal fluid (CSF) are detectable at early preclinical stages of Alzheimer's disease (AD). However, whether Aβ levels can predict downstream AD pathological features in cognitively unimpaired (CU) individuals remains unclear. With this in mind, we aimed at investigating whether a combination of soluble Aβ isoforms can predict tau pathology (T+) and neurodegeneration (N+) positivity. Methods: We used CSF measurements of three soluble Aβ peptides (Aβ1‑38, Aβ1‑40 and Aβ1‑42) in CU individuals (n = 318) as input features in machine learning (ML) models aiming at predicting T+ and N+. Input data was used for building 2046 tuned predictive ML models with a nested cross-validation technique. Additionally, proteomics data was employed to investigate the functional enrichment of biological processes altered in T+ and N+ individuals. Results: Our findings indicate that Aβ isoforms can predict T+ and N+ with an area under the curve (AUC) of 0.929 and 0.936, respectively. Additionally, proteomics analysis identified 17 differentially expressed proteins (DEPs) in individuals wrongly classified by our ML algorithm. More specifically, enrichment analysis of gene ontology biological processes revealed an upregulation in myelinization and glucose metabolism-related processes in CU individuals wrongly predicted as T+. A significant enrichment of DEPs in pathways including biosynthesis of amino acids, glycolysis/gluconeogenesis, carbon metabolism, cell adhesion molecules and prion disease was also observed. Conclusions: Our results demonstrate that, by applying a refined ML analysis, a combination of Ab isoforms can predict T+ and N+ with a high AUC. CSF proteomics analysis highlighted a promising group of proteins that can be further explored for improving T+ and N+ prediction.

Tracking longitudinal tau tangles accumulation across the Alzheimer’s disease continuum is crucial to better understand the natural history of tau pathology and for clinical trials. Although the available first-generation tau PET tracers detect tau accumulation in symptomatic individuals, their nanomolar affinity offers limited sensitivity to detect early tau accumulation in asymptomatic subjects. Here, we hypothesized the novel subnanomolar affinity tau tangles tracer 18F-MK-6240 can detect longitudinal tau accumulation in asymptomatic and symptomatic subjects. We studied 125 living individuals (65 cognitively unimpaired elderly amyloid-β-negative, 22 cognitively unimpaired elderly amyloid-β-positive, 21 mild cognitive impairment amyloid-β-positive and 17 Alzheimer’s disease dementia amyloid-β-positive individuals) with baseline amyloid-β 18F-AZD4694 PET and baseline and follow-up tau 18F-MK-6240 PET. The 18F-MK-6240 standardized uptake value ratio (SUVR) was calculated at 90–110 min after tracer injection and the cerebellar crus I was used as the reference region. In addition, we assessed the in vivo18F-MK-6240 SUVR and post-mortem phosphorylated tau pathology in two participants with Alzheimer’s disease dementia who died after the PET scans. We found that the cognitively unimpaired amyloid-β-negative individuals had significant longitudinal tau accumulation confined to the PET Braak-like stage I (3.9%) and II (2.8%) areas. The cognitively unimpaired amyloid-β-positive individuals showed greater tau accumulation in Braak-like stage I (8.9%) compared with later Braak stages. The patients with mild cognitive impairment and those who were Alzheimer’s dementia amyloid-β-positive exhibited tau accumulation in Braak regions III–VI but not I–II. Cognitively impaired amyloid-β-positive individuals that were Braak II–IV at baseline displayed a 4.6–7.5% annual increase in tau accumulation in the Braak III–IV regions, whereas those who were cognitively impaired amyloid-β-positive Braak V–VI at baseline showed an 8.3–10.7% annual increase in the Braak regions V–VI. Neuropathological assessments confirmed PET-based Braak stages V–VI in the two brain donors. Our results suggest that the 18F-MK-6240 SUVR is able to detect longitudinal tau accumulation in asymptomatic and symptomatic Alzheimer’s disease. The highest magnitude of 18F-MK-6240 SUVR accumulation moved from the medial temporal to sensorimotor cortex across the disease clinical spectrum. Trials using the 18F-MK-6240 SUVR in cognitively unimpaired individuals would be required to use regions of interest corresponding to early Braak stages, whereas trials in cognitively impaired subjects would benefit from using regions of interest associated with late Braak stages. Anti-tau trials should take into consideration an individual’s baseline PET Braak-like stage to minimize the variability introduced by the hierarchical accumulation of tau tangles in the human brain. Finally, our post-mortem findings supported use of the 18F-MK-6240 SUVR as a biomarker to stage tau pathology in patients with Alzheimer’s disease.

Recent studies suggest a framework where white-matter (WM) atrophy plays an important role in fronto-temporal dementia (FTD) pathophysiology. However, these studies often overlook the fact that WM tracts bridging different brain regions may have different vulnerabilities to the disease and the relative contribution of grey-matter (GM) atrophy to this WM model, resulting in a less comprehensive understanding of the relationship between clinical symptoms and pathology. Using a common factor analysis to extract a semantic and an executive factor, we aimed to test the relative contribution of WM and GM of specific tracts in predicting cognition in the Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI). We found that semantic symptoms were mainly dependent on short-range WM fibre disruption, while damage to long-range WM fibres was preferentially associated to executive dysfunction with the GM contribution to cognition being predominant for local processing. These results support the importance of the disruption of specific WM tracts to the core cognitive symptoms associated with FTD. As large-scale WM tracts, which are particularly vulnerable to vascular disease, were highly associated with executive dysfunction, our findings highlight the importance of controlling for risk factors associated with deep WM disease, such as vascular risk factors, in patients with FTD in order not to potentiate underlying executive dysfunction.

Purpose This study aims to determine whether comparable target regions of interest (ROIs) and cut-offs can be used across [18F]flortaucipir, [18F]RO948, and [18F]MK6240 tau positron emission tomography (PET) tracers for differential diagnosis of Alzheimer’s disease (AD) dementia vs either cognitively unimpaired (CU) individuals or non-AD neurodegenerative diseases. Methods A total of 1755 participants underwent tau PET using either [18F]flortaucipir (n = 975), [18F]RO948 (n = 493), or [18F]MK6240 (n = 287). SUVR values were calculated across four theory-driven ROIs and several tracer-specific data-driven (hierarchical clustering) regions of interest (ROIs). Diagnostic performance and cut-offs for ROIs were determined using receiver operating characteristic analyses and the Youden index, respectively. Results Comparable diagnostic performance (area under the receiver operating characteristic curve [AUC]) was observed between theory- and data-driven ROIs. The theory-defined temporal meta-ROI generally performed very well for all three tracers (AUCs: 0.926–0.996). An SUVR value of approximately 1.35 was a common threshold when using this ROI. Conclusion The temporal meta-ROI can be used for differential diagnosis of dementia patients with [18F]flortaucipir, [18F]RO948, and [18F]MK6240 tau PET with high accuracy, and that using very similar cut-offs of around 1.35 SUVR. This ROI/SUVR cut-off can also be applied across tracers to define tau positivity.

Alzheimer’s disease is the leading cause of dementia worldwide and is characterized by a long preclinical phase in which amyloid-β and tau accumulate in the absence of cognitive decline. In vivo biomarkers for Alzheimer’s disease are expensive, invasive and inaccessible, yet are critical for accurate disease diagnosis and patient management. Recent ultrasensitive methods to measure plasma phosphorylated tau 181 (p-tau181) display strong correlations with tau positron emission tomography, p-tau181 in CSF, and tau pathology at autopsy. The clinical utility of plasma-based p-tau181 biomarkers is unclear. In a longitudinal multicentre observational study, we assessed 1113 non-demented individuals (509 cognitively unimpaired elderly and 604 individuals with mild cognitive impairment) from the Alzheimer’s Disease Neuroimaging Initiative who underwent neuropsychological assessments and were evaluated for plasma p-tau181. The primary outcome was a memory composite z-score. Mixed-effect models assessed rates of memory decline in relation to baseline plasma p-tau181, and whether plasma p-tau181 significantly predicted memory decline beyond widely available clinical and genetic data (age, sex, years of education, cardiovascular and metabolic conditions, and APOEε4 status). Participants were followed for a median of 4.1 years. Baseline plasma p-tau181 was associated with lower baseline memory (β estimate: −0.49, standard error: 0.06, t-value: −7.97), as well as faster rates of memory decline (β estimate: −0.11, standard error: 0.01, t-value: −7.37). Moreover, the inclusion of plasma p-tau181 resulted in improved prediction of memory decline beyond clinical and genetic data (marginal R2 of 16.7–23%, χ2 = 100.81, P, Therriault et al. report that a plasma-based biomarker for phosphorylated tau was associated with memory decline. This biomarker could help predict future cognitive decline associated with Alzheimer’s disease in people who have mild cognitive symptoms, or no symptoms at all., Graphical Abstract Graphical Abstract

Background Mitochondrial electron transport chain abnormalities have been reported in postmortem pathological specimens of Alzheimer’s disease (AD). However, it remains unclear how amyloid and tau are associated with mitochondrial dysfunction in vivo. The purpose of this study is to assess the local relationships between mitochondrial dysfunction and AD pathophysiology in mild AD using the novel mitochondrial complex I PET imaging agent [18F]BCPP-EF. Methods Thirty-two amyloid and tau positive mild stage AD dementia patients (mean age ± SD: 71.1 ± 8.3 years) underwent a series of PET measurements with [18F]BCPP-EF mitochondrial function, [11C]PBB3 for tau deposition, and [11C] PiB for amyloid deposition. Age-matched normal control subjects were also recruited. Inter and intrasubject comparisons of levels of mitochondrial complex I activity, amyloid and tau deposition were performed. Results The [18F]BCPP-EF uptake was significantly lower in the medial temporal area, highlighting the importance of the mitochondrial involvement in AD pathology. [11C]PBB3 uptake was greater in the temporo-parietal regions in AD. Region of interest analysis in the Braak stage I-II region showed significant negative correlation between [18F]BCPP-EF SUVR and [11C]PBB3 BPND (R = 0.2679, p = 0.04), but not [11C] PiB SUVR. Conclusions Our results indicated that mitochondrial complex I is closely associated with tau load evaluated by [11C]PBB3, which might suffer in the presence of its off-target binding. The absence of association between mitochondrial complex I dysfunction with amyloid load suggests that mitochondrial dysfunction in the trans-entorhinal and entorhinal region is a reflection of neuronal injury occurring in the brain of mild AD.

The apolipoprotein E gene (APOE) is the most important genetic risk factor for sporadic Alzheimer disease, with the ε4 allele being associated with increased cerebral amyloid-β and tau pathologies. Although APOE has been suggested to have a stronger effect in women as compared to men, there is a lack of comprehensive assessment on how the interactive effect of APOE and sex modulates regional vulnerability to tau accumulation. We previously have shown the regional vulnerability to the interactive effect of tau and APOE, yet the sex difference was not specifically addressed. In this study, we leveraged PET imaging data from the Translational Biomarkers in Aging and Dementia cohort at McGill University Research Centre for Studies in Aging to elucidate the APOE-by-sex interactive effect on tau burden. We hypothesized sex-dependent regional vulnerability to tau deposition. PET radiopharmaceuticals [18F]AZD4694 and [18F]MK6240 were used to assess amyloid-β and tau level respectively in 277 subjects from the Translational Biomarkers in Aging and Dementia cohort. We found that the interaction between APOE and sex, rather than their independent main effects, was associated with abnormal tau accumulation in medial temporal regions. Specifically, we found that female APOEε4 carriers showed significantly higher tau burden in early tau deposition regions including the hippocampus, entorhinal and parahippocampal cortices, after accounting for age, educational attainment, clinical diagnosis and neocortical amyloid load. We replicated these findings in 221 subjects from the Alzheimer’s Disease Neuroimaging Initiative cohort, in which a different tau-PET radioligand, [18F]flortaucipir, was used to assess tau burden. In conclusion, this study provides evidence from two cohort studies that interactive rather than independent effect of APOE and sex potentiates early tau deposition in women. Our results have important implications for clinical trials and practice, which should take into consideration both APOEε4 carriage status and sex for identifying individuals with the highest probability of developing tau accumulation and clinical progression., Wang et al. report that APOEε4 potentiates tau burden in medial temporal regions including hippocampus, entorhinal and parahippocampal cortices in women, but not in men. The results suggest that APOE-by-sex interactive effect, rather than their main effects, modulates regional vulnerability to tau accumulation., Graphical Abstract Graphical Abstract

Alzheimer’s disease biomarkers are primarily evaluated through MRI, PET and CSF methods in order to diagnose and monitor disease. Recently, advances in the assessment of blood-based biomarkers have shown promise for simple, inexpensive, accessible and minimally invasive tools with diagnostic and prognostic value for Alzheimer’s disease. Most recently, plasma phosphorylated tau181 has shown excellent performance. The relationship between plasma phosphorylated tau181 and cerebral metabolic dysfunction assessed by [18F]fluorodeoxyglucose PET in Alzheimer’s disease is still unknown. This study was performed on 892 older individuals (297 cognitively unimpaired; 595 cognitively impaired) from the Alzheimer’s Disease Neuroimaging Initiative cohort. Plasma phosphorylated tau181 was assessed using single molecular array technology and metabolic dysfunction was indexed by [18F]fluorodeoxyglucose PET. Cross-sectional associations between plasma and CSF phosphorylated tau181 and [18F]fluorodeoxyglucose were assessed using voxelwise linear regression models, with individuals stratified by diagnostic group and by β-amyloid status. Associations between baseline plasma phosphorylated tau181 and longitudinal (24 months) rate of brain metabolic decline were also assessed in 389 individuals with available data using correlations and voxelwise regression models. Plasma phosphorylated tau181 was elevated in β-amyloid positive and cognitively impaired individuals as well as in apolipoprotein E ε4 carriers and was significantly associated with age, worse cognitive performance and CSF phosphorylated tau181. Cross-sectional analyses showed strong associations between plasma phosphorylated tau181 and [18F]fluorodeoxyglucose PET in cognitively impaired and β-amyloid positive individuals. Voxelwise longitudinal analyses showed that baseline plasma phosphorylated tau181 concentrations were significantly associated with annual rates of metabolic decline in cognitively impaired individuals, bilaterally in the medial and lateral temporal lobes. The associations between plasma phosphorylated tau181 and reduced brain metabolism, primarily in cognitively impaired and in β-amyloid positive individuals, supports the use of plasma phosphorylated tau181 as a simple, low-cost, minimally invasive and accessible tool to both assess current and predict future metabolic dysfunction associated with Alzheimer’s disease, comparatively to PET, MRI and CSF methods., Graphical Abstract Graphical Abstract, Lussier et al. report that plasma phosphorylated tau181 is associated cross-sectionally with CSF phosphorylated tau181 and [18F]fluorodeoxyglucose PET in 823 individuals from the Alzheimer’s Disease Neuroimaging Initiative cohort. The authors also report a significant association between baseline plasma p-tau181 and longitudinal change in brain glucose metabolism indexed by [18F]fluorodeoxyglucose PET.

Introduction Neurofilament light chain (NfL) is a promising blood biomarker to detect neurodegeneration in Alzheimer's disease (AD) and other brain disorders. However, there are limited reports of how longitudinal NfL relates to imaging biomarkers. We herein investigated the relationship between blood NfL and brain metabolism in AD. Methods Voxelwise regression models tested the cross-sectional association between [18F]fluorodeoxyglucose ([18F]FDG) and both plasma and cerebrospinal fluid NfL in cognitively impaired and unimpaired subjects. Linear mixed models were also used to test the longitudinal association between NfL and [18F]FDG in amyloid positive (Aβ+) and negative (Aβ−) subjects. Results Higher concentrations of plasma and cerebrospinal fluid NfL were associated with reduced [18F]FDG uptake in correspondent brain regions. In Aβ+ participants, NfL associates with hypometabolism in AD-vulnerable regions. Longitudinal changes in the association [18F]FDG-NfL were confined to cognitively impaired Aβ+ individuals. Discussion These findings indicate that plasma NfL is a proxy for neurodegeneration in AD-related regions in Aβ+ subjects., Highlights • Plasma and CSF neurofilament light show similar pattern of association with [18F]FDG. • In Aβ+ group, brain hypometabolism associates with NfL in Alzheimer's disease signature regions. • The association [18F]fluorodeoxyglucose-plasma NfL increases over 24 months in Aβ+ patients.

The link between brain amyloid-β (Aβ), metabolism, and dementia symptoms remains a pressing question in Alzheimer’s disease. Here, using positron emission tomography ([18F]florbetapir tracer for Aβ and [18F]FDG tracer for glucose metabolism) with a novel analytical framework, we found that Aβ aggregation within the brain’s default mode network leads to regional hypometabolism in distant but functionally connected brain regions. Moreover, we found that an interaction between this hypometabolism with overlapping Aβ aggregation is associated with subsequent cognitive decline. These results were also observed in transgenic Aβ rats that do not form neurofibrillary tangles, which support these findings as an independent mechanism of cognitive deterioration. These results suggest a model in which distant Aβ induces regional metabolic vulnerability, whereas the interaction between local Aβ with a vulnerable environment drives the clinical progression of dementia., Amyloid-β (Aβ) deposition occurs in Alzheimer's disease but its relation to disease features such as local brain hypometabolism or cognitive decline is unclear. Here, the authors show that Aβ aggregation in the brain’s default mode network leads to hypometabolism in distant but functionally connected areas.

Background Neuropsychiatric symptoms (NPS) are frequent in aging and Alzheimer's disease (AD). Here we study the relationship between NPS and AD pathologies in vivo. Method Two hundred and twenty‐one individuals from the TRIAD cohort (143 cognitively unimpaired, 52 mild cognitive impairment, and 26 AD) underwent [18F]MK6240‐tau‐positron emission tomography (PET), [18F]AZD4694‐amyloid‐PET, magnetic resonance imaging, and neuropsychological evaluations. Spearman correlations and voxel‐based regression models evaluated the relationship between Neuropsychiatric Inventory Questionnaire (NPI‐Q) scores, and tau‐PET, amyloid‐PET, and voxel‐based morphometry. Results Fifty percent of individuals presented NPS; these correlated with tau, not amyloid beta or neurodegeneration. Associations between NPI‐Q score and tau‐PET were stronger in the parietal association area, superior frontal, temporal, and medial occipital lobes. NPI‐Q domains associated with distinct patterns of tau uptake. Conclusions NPS are predominantly related to tau in aging and dementia. Regions affected are part of the behavioral circuits, and vulnerable to early AD pathology. Domain‐specific analyses showed NPS are related to the AD pathophysiological processes in a symptom‐specific manner.

Biomarkers for early phosphorylation of tau constitute an unmet need for disease modifying intervention in early stages of Alzheimer’s disease (AD). Recent advances in targeted mass spectrometry and immunoassays have revealed phosphorylation sites, in the cerebrospinal fluid (CSF), with potentially greater utility as preclinical and diagnostic biomarkers as compared to the well validated biomarker – phosphorylated tau at threonine 181 (p-tau181). Phosphorylated tau (p-tau) epitopes in cerebrospinal fluid (CSF) are highly accurate biomarkers for Alzheimer’s disease (AD) neuropathology and are already increased before cognitive symptoms have manifested. However, it is unknown if these preclinical increases transpire earlier, prior to amyloid-beta (Aβ) positivity threshold, and if an ordinal sequence of p-tau epitopes occurs at this incipient phase. In this study, we measured cerebrospinal (CSF) p-tau181, p-tau217 and p-tau231 in 171 participants across the AD continuum compared to AD neuropathology as indexed by Ab ([18F]AZD4694) and tau ([18F]MK6240) position emission tomography. CSF P-tau217 and p-tau231 predicted Aβ and tau at the preclinical and dementia stages to a similar degree but p-tau231 attained abnormal levels first. P-tau231 was more sensitive to the earliest changes in Aβ in the medial orbitofrontal, precuneus and posterior cingulate cortices before global Aβ PET positivity had been achieved. Our findings demonstrate that CSF p-tau231 increases early in development of AD pathology and is a principal candidate for detecting incipient Aβ pathology for therapeutic trial application.

Background Recent studies suggest that plasma phosphorylated tau181 (p-tau181) is a highly specific biomarker for Alzheimer’s disease (AD)-related tau pathology. It has great potential for the diagnostic and prognostic evaluation of AD, since it identifies AD with the same accuracy as tau PET and CSF p-tau181 and predicts the development of AD dementia in cognitively unimpaired (CU) individuals and in those with mild cognitive impairment (MCI). Plasma p-tau181 may also be used as a biomarker in studies exploring disease pathogenesis, such as genetic or environmental risk factors for AD-type tau pathology. The aim of the present study was to investigate the relation between polygenic risk scores (PRSs) for AD and plasma p-tau181. Methods Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) was used to examine the relation between AD PRSs, constructed based on findings in recent genome-wide association studies, and plasma p-tau181, using linear regression models. Analyses were performed in the total sample (n = 818), after stratification on diagnostic status (CU (n = 236), MCI (n = 434), AD dementia (n = 148)), and after stratification on Aβ pathology status (Aβ positives (n = 322), Aβ negatives (n = 409)). Results Associations between plasma p-tau181 and APOE PRSs (p = 3e−18–7e−15) and non-APOE PRSs (p = 3e−4–0.03) were seen in the total sample. The APOE PRSs were associated with plasma p-tau181 in all diagnostic groups (CU, MCI, and AD dementia), while the non-APOE PRSs were associated only in the MCI group. The APOE PRSs showed similar results in amyloid-β (Aβ)-positive and negative individuals (p = 5e−5–1e−3), while the non-APOE PRSs were associated with plasma p-tau181 in Aβ positives only (p = 0.02). Conclusions Polygenic risk for AD including APOE was found to associate with plasma p-tau181 independent of diagnostic and Aβ pathology status, while polygenic risk for AD beyond APOE was associated with plasma p-tau181 only in MCI and Aβ-positive individuals. These results extend the knowledge about the relation between genetic risk for AD and p-tau181, and further support the usefulness of plasma p-tau181 as a biomarker of AD.

Alzheimer’s disease (AD) is characterised by a long preclinical phase. Although phosphorylated tau (p‐tau) species such as p‐tau217 and p‐tau231 provide accurate detection of early pathological changes, other biomarkers capable of staging disease progression during preclinical AD are still needed. Combining exploratory and targeted mass spectrometry methods in neuropathologically confirmed brain tissue, we observed that p‐tau235 is a prominent feature of AD pathology. In addition, p‐tau235 seemed to be preceded by p‐tau231, in what appeared to be a sequential phosphorylation event. To exploit its biomarker potential in cerebrospinal fluid (CSF), we developed and validated a new p‐tau235 Simoa assay. Using three clinical cohorts, we demonstrated that (i) CSF p‐235 increases early in AD continuum, and (ii) changes in CSF p‐tau235 and p‐tau231 levels during preclinical AD are consistent with the sequential phosphorylation evidence in AD brain. In conclusion, CSF p‐tau235 appears to be not only a highly specific biomarker of AD but also a promising staging biomarker for the preclinical phase. Thus, it could prove useful tracking disease progression and help enriching clinical trial recruitment., A combination of mass spectrometry analysis of brain tissue and ultrasensitive immunoassays in three independent CSF cohorts identifies p‐tau235 as a novel biomarker for Alzheimer's disease (AD) – from preclinical stages to dementia.

Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King’s College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs., Cerebrospinal fluid neurofilament light (NfL) is a biomarker for neurodegeneration that can also be assessed in blood. Here the authors show in a validation study the potential for plasma NfL as a biomarker for several neurodegenerative diseases.

Objective:To assess the frequency of biologically-defined Alzheimer’s disease (AD) in relation to age, sex, APOEε4, and clinical diagnosis in a prospective cohort study evaluated with amyloid-PET and tau-PET.Methods:We assessed cognitively unimpaired (CU) elderly (n=166), amnestic MCI (n=77) and probable AD dementia (n=62) subjects who underwent evaluation by dementia specialists and neuropsychologists in addition to amyloid-PET with [18F]AZD4694 and tau-PET with [18F]MK6240. Individuals were grouped according to their AD biomarker profile. Positive predictive value for biologically-defined AD was assessed in relation to clinical diagnosis. Frequency of AD biomarker profiles were assessed using logistic regressions with odds ratios and 95% CIs.Results:The clinical diagnosis of probable AD dementia demonstrated good agreement with biologically-defined AD (positive predictive value: 85.2%). 7.88% of CU elderly subjects were positive for both amyloid-PET and tau-PET. Frequency of biologically-defined AD increased with age (OR: 1.14; pAPOEε4 allele carriers (Single ε4: OR: 3.82; pε4: OR: 17.55, pDiscussion:While we observed strong, but not complete, agreement between clinically-defined “probable AD” dementia and biomarker positivity for both amyloid-β and tau, we also observed that biologically-defined AD was not rare in CU elderly. Abnormal tau-PET was almost exclusively observed in individuals with abnormal amyloid-PET. Our results highlight that even in tertiary care memory clinics, detailed evaluation by dementia specialists systematically underestimates the frequency of biologically-defined AD and related entities.Classification of evidence:This study provides Class I evidence that biologically-defined AD (abnormal amyloid PET and tau PET) was observed in 85.2% of people with clinically defined AD and 7.88% of cognitively unimpaired elderly.