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Our data from several clinical trials of individuals with asymptomatic AD demonstrates that plasma Aβ42/40 quantification by mass spectrometry can serve as a reliable biomarker for predicting elevated brain amyloid as detected by PET. We investigated how adding plasma p-tau measures to our plasma Aβ42/40 algorithm to streamline identification of eligible participants and reduce burden and trial cost. To determine if the addition of plasma p-tau181 and/or p-tau217 concentrations can improve plasma Aβ42/40 algorithms to correctly identify participants with amyloid burden of >20 centiloids with the NAV4694 tracer among individuals screening for participation in the AHEAD preclinical AD trial. Plasma amyloid and tau were measured using C N Diagnostics mass spectrometry. Participant samples (N = 1085) collected prior to the incorporation of plasma Aβ42/40 testing during screening were used. Plasma samples consisted of those with adequate amyloid PET levels (n = 364; 33%) to be eligible for AHEAD and those who did not and screen failed (n = 747; 67%). We quantified Aβ (Aβ42/40) and tau species, including the phosphorylated (p-tau) and non-phosphorylated (np-tau) forms of tau181 and tau217. A ratio of p-tau to np-tau was calculated (p-tau181r and p-tau217r) to normalize inter-individual differences in np-tau. We conducted Receiver Operating Characteristic (ROC) curve analyses fagainst amyloid PET status (>20 centiloids). We fit a Mixture of Experts model and included p-tau181r and p-tau217r in the predictive algorithm (Aβ42/40, Age and APOE) for amyloid PET status. Plasma samples from N = 1085 composed of 67% Female, 13.5% Hispanic, 3.7% Black or African American with a mean age of 67.6 (SD = 6.1) years. 45% of participants had at least one APOE4 allele. The Area Under the Curve (AUC) for Aβ42/40 was 0.87 (95% CI; 0.84, 0.89), consistent with prior reports. For plasma tau, we found AUCs of 0.74 (95% CI; 0.71, 0.77) with p-tau181, to 0.91 (95% CI; 0.90, 0.93) with p-tau217r. The model including covariates p-tau217r, Aβ42/40, Age and APOE improved AUC to 0.95 (95% CI; 0.93, 0.96). Our data suggests that plasma p-tau217r in addition to Aβ42/40 ratio can significantly improve anti-amyloid clinical trial screening burden and timelines for recruitment.

Plasma biomarkers related to amyloid, tau, and neurodegeneration (ATN) show great promise for identifying these pathological features of Alzheimer’s Disease (AD) as shown by recent clinical studies and selected autopsy studies. We have evaluated ATN plasma biomarkers in a series of 312 well-characterized longitudinally followed research subjects with plasma available within 5 years or less before autopsy and examined these biomarkers in relation to a spectrum of AD and related pathologies. Plasma Aβ42, Aβ40, total Tau, P-tau181, P-tau231 and neurofilament light (NfL) were measured using Single molecule array (Simoa) assays. Neuropathological findings were assessed using standard research protocols. Comparing plasma biomarkers with pathology diagnoses and ratings, we found that P-tau181 (AUC = 0.856) and P-tau231 (AUC = 0.773) showed the strongest overall sensitivity and specificity for AD neuropathological change (ADNC). Plasma P-tau231 showed increases at earlier ADNC stages than other biomarkers. Plasma Aβ42/40 was decreased in relation to amyloid and AD pathology, with modest diagnostic accuracy (AUC = 0.601). NfL was increased in non-AD cases and in a subset of those with ADNC. Plasma biomarkers did not show changes in Lewy body disease (LBD), hippocampal sclerosis of aging (HS) or limbic-predominant age-related TDP-43 encephalopathy (LATE) unless ADNC was present. Higher levels of P-tau181, 231 and NfL predicted faster cognitive decline, as early as 10 years prior to autopsy, even among people with normal cognition or mild cognitive impairment. These results support plasma P-tau181 and 231 as diagnostic biomarkers related to ADNC that also can help to predict future cognitive decline, even in predementia stages. Although NfL was not consistently increased in plasma in AD and shows increases in several neurological disorders, it had utility to predict cognitive decline. Plasma Aβ42/40 as measured in this study was a relatively weak predictor of amyloid pathology, and different assay methods may be needed to improve on this. Additional plasma biomarkers are needed to detect the presence and impact of LBD and LATE pathology.

Alternative splicing of the gene MAPT produces several isoforms of tau protein. Overexpression of these isoforms is characteristic of tauopathies, which are currently untreatable neurodegenerative diseases. Though non-canonical functions of tau have drawn interest, the role of tau isoforms in these diseases has not been fully examined and may reveal new details of tau-driven pathology. In particular, tau has been shown to promote activation of transposable elements—highly regulated nucleotide sequences that replicate throughout the genome and can promote immunologic responses and cellular stress. This study examined tau isoforms’ roles in promoting cell damage and dysregulation of genes and transposable elements at a family-specific and locus-specific level. We performed immunofluorescence, Western blot and cytotoxicity assays, along with paired-end RNA sequencing on differentiated SH-SY5Y cells infected with lentiviral constructs of tau isoforms and treated with amyloid-beta oligomers. Our transcriptomic findings were validated using publicly available RNA-sequencing data from Alzheimer’s disease, progressive supranuclear palsy and control human samples from the Accelerating Medicine’s Partnership for AD (AMP-AD). Significance for biochemical assays was determined using Wilcoxon ranked-sum tests and false discovery rate. Transcriptome analysis was conducted through DESeq2 and the TEToolkit suite available from the Hammell lab at Cold Spring Harbor Laboratory. Our analyses show overexpression of different tau isoforms and their interactions with amyloid-beta in SH-SY5Y cells result in isoform-specific changes in the transcriptome, with locus-specific transposable element dysregulation patterns paralleling those seen in patients with Alzheimer’s disease and progressive supranuclear palsy. Locus-level transposable element expression showed increased dysregulation of L1 and Alu sites, which have been shown to drive pathology in other neurological diseases. We also demonstrated differences in rates of cell death in SH-SY5Y cells depending on tau isoform overexpression. These results demonstrate the importance of examining tau isoforms’ role in neurodegeneration and of further examining transposable element dysregulation in tauopathies and its role in activating the innate immune system.

Increased production of hydroxyl radical is the main source of oxidative damage in mammalian DNA that accumulates in Alzheimer's disease (AD). Reactive oxygen species (ROS) react with both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) to generate 8-hydroxy-2'-deoxyguanosine (8-OHdG), both of which can be measured in the urine. Knowledge of this pathway has positioned measurement of urine 8-OHdG as a reliable index of DNA oxidation and a potential biomarker target for tracking early cellular dysfunction in AD. Furthermore, epigenetic studies demonstrate decreased global DNA methylation levels (e.g. 5-methyl-2'-deoxycytidine, 5-mdC) in AD tissues. Moreover, stress hormones can activate neuronal oxidative stress which will stimulate the release of additional stress hormones and result in damages to hippocampal neurons in the AD brain. Our previous work suggests that treating AD transgenic mice the type-1 corticotropin-releasing factor receptor (CRFR1) antagonist, R121919, to reduce stress signaling, prevented onset of cognitive impairment, synaptic/dendritic loss and Aβ plaque accumulation. Therefore, to investigate whether levels of DNA oxidation can be impacted by the same therapeutic approach, urine levels of hydrogen peroxide, 8-OHdG, 5-mdC and total antioxidant capacity (TAC) were analyzed using an AD Tg mouse model. We found that Tg animals had an 80% increase in hydrogen peroxide levels compared to wild type (Wt) counterparts, an effect that could be dramatically reversed by the chronic administration with R121919. A significant decrease of 8-OHdG levels was observed in Tg mice treated with CRFR1 antagonist. Collectively our data suggest that the beneficial effects of CRFR1 antagonism seen in Tg mice may be mechanistically linked to the modulation of oxidative stress pathways.

Multiple Systems Atrophy (MSA) is a rare, sporadic, age-related synucleinopathy characterized by Parkinson-like motor symptoms and ataxia. There is no therapy for MSA other than symptomatic treatment. MSA is characterized pathologically by glial cytoplasmic inclusions (GCI) of α-synuclein (αSyn) occurring in oligodendrocytes leading to loss of myelination in the brain. We recently utilized a peptide-mediated delivery method to systemically transport an anti-sense oligonucleotide (ASO) targeted to αSyn in a mouse model of MSA. We hypothesized that systemic delivery of αSyn ASO by peptide mediated delivery to a mouse model of MSA would reduce the αSyn accumulation in oligodendrocytes and reduce the overt pathology associated with MSA. Following monthly treatments of the αSyn ASO, we found increased myelination in the corpus callosum and the cerebellum. We also observed increased numbers of oligodendrocytes and reduced gliosis; however, we did not detect changes in overall αSyn in the areas of the brain we examined. Upon further analysis, we determined the peptide-mediated delivery of αSyn ASO was not taken up by oligodendrocytes. Thus, we have successfully alleviated some of the pathology associated with MSA in a mouse model; however, without direct delivery to oligodendrocytes, other approaches may need to supplement this therapy.

Background Multiple Systems Atrophy (MSA) is a rare, sporadic, age‐related synucleinopathy characterized by Parkinson‐like motor symptoms and ataxia. There is no therapy for MSA other than symptomatic treatment. MSA is characterized pathologically by glial cytoplasmic inclusions (GCI) of α‐synuclein (αSyn) occurring in oligodendrocytes leading to loss of myelination in the brain. We recently utilized a peptide‐mediated delivery method to systemically transport an anti‐sense oligonucleotide (ASO) targeted to αSyn in a mouse model of MSA. Method We hypothesized that systemic delivery of αSyn ASO by peptide mediated delivery to a mouse model of MSA would reduce the αSyn accumulation in oligodendrocytes and reduce the overt pathology associated with MSA. Result Following monthly treatments of the αSyn ASO, we found increased myelination in the corpus callosum and the cerebellum. We also observed increased numbers of oligodendrocytes and reduced gliosis; however, we did not detect changes in overall αSyn in the areas of the brain we examined. Upon further analysis, we determined the peptide‐mediated delivery of αSyn ASO was not taken up by oligodendrocytes. Conclusion Thus, we have successfully alleviated some of the pathology associated with MSA in a mouse model; however, without direct delivery to oligodendrocytes, other approaches may need to supplement this therapy.

Noncoding genetic variation is a major driver of phenotypic diversity, but functional interpretation is challenging. To better understand common genetic variation associated with brain diseases, we defined noncoding regulatory regions for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with variants in transcriptional enhancers and promoters in neurons, sporadic Alzheimer’s disease (AD) variants were largely confined to microglia enhancers. Interactome maps connecting disease-risk variants in cell-type–specific enhancers to promoters revealed an extended microglia gene network in AD. Deletion of a microglia-specific enhancer harboring AD-risk variants ablated BIN1 expression in microglia, but not in neurons or astrocytes. These findings revise and expand the list of genes likely to be influenced by noncoding variants in AD and suggest the probable cell types in which they function.

Intranasal insulin (INI) has shown promise as a treatment for Alzheimer’s disease (AD) in pilot clinical trials. In a recent phase 2 trial, participants with mild cognitive impairment (MCI) or AD who were treated with INI with one of two delivery devices showed improved cerebral spinal fluid (CSF) biomarker profiles and slower symptom progression compared with placebo. In the cohort which showed benefit, we measured changes in CSF markers of inflammation, immune function and vascular integrity and assessed their relationship with changes in cognition, brain volume, and CSF amyloid and tau concentrations. The insulin-treated group had increased CSF interferon-γ (p = 0.032) and eotaxin (p = 0.049), and reduced interleukin-6 (p = 0.048) over the 12 month trial compared to placebo. Trends were observed for increased CSF macrophage-derived chemokine for the placebo group (p = 0.083), and increased interleukin-2 in the insulin-treated group (p = 0.093). Insulin-treated and placebo groups showed strikingly different patterns of associations between changes in CSF immune/inflammatory/vascular markers and changes in cognition, brain volume, and amyloid and tau concentrations. In summary, INI treatment altered the typical progression of markers of inflammation and immune function seen in AD, suggesting that INI may promote a compensatory immune response associated with therapeutic benefit.

It was recently discovered that brain cells release extracellular vesicles (EV) which can pass from brain into blood. These findings raise the possibility that brain-derived EV's present in blood can be used to monitor disease processes occurring in the cerebrum. Since the levels of certain micro-RNAs (miRNAs) have been reported to be altered in Alzheimer's disease (AD) brain, we sought to assess miRNA dysregulation in AD brain tissue and to determine if these changes were reflected in neural EVs isolated from blood of subjects with AD. To this end, we employed high-content miRNA arrays to search for differences in miRNAs in RNA pools from brain tissue of AD ( = 5), high pathological control (HPC) ( = 5), or cognitively intact pathology-free controls ( = 5). Twelve miRNAs were altered by >1.5-fold in AD compared to controls, and six of these were also changed compared to HPCs. Analysis of hits in brain extracts from 11 AD, 7 HPCs and 9 controls revealed a similar fold difference in these six miRNAs, with three showing statistically significant group differences and one with a strong trend toward group differences. Thereafter, we focused on the four miRNAs that showed group differences and measured their content in neurally derived blood EVs isolated from 63 subjects: 16 patients with early stage dementia and a CSF Aβ42+ tau profile consistent with AD, 16 individuals with mild cognitive impairment (MCI) and an AD CSF profile, and 31 cognitively intact controls with normal CSF Aβ42+ tau levels. ROC analysis indicated that measurement of miR-132-3p in neurally-derived plasma EVs showed good sensitivity and specificity to diagnose AD, but did not effectively separate individuals with AD-MCI from controls. Moreover, when we measured the levels of a related miRNA, miR-212, we found that this miRNA was also decreased in neural EVs from AD patients compared to controls. Our results suggest that measurement of miR-132 and miR-212 in neural EVs should be further investigated as a diagnostic aid for AD and as a potential theragnostic.

Background Treatment of mild-moderate Alzheimer’s disease (AD) subjects ( N  = 119) for 52 weeks with the SIRT1 activator resveratrol (up to 1 g by mouth twice daily) attenuates progressive declines in CSF Aβ40 levels and activities of daily living (ADL) scores. Methods For this retrospective study, we examined banked CSF and plasma samples from a subset of AD subjects with CSF Aβ42 <600 ng/ml (biomarker-confirmed AD) at baseline ( N  = 19 resveratrol-treated and N  = 19 placebo-treated). We utilized multiplex Xmap technology to measure markers of neurodegenerative disease and metalloproteinases (MMPs) in parallel in CSF and plasma samples. Results Compared to the placebo-treated group, at 52 weeks, resveratrol markedly reduced CSF MMP9 and increased macrophage-derived chemokine (MDC), interleukin (IL)-4, and fibroblast growth factor (FGF)-2. Compared to baseline, resveratrol increased plasma MMP10 and decreased IL-12P40, IL12P70, and RANTES. In this subset analysis, resveratrol treatment attenuated declines in mini-mental status examination (MMSE) scores, change in ADL (ADCS-ADL) scores, and CSF Aβ42 levels during the 52-week trial, but did not alter tau levels. Conclusions Collectively, these data suggest that resveratrol decreases CSF MMP9, modulates neuro-inflammation, and induces adaptive immunity. SIRT1 activation may be a viable target for treatment or prevention of neurodegenerative disorders. Trial registration ClinicalTrials.gov NCT01504854