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BackgroundAlzheimer's disease (AD) is a progressive, multifactorial, neurodegenerative disorder affecting >6 million Americans. Chronic, low-grade neuroinflammation, and insulin resistance may drive AD pathogenesis. We explored the neurophysiological and neuropsychological effects of NE3107, an oral, anti-inflammatory, insulin-sensitizing molecule, in AD.MethodsIn this phase 2, open-label study, 23 patients with mild cognitive impairment or mild dementia received 20-mg oral NE3107 twice daily for 3 months. Primary endpoints assessed changes from baseline in neurophysiological health and oxidative stress (glutathione level) using advanced neuroimaging analyses. Secondary endpoints evaluated changes from baseline in neuropsychological health using cognitive assessments, including the 11-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment, Clinical Dementia Rating, Quick Dementia Rating Scale, Alzheimer's Disease Composite Score, and Global Rating of Change (GRC). Exploratory endpoints assessed changes from baseline in neuroinflammation biomarkers (tumor necrosis factor alpha, TNF-α) and AD (amyloid beta and phosphorylated tau [P-tau]).ResultsNE3107 was associated with clinician-rated improvements in cerebral blood flow and functional connectivity within the brain. In patients with MMSE ≥ 20 (mild cognitive impairment to mild AD; n = 17), NE3107 was associated with directional, but statistically nonsignificant, changes in brain glutathione levels, along with statistically significant improvements in ADAS-Cog11 (P = .017), Clinical Dementia Rating (P = .042), Quick Dementia Rating Scale (P = .002), Alzheimer's Disease Composite Score (P = .0094), and clinician-rated GRC (P

Considering the growing age of the world population, the incidence of epilepsy in older adults is expected to increase significantly. It has been suggested that late-onset temporal lobe epilepsy (LO-TLE) may be neurodegenerative in origin and overlap with Alzheimer's disease (AD). Herein, we aimed to characterize the pattern of cortical atrophy and CSF biomarkers of AD (total and phosphorylated tau and amyloid-β) in a selected population of LO-TLE of unknown origin. We prospectively enrolled individuals with temporal lobe epilepsy onset after the age of 50 and no cognitive impairment. They underwent a structural MRI scan and CSF biomarkers measurement. Imaging and biomarkers data were compared to three retrospectively collected groups: (i) age-sex-matched healthy controls; (ii) patients with mild cognitive impairment (MCI) and abnormal CSF AD biomarkers (MCI-AD); and (iii) patients with MCI and normal CSF AD biomarkers (MCI-noAD). From a pool of 52 patients, 20 consecutive eligible LO-TLE patients with a mean disease duration of 1.8 years were recruited. As control populations, 25 patients with MCI-AD, 25 patients with MCI-noAD and 25 healthy controls were enrolled. CSF biomarkers returned normal values in LO-TLE, significantly different from patients with MCI due to AD. There were no differences in cortico-subcortical atrophy between epilepsy patients and healthy controls, while patients with MCI demonstrated widespread injuries of cortico-subcortical structures. Individuals with LO-TLE, characterized by short disease duration and normal CSF amyloid-β and tau protein levels, showed patterns of cortical thickness and subcortical volumes not significantly different from healthy controls, but highly different from patients with MCI, either due to AD or not. [ABSTRACT FROM AUTHOR]

Preeclampsia (preE) is a severe multisystem hypertensive syndrome of pregnancy associated with ischemia/hypoxia, angiogenic imbalance, apolipoprotein E (ApoE)-mediated dyslipidemia, placental insufficiency, and inflammation at the maternal–fetal interface. Our recent data further suggest that preE is associated with impaired autophagy, vascular dysfunction, and proteinopathy/tauopathy disorder, similar to neurodegenerative diseases such as Alzheimer's disease (AD), including the presence of the cis stereo-isoform of phosphorylated tau (cis P-tau), amyloid-β, and transthyretin in the placenta and circulation. This review provides an overview of the factors that may lead to the induction and accumulation of cis P-tau-like proteins by focusing on the inactivation of peptidyl-prolyl cis–trans isomerase (Pin1) that catalyzes the cis to trans isomerization of P-tau. We also highlighted the novel role of the Pin1-cis P-tau-ApoE axis in the development of preE, and propagation of cis P-tau-mediated abnormal protein aggregation (tauopathy) from the placenta to cerebral tissues later in life, leading to neurodegenerative conditions. In the case of preE, proteinopathy/tauopathy may interrupt trophoblast differentiation and induce cell death, similar to the events occurring in neurons. These events may eventually damage the endothelium and cause systemic features of disorders such as preE. Despite impressive research and therapeutic advances in both fields of preE and neurodegenerative diseases, further investigation of Pin1-cis P-tau and ApoE-related mechanistic underpinnings may unravel novel therapeutic options, and new transcriptional and proteomic markers. This review will also cover genetic polymorphisms in the ApoE alleles leading to dyslipidemia induction that may regulate the pathways causing preE or dementia-like features in the reproductive age or later in life, respectively. [ABSTRACT FROM AUTHOR]

Abstract Diagnosing Alzheimer’s disease (AD) through pathological markers is typically costly and invasive. This study aims to find a noninvasive, cost-effective method using portable electroencephalography (EEG) to detect changes in AD-related biomarkers in cerebrospinal fluid (CSF). A total of 102 patients, both with and without AD-related biomarker changes (amyloid beta and phosphorylated tau), were recorded using a 2-minute resting-state portable EEG. A machine-learning algorithm then analyzed the EEG data to identify these biomarker changes. The results showed that the machine learning model could distinguish patients with AD-related biomarker changes, achieving 68.1% accuracy (AUROC 0.75) for amyloid beta and 71.2% accuracy (AUROC 0.77) for phosphorylated tau, with gamma activities being key features. When excluding cases with idiopathic normal pressure hydrocephalus, accuracy improved to 74.1% (AUROC 0.80) for amyloid beta and 73.1% (AUROC 0.80) for phosphorylated tau. This study suggests that portable EEG combined with machine learning is a promising noninvasive and cost-effective tool for early AD-related pathological marker screening, which could enhance neurophysiological understanding and diagnostic accessibility.

Alzheimer’s disease (AD) is the most prevalent type of dementia; therefore, there is a high demand for therapeutic medication targeting it. In this context, extensive research has been conducted to identify molecular targets for drugs. AD manifests through two primary pathological signs: senile plaques and neurofibrillary tangles, caused by accumulations of amyloid-beta (Aβ) and phosphorylated tau, respectively. Thus, studies concerning the molecular mechanisms underlying AD etiology have primarily focused on Aβ generation and tau phosphorylation, with the anticipation of uncovering a signaling pathway impacting these molecular processes. Over the past two decades, studies using not only experimental model systems but also examining human brains have accumulated fragmentary evidences suggesting that REELIN signaling pathway is deeply involved in AD. Here, we explore REELIN signaling pathway and its involvement in memory function within the brain and review studies investigating molecular connections between REELIN signaling pathway and AD etiology. This review aims to understand how the manipulation (activation) of this pathway might ameliorate the disease’s etiology.

Introduction: The prognostic role of plasma neurofilament light chain (NfL), phospho-tau, beta-amyloid, and GFAP is still debated in Parkinson's disease (PD). Methods: Plasma p-tau181, p-tau231, Aβ1-40, Aβ1-42, GFAP, and NfL were measured by SIMOA in 136 PD with 2.9 + 1.7 years of follow-up and 76 controls. Differences in plasma levels between controls and PD and their correlation with clinical severity and progression rates were evaluated using linear regression analyses. Results: Patients exhibited similar distribution of plasma biomarkers but higher P-tau181, P-tau231 and lower Aβ1-42 compared with controls. NfL and GFAP correlated with baseline motor and non-motor severity measures. At follow-up, NfL emerged as the best predictor of progression with marginal effect of GFAP and p-tau181 adjusting for age, sex, disease duration, and baseline motor severity. Conclusion: The present findings confirmed plasma NfL as best predictor of progression in PD, with a marginal role of p-tau181 and GFAP. [ABSTRACT FROM AUTHOR]

Tau interacts with multiple heterogeneous nuclear ribonucleoproteins (hnRNPs)—a family of RNA binding proteins that regulate multiple known cellular functions, including mRNA splicing, mRNA transport, and translation regulation. We have previously demonstrated particularly significant interactions between phosphorylated tau and three hnRNPs (hnRNP A1, hnRNP A2B1, and hnRNP K). Although multiple hnRNPs have been previously implicated in tauopathies, knowledge of whether these hnRNPs colocalize with tau aggregates or show cellular mislocalization in disease is limited. Here, we performed a neuropathological study examining the colocalization between hnRNP A1, hnRNP A2B1, hnRNP K, and phosphorylated tau in two brain regions (hippocampus and frontal cortex) in six disease groups (Alzheimer's disease, mild cognitive impairment, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, and controls). Contrary to expectations, hnRNP A1, hnRNP A2B1, and hnRNP K did not colocalize with AT8‐immunoreactive phosphorylated tau pathology in any of the tauopathies examined. However, we did observe significant cellular mislocalization of hnRNP A1, hnRNP A2B1 and hnRNP K in tauopathies, with unique patterns of mislocalization observed for each hnRNP. These data point to broad dysregulation of hnRNP A1, A2B1 and K across tauopathies with implications for disease processes and RNA regulation. [ABSTRACT FROM AUTHOR]

Hyperphosphorylation of the microtubule-associated protein tau is hypothesized to lead to the development of neurofibrillary tangles in select brain regions during normal aging and in Alzheimer disease (AD). The distribution of neurofibrillary tangles is staged by its involvement starting in the transentorhinal regions of the brain and in final stages progress to neocortices. However, it has also been determined neurofibrillary tangles can extend into the spinal cord and select tau species are found in peripheral tissues and this may be depended on AD disease stage. To further understand the relationships of peripheral tissues to AD, we utilized biochemical methods to evaluate protein levels of total tau and phosphorylated tau (p-tau) as well as other neuronal proteins (i.e., tyrosine hydroxylase (TH), neurofilament heavy chain (NF-H), and microtubule-associated protein 2 (MAP2)) in the submandibular gland and frontal cortex of human cases across different clinicopathological stages of AD (n = 3 criteria not met or low, n = 6 intermediate, and n = 9 high likelihood that dementia is due to AD based on National Institute on Aging-Reagan criteria). We report differential protein levels based on the stage of AD, anatomic specific tau species, as well as differences in TH and NF-H. In addition, exploratory findings were made of the high molecular weight tau species big tau that is unique to peripheral tissues. Although sample sizes were small, these findings are, to our knowledge, the first comparison of these specific protein changes in these tissues.

Highlights: Progressive Supranuclear Palsy (PSP) presents with various clinical phenotypes, making accurate diagnosis difficult. No biomarker systems, such as the AT(N) system for Alzheimer's Disease (AD), have been established yet. In PSP, core AD cerebrospinal fluid biomarkers show a unique pattern, where Aβ42, Aβ40, p-tau, and t-tau levels are decreased while NfL levels are remarkably increased. Progressive Supranuclear Palsy (PSP) is the most common four-repeat tauopathy. PSP cases are typically characterized by vertical gaze palsy and postural instability; however, various phenotypes have been reported, making antemortem diagnosis based on clinical symptoms challenging. The development of biomarkers reflecting brain pathology and the ability to diagnose patients based on these biomarkers are essential for developing future intervention strategies, including disease-modifying therapies. However, despite many dedicated efforts, no highly specific fluid biomarker for PSP has yet been established. Conversely, several cerebrospinal fluid (CSF) biomarkers of Alzheimer's Disease (AD) have been established, and an AT(N) classification system has been proposed. Typically, among patients with AD, CSF amyloid β42 (Aβ42), but not Aβ40, is decreased, resulting in a reduction in the Aβ42/Aβ40 ratio, while tau phosphorylated at threonine 181 (p-tau181) and total tau (t-tau) are increased. Interestingly, the core CSF AD biomarkers show unique patterns in patients with PSP. Furthermore, reports have indicated that the CSF levels of both Aβ42 and Aβ40 are decreased independently of Aβ accumulation in PSP. Therefore, the Aβ42/Aβ40 ratio could potentially be used to differentiate PSP from AD. Additionally, studies have reported that CSF p-tau and t-tau are reduced in PSP, and that the neurofilament light chain is remarkably increased compared to healthy controls and patients with AD, even though PSP is a neurodegenerative disease associated with tau accumulation. These PSP-specific changes in AD-related core biomarkers may reflect the pathology of PSP and contribute to its diagnosis. As such, elucidating the mechanisms underlying the observed decreases in Aβ and tau levels could facilitate a better understanding of the pathogenesis of PSP. [ABSTRACT FROM AUTHOR]

INTRODUCTION: More robust non‐human primate models of Alzheimer's disease (AD) will provide new opportunities to better understand the pathogenesis and progression of AD. METHODS: We designed a CRISPR/Cas9 system to achieve precise genomic deletion of exon 9 in cynomolgus monkeys using two guide RNAs targeting the 3′ and 5′ intron sequences of PSEN1 exon 9. We performed biochemical, transcriptome, proteome, and biomarker analyses to characterize the cellular and molecular dysregulations of this non‐human primate model. RESULTS: We observed early changes of AD‐related pathological proteins (cerebrospinal fluid Aβ42 and phosphorylated tau) in PSEN1 mutant (ie, PSEN1‐ΔE9) monkeys. Blood transcriptome and proteome profiling revealed early changes in inflammatory and immune molecules in juvenile PSEN1‐ΔE9 cynomolgus monkeys. DISCUSSION: PSEN1 mutant cynomolgus monkeys recapitulate AD‐related pathological protein changes, and reveal early alterations in blood immune signaling. Thus, this model might mimic AD‐associated pathogenesis and has potential utility for developing early diagnostic and therapeutic interventions. Highlights: A dual‐guide CRISPR/Cas9 system successfully mimics AD PSEN1‐ΔE9 mutation by genomic excision of exon 9.PSEN1 mutant cynomolgus monkey‐derived fibroblasts exhibit disrupted PSEN1 endoproteolysis and increased Aβ secretion.Blood transcriptome and proteome profiling implicate early inflammatory and immune molecular dysregulation in juvenile PSEN1 mutant cynomolgus monkeys.Cerebrospinal fluid from juvenile PSEN1 mutant monkeys recapitulates early changes of AD‐related pathological proteins (increased Aβ42 and phosphorylated tau). [ABSTRACT FROM AUTHOR]

INTRODUCTION: The established cerebrospinal fluid (CSF) phosphorylated tau181 (p‐tau181) may not reliably reflect concomitant Alzheimer's disease (AD) and primary age‐related tauopathy (PART) found in Creutzfeldt–Jakob disease (CJD) at autopsy. METHODS: We investigated CSF N‐terminal p‐tau181, p‐tau217, and p‐tau231 with in‐house Simoa assays in definite CJD (n = 29), AD dementia (n = 75), mild cognitive impairment (MCI) due to AD (n = 65), and subjective cognitive decline (SCD, n = 28). Post‐mortem examination performed in patients with CJD 1.3 (0.3–14.3) months after CSF collection revealed no co‐pathology in 10, concomitant AD in 8, PART in 8, and other co‐pathologies in 3 patients. RESULTS: N‐terminal p‐tau was increased in CJD versus SCD (p < 0.0001) and correlated with total tau (t‐tau) in the presence of AD and PART co‐pathology (rho = 0.758–0.952, p ≤ 001). Concentrations in CJD+AD were indistinguishable from AD dementia, with the largest fold‐change in p‐tau217 (11.6), followed by p‐tau231 and p‐tau181 (3.2–4.5). DISCUSSION: Variable fold‐changes and correlation with t‐tau suggest that p‐tau closely associates with neurodegeneration and concomitant AD in CJD. Highlights: N‐terminal phosphorylated tau (p‐tau) biomarkers are increased in Creutzfeldt–Jakob disease (CJD) with and without concomitant AD.P‐tau217, p‐tau231, and p‐tau181 correlate with total tau (t‐tau) and increase in the presence of amyloid beta (Aβ) co‐pathology.N‐terminal p‐tau181 and p‐tau231 in Aβ‐negative CJD show variation among PRNP genotypes.Compared to mid‐region–targeting p‐tau181, cerebrospinal fluid (CSF) N‐terminal p‐tau has greater potential to reflect post‐mortem neuropathology in the CJD brain. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Cognitive reserve might mitigate the risk of Alzheimer's dementia among memory clinic patients. No study has examined the potential modifying role of stress on this relation. METHODS: We examined cross‐sectional associations of the cognitive reserve index (CRI; education, occupational complexity, physical and leisure activities, and social health) with cognitive performance and AD‐related biomarkers among 113 memory clinic patients. The longitudinal association between CRI and cognition over a 3‐year follow‐up was assessed. We examined whether associations were influenced by perceived stress and five measures of diurnal salivary cortisol. RESULTS: Higher CRI scores were associated with better cognition. Adjusting for cortisol measures reduced the beneficial association of CRI on cognition. A higher CRI score was associated with better working memory in individuals with higher (favorable) cortisol AM/PM ratio, but not among individuals with low cortisol AM/PM ratio. No association was found between CRI and AD‐related biomarkers. DISCUSSION: Physiological stress reduces the neurocognitive benefits of cognitive reserve among memory clinic patients. Highlights: Physiological stress may reduce the neurocognitive benefits accrued from cognitively stimulating and enriching life experiences (cognitive reserve [CR]) in memory clinic patients.Cortisol awakening response modified the relation between CR and P‐tau181, a marker of Alzheimer's disease (AD).Effective stress management techniques for AD and related dementia prevention are warranted. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Alzheimer's disease (AD) blood biomarkers show promise for clinical diagnosis but their reliability in chronic kidney disease (CKD) is debated. This study investigates the impact of kidney transplant (KT) on AD biomarkers in CKD. METHODS: We assessed AD biomarkers in 46 CKD patients pre‐KT, at 12 weeks and 12 months post‐KT, with baseline measures from 13 non‐CKD controls. Using linear mixed models, we examined associations with participant groups, estimated glomerular filtration rate (eGFR) and cognition. RESULTS: CKD patients showed elevated levels of neurofilament light (117 ± 72 vs. 11 ± 5 pg/mL), phosphorylated tau 181 (75 ± 42 vs. 13 ± 8 pg/mL), glial fibrillary acidic protein (193 ± 127 vs. 94 ± 39 pg/mL), amyloid β 42 (17 ± 5 vs. 5 ± 1 pg/mL), and amyloid β 40 (259 ± 96 vs. 72 ± 17 pg/mL) compared to controls. Post‐KT, biomarker levels approached normal with improved eGFR, paralleled by enhanced cognitive function. DISCUSSION: AD blood biomarker elevations in CKD are reversible with improved kidney function through KT. Highlights: AD biomarker levels are extremely high in severe CKD.AD biomarker levels are higher in patients with kidney failure on dialysis when compared to CKD patients not on dialysis.These elevations in AD biomarker levels in kidney failure are reversable and decrease dramatically after kidney transplantation.The change in biomarker levels after transplantation align with changes in kidney function.The change in biomarker levels after transplantation align with changes in cognitive function. [ABSTRACT FROM AUTHOR]

Abstract Background Measurement of beta-amyloid (Aβ) and phosphorylated tau (p-tau) levels offers the potential for early detection of neurocognitive impairment. Still, the probability of developing a clinical syndrome in the presence of these protein changes (A+ and T+) remains unclear. By performing a systematic review and meta-analysis, we investigated the risk of mild cognitive impairment (MCI) or dementia in the non-demented population with A+ and A- alone and in combination with T+ and T- as confirmed by PET or cerebrospinal fluid examination. Methods A systematic search of prospective and retrospective studies investigating the association of Aβ and p-tau with cognitive decline was performed in three databases (MEDLINE via PubMed, EMBASE, and CENTRAL) on January 9, 2024. The risk of bias was assessed using the Cochrane QUIPS tool. Odds ratios (OR) and Hazard Ratios (HR) were pooled using a random-effects model. The effect of neurodegeneration was not studied due to its non-specific nature. Results A total of 18,162 records were found, and at the end of the selection process, data from 36 cohorts were pooled (n= 7,793). Compared to the unexposed group, the odds ratio (OR) for conversion to dementia in A+ MCI patients was 5.18 [95% CI 3.93; 6.81]. In A+ CU subjects, the OR for conversion to MCI or dementia was 5.79 [95% CI 2.88; 11.64]. Cerebrospinal fluid Aβ42 or Aβ42/40 analysis and amyloid PET imaging showed consistent results. The OR for conversion in A+T+ MCI subjects (11.60 [95% CI 7.96; 16.91]) was significantly higher than in A+T- subjects (2.73 [95% CI 1.65; 4.52]). The OR for A-T+ MCI subjects was non-significant (1.47 [95% CI 0.55; 3.92]). CU subjects with A+T+ status had a significantly higher OR for conversion (13.46 [95% CI 3.69; 49.11]) than A+T- subjects (2.04 [95% CI 0.70; 5.97]). Meta-regression showed that the ORs for Aβ exposure decreased with age in MCI. (beta = -0.04 [95% CI -0.03 to -0.083]). Conclusions Identifying Aβ-positive individuals, irrespective of the measurement technique employed (CSF or PET), enables the detection of the most at-risk population before disease onset, or at least at a mild stage. The inclusion of tau status in addition to Aβ, especially in A+T+ cases, further refines the risk assessment. Notably, the higher odds ratio associated with Aβ decreases with age. Trial registration The study was registered in PROSPERO (ID: CRD42021288100).

Neuropathologic criteria for progressive supranuclear palsy (PSP) proposed by a National Institute of Neurological Disorders and Stroke (NINDS) working group were published in 1994 and based on the presence of neurofibrillary tangles in basal ganglia and brainstem. These criteria did not stipulate detection methods or incorporate glial tau pathology. In this study, a group of 14 expert neuropathologists scored digital slides from 10 brain regions stained with hematoxylin and eosin (H&E) and phosphorylated tau (AT8) immunohistochemistry. The cases included 15 typical and atypical PSP cases and 10 other tauopathies. Blinded to clinical and neuropathological information, raters provided a categorical diagnosis (PSP or not-PSP) based upon provisional criteria that required neurofibrillary tangles or pretangles in two of three regions (substantia nigra, subthalamic nucleus, globus pallidus) and tufted astrocytes in one of two regions (peri-Rolandic cortices, putamen). The criteria showed high sensitivity (0.97) and specificity (0.91), as well as almost perfect inter-rater reliability for diagnosing PSP and differentiating it from other tauopathies (Fleiss kappa 0.826). Most cases (17/25) had 100% agreement across all 14 raters. The Rainwater Charitable Foundation criteria for the neuropathologic diagnosis of PSP feature a simplified diagnostic algorithm based on phosphorylated tau immunohistochemistry and incorporate tufted astrocytes as an essential diagnostic feature.

• Hyaluronan (HA) and its role in AD pathology and HA synthases (HASs) are studied. • HAS1 is uniquely altered in the AD brain, affecting microenvironmental remodeling. • The AβPP-tau-HAS1 axis plays a crucial role in AD gene transcription. • GSK3β inhibitor blocking tau phosphorylation affects HAS1 and HA synthesis. • Transcriptomic data reveals non-ubiquitinated HAS1′s link to AD, offering new insights. As the backbone of the extracellular matrix (ECM) and the perineuronal nets (PNNs), hyaluronic acid (HA) provides binding sites for proteoglycans and other ECM components. Although the pivotal of HA has been recognized in Alzheimer's disease (AD), few studies have addressed the relationship between AD pathology and HA synthases (HASs). Here, HASs in different regions of AD brains were screened in transcriptomic database and validated in AβPP/PS1 mice. We found that HAS1 was distributed along the axon and nucleus. Its transcripts were reduced in AD patients and AβPP/PS1 mice. Phosphorylated tau (p-tau) mediates AβPP-induced cytosolic-nuclear translocation of HAS1, and negatively regulated the stability, monoubiquitination, and oligomerization of HAS1, thus reduced the synthesis and release of HA. Furthermore, non-ubiquitinated HAS1 mutant lost its enzyme activity, and translocated from the cytosol into the nucleus, forming nuclear speckles (NS). Unlike the splicing-related NS, less than 1 % of the non-ubiquitinated HAS1 co-localized with SRRM2, proving the regulatory role of HAS1 in gene transcription, indirectly. Thus, differentially expressed genes (DEGs) related to both non-ubiquitinated HAS1 mutant and AD were screened using transcriptomic datasets. Thirty-nine DEGs were identified, with 64.1 % (25/39) showing consistent results in both datasets. Together, we unearthed an important function of the AβPP-p-tau-HAS1 axis in microenvironment remodeling and gene transcription during AD progression, involving the ubiquitin-proteasome, lysosome, and NS systems. [ABSTRACT FROM AUTHOR]

Recently, novel non-pharmacological interventions, such as photobiomodulation (PBM) therapy, have shown promise for the treatment of Alzheimer's disease (AD). This article outlines the translation from the preclinical to clinical stages of an innovative brain-gut PBM therapy in a mouse model of AD, a pilot clinical trial involving mild-to-moderate AD patients, and a continuing pivotal clinical trial with a similar patient population. In a mouse model of AD (Aß25-35), daily application of brain-gut PBM therapy to both the head and the abdomen produced a neuroprotective effect against the neurotoxic effects of an Aß25-35 peptide injection by normalizing all the modified behavioral and biochemical parameters. The pilot clinical trial to evaluate brain-gut PBM therapy demonstrated the tolerability and feasibility of the novel PBM-based treatment for mild-to-moderate AD patients. Compared to the sham patients, the PBM-treated patients had lower Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) comprehension sub-scores, higher forward verbal spans, and lower Trail Making Test (TMT) Part B (TMT-B) execution times, which suggest an improvement in cognitive functions. This pilot study provided important information for the design of a novel pivotal clinical trial, currently in progress, to assess the efficacy of brain-gut PBM therapy in a larger sample of AD patients. This pivotal clinical trial could demonstrate that brain-gut PBM therapy is a safe, well-tolerated, and efficient disease-modifying treatment for mild-to-moderate AD patients and that it has medical and economic benefits. [ABSTRACT FROM AUTHOR]

BACKGROUND: We aimed to evaluate the precision of Alzheimer's disease (AD) and neurodegeneration biomarker measurements from venous dried plasma spots (DPSvenous) for the diagnosis and monitoring of neurodegenerative diseases in remote settings. METHODS: In a discovery (n = 154) and a validation cohort (n = 115), glial fibrillary acidic protein (GFAP); neurofilament light (NfL); amyloid beta (Aβ) 40, Aβ42; and phosphorylated tau (p‐tau181 and p‐tau217) were measured in paired DPSvenous and ethylenediaminetetraacetic acid plasma samples with single‐molecule array. In the validation cohort, a subset of participants (n = 99) had cerebrospinal fluid (CSF) biomarkers. RESULTS: All DPSvenous and plasma analytes correlated significantly, except for Aβ42. In the validation cohort, DPSvenous GFAP, NfL, p‐tau181, and p‐tau217 differed between CSF Aβ‐positive and ‐negative individuals and were associated with worsening cognition. DISCUSSION: Our data suggest that measuring blood biomarkers related to AD pathology and neurodegeneration from DPSvenous extends the utility of blood‐based biomarkers to remote settings with simplified sampling conditions, storage, and logistics. Highlights: A wide array of biomarkers related to Alzheimer's disease (AD) and neurodegeneration were detectable in dried plasma spots (DPSvenous).DPSvenous biomarkers correlated with standard procedures and cognitive status.DPSvenous biomarkers had a good diagnostic accuracy discriminating amyloid status.Our findings show the potential interchangeability of DPSvenous and plasma sampling.DPSvenous may facilitate remote and temperature‐independent sampling for AD biomarker measurement.Innovative tools for blood biomarker sampling may help recognizing the earliest changes of AD. [ABSTRACT FROM AUTHOR]

INTRODUCTION: A major limitation in Alzheimer's disease (AD) research is the lack of the ability to measure cognitive performance at scale—robustly, remotely, and frequently. Currently, there are no established online digital platforms validated against plasma biomarkers of AD. METHODS: We used a novel web‐based platform that assessed different cognitive functions in AD patients (N = 46) and elderly controls (N = 53) who were also evaluated for plasma biomarkers (amyloid beta 42/40 ratio, phosphorylated tau ([p‐tau]181, glial fibrillary acidic protein, neurofilament light chain). Their cognitive performance was compared to a second, larger group of elderly controls (N = 352). RESULTS: Patients with AD were significantly impaired across all digital cognitive tests, with performance correlating with plasma biomarker levels, particularly p‐tau181. The combination of p‐tau181 and the single best‐performing digital test achieved high accuracy in group classification. DISCUSSION: These findings show how online testing can now be deployed in patients with AD to measure cognitive function effectively and related to blood biomarkers of the disease. Highlights: This is the first study comparing online digital testing to plasma biomarkers.Alzheimer's disease patients and two independent cohorts of elderly controls were assessed.Cognitive performance correlated with plasma biomarkers, particularly phosphorylated tau (p‐tau)181.Glial fibrillary acidic protein and neurofilament light chain, and less so the amyloid beta 42/40 ratio, were also associated with performance.The best cognitive metric performed at par to p‐tau181 in group classification. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a major risk for the aging population. The pathological hallmarks of AD-an abnormal deposition of amyloid β-protein (Aβ) and phosphorylated tau (pTau)-have been demonstrated in the retinas of AD patients, including in prodromal patients with mild cognitive impairment (MCI). Aβ pathology, especially the accumulation of the amyloidogenic 42-residue long alloform (Aβ42), is considered an early and specific sign of AD, and together with tauopathy, confirms AD diagnosis. To visualize retinal Aβ and pTau, state-of-the-art methods use fluorescence. However, administering contrast agents complicates the imaging procedure. To address this problem from fundamentals, ex-vivo studies were performed to develop a label-free hyperspectral imaging method to detect the spectral signatures of Aβ42 and pS396-Tau, and predicted their abundance in retinal cross-sections. For the first time, we reported the spectral signature of pTau and demonstrated an accurate prediction of Aβ and pTau distribution powered by deep learning. We expect our finding will lay the groundwork for label-free detection of AD.

Abstract Background Cardiometabolic multimorbidity is associated with an increased risk of dementia, but the pathogenic mechanisms linking them remain largely undefined. We aimed to assess the associations of cardiometabolic multimorbidity with cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) pathology to enhance our understanding of the underlying mechanisms linking cardiometabolic multimorbidity and AD. Methods This study included 1464 cognitively intact participants from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) database. Cardiometabolic diseases (CMD) are a group of interrelated disorders such as hypertension, diabetes, heart diseases (HD), and stroke. Based on the CMD status, participants were categorized as CMD-free, single CMD, or CMD multimorbidity. CMD multimorbidity is defined as the coexistence of two or more CMDs. The associations of cardiometabolic multimorbidity and CSF biomarkers were examined using multivariable linear regression models with demographic characteristics, the APOE ε4 allele, and lifestyle factors as covariates. Subgroup analyses stratified by age, sex, and APOE ε4 status were also performed. Results A total of 1464 individuals (mean age, 61.80 years; age range, 40–89 years) were included. The markers of phosphorylated tau-related processes (CSF P-tau181: β = 0.165, P = 0.037) and neuronal injury (CSF T-tau: β = 0.065, P = 0.033) were significantly increased in subjects with CMD multimorbidity (versus CMD-free), but not in those with single CMD. The association between CMD multimorbidity with CSF T-tau levels remained significant after controlling for Aβ42 levels. Additionally, significantly elevated tau-related biomarkers were observed in patients with specific CMD combinations (i.e., hypertension and diabetes, hypertension and HD), especially in long disease courses. Conclusions The presence of cardiometabolic multimorbidity was associated with tau phosphorylation and neuronal injury in cognitively normal populations. CMD multimorbidity might be a potential independent target to alleviate tau-related pathologies that can cause cognitive impairment.

Preeclampsia (preE) is a severe multisystem hypertensive syndrome of pregnancy associated with ischemia/hypoxia, angiogenic imbalance, apolipoprotein E (ApoE)-mediated dyslipidemia, placental insufficiency, and inflammation at the maternal–fetal interface. Our recent data further suggest that preE is associated with impaired autophagy, vascular dysfunction, and proteinopathy/tauopathy disorder, similar to neurodegenerative diseases such as Alzheimer’s disease (AD), including the presence of the cis stereo-isoform of phosphorylated tau (cis P-tau), amyloid-β, and transthyretin in the placenta and circulation. This review provides an overview of the factors that may lead to the induction and accumulation of cis P-tau-like proteins by focusing on the inactivation of peptidyl-prolyl cis–trans isomerase (Pin1) that catalyzes the cis to trans isomerization of P-tau. We also highlighted the novel role of the Pin1-cis P-tau-ApoE axis in the development of preE, and propagation of cis P-tau-mediated abnormal protein aggregation (tauopathy) from the placenta to cerebral tissues later in life, leading to neurodegenerative conditions. In the case of preE, proteinopathy/tauopathy may interrupt trophoblast differentiation and induce cell death, similar to the events occurring in neurons. These events may eventually damage the endothelium and cause systemic features of disorders such as preE. Despite impressive research and therapeutic advances in both fields of preE and neurodegenerative diseases, further investigation of Pin1-cis P-tau and ApoE-related mechanistic underpinnings may unravel novel therapeutic options, and new transcriptional and proteomic markers. This review will also cover genetic polymorphisms in the ApoE alleles leading to dyslipidemia induction that may regulate the pathways causing preE or dementia-like features in the reproductive age or later in life, respectively.

Intraindividual variability (IIV) across neuropsychological measures within a single testing session is a promising marker predictive of cognitive decline and development of Alzheimer's disease (AD). We have previously shown that greater IIV is cross-sectionally associated with reduced cerebral blood flow (CBF), but not with cortical thickness or brain volume, in older adults without dementia who were amyloid beta (Aβ) positive. However, there is little known about the association between change in IIV and CBF over time. Therefore, we examined 12-month longitudinal change in IIV and interactions of IIV and AD biomarker status on changes in regional CBF. Fifty-three non-demented Alzheimer's Disease Neuroimaging Initiative (ADNI) participants underwent lumbar puncture to obtain cerebrospinal fluid (CSF) at baseline and neuropsychological testing and magnetic resonance imaging (MRI) exams at baseline and 12-month follow-up evaluation. IIV was calculated as the intraindividual standard deviation across 6 demographically-corrected neuropsychological measures. Pulsed arterial spin labeling (ASL) MRI was acquired to quantify CBF and FreeSurfer-derived a priori CBF regions of interest (ROIs) were examined. AD biomarker positivity was determined using a published CSF p-tau/Aβ ratio cut-score. Change scores were calculated for IIV, CBF, and mean neuropsychological performance from baseline to 12 months. Hierarchical linear regression models showed that after adjusting for age and gender, there was a significant interaction between IIV change and biomarker-positivity (p-tau/Aβ+) for change in entorhinal and hippocampal CBF but not for the other ROIs. Specifically, increases in IIV were associated with reductions in entorhinal and hippocampal CBF among individuals who were biomarker-positive (n = 21). In contrast, there were no significant associations between change in IIV and CBF among those who were biomarker-negative (n = 32). Findings remained similar when analyses were performed adjusting for change in mean level of neuropsychological performance. Changes in IIV may be sensitive to changes in regional hypoperfusion in AD-vulnerable regions among AD biomarker-positive individuals, above and beyond demographics and mean neuropsychological performance. These findings provide further evidence supporting IIV as a potential marker of cerebrovascular brain changes in individuals at risk for dementia.

IntroductionDespite women showing greater Alzheimer's disease (AD) prevalence, tau burden, and immune/neuroinflammatory response, whether neuroinflammation impacts cognition differently in women versus men and the biological basis of this impact remain unknown. We examined sex differences in how cerebrospinal fluid (CSF) neuroinflammation relates to cognition across the aging-mild cognitive impairment (MCI)-AD continuum and the mediating role of phosphorylated tau (p-tau) versus other AD biomarkers.MethodsParticipants included 284 individuals from the Alzheimer's Disease Neuroimaging Initiative study. CSF neuroinflammatory markers included interleukin-6, tumor necrosis factor α, soluble tumor necrosis factor receptor 2 (sTNFR2), and chitinase-3-like protein 1. AD biomarkers were CSF p-tau181 and amyloid beta1-42 levels and magnetic resonance imaging measures of hippocampal and white matter hyperintensity volumes.ResultsWe found a sex-by-sTNFR2 interaction on Mini-Mental State Examination and Clinical Dementia Rating-Sum of Boxes. Higher levels of sTNFR2 related to poorer cognition in women only. Among biomarkers, only p-tau181 eliminated the female-specific relationships between neuroinflammation and cognition.DiscussionWomen may be more susceptible than men to the adverse effects of sTNFR2 on cognition with a potential etiological link with tau to these effects.

Abstract INTRODUCTION A major limitation in Alzheimer's disease (AD) research is the lack of the ability to measure cognitive performance at scale—robustly, remotely, and frequently. Currently, there are no established online digital platforms validated against plasma biomarkers of AD. METHODS We used a novel web‐based platform that assessed different cognitive functions in AD patients (N = 46) and elderly controls (N = 53) who were also evaluated for plasma biomarkers (amyloid beta 42/40 ratio, phosphorylated tau ([p‐tau]181, glial fibrillary acidic protein, neurofilament light chain). Their cognitive performance was compared to a second, larger group of elderly controls (N = 352). RESULTS Patients with AD were significantly impaired across all digital cognitive tests, with performance correlating with plasma biomarker levels, particularly p‐tau181. The combination of p‐tau181 and the single best‐performing digital test achieved high accuracy in group classification. DISCUSSION These findings show how online testing can now be deployed in patients with AD to measure cognitive function effectively and related to blood biomarkers of the disease. Highlights This is the first study comparing online digital testing to plasma biomarkers. Alzheimer's disease patients and two independent cohorts of elderly controls were assessed. Cognitive performance correlated with plasma biomarkers, particularly phosphorylated tau (p‐tau)181. Glial fibrillary acidic protein and neurofilament light chain, and less so the amyloid beta 42/40 ratio, were also associated with performance. The best cognitive metric performed at par to p‐tau181 in group classification.

Introduction: Alzheimer's disease (AD), the most common neurodegenerative disease, is characterized by accumulated amyloid-β (Aβ) plaques, aggregated phosphorylated tau protein, gliosis-associated neuroinflammation, synaptic dysfunction, and cognitive impairment. Many cohort studies indicate that tooth loss is a risk factor for AD. The detailed mechanisms underlying the association between AD and tooth loss, however, are not yet fully understood. Methods: We explored the involvement of early tooth loss in the neuropathogenesis of the adult AppNL-G-F mouse AD model. The maxillary molars were extracted bilaterally in 1-month-old male mice soon after tooth eruption. Results: Plasma corticosterone levels were increased and spatial learning memory was impaired in these mice at 6 months of age. The cerebral cortex and hippocampus of AD mice with extracted teeth showed an increased accumulation of Aβ plaques and phosphorylated tau proteins, and increased secretion of the proinflammatory cytokines, including interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α), accompanied by an increased number of microglia and astrocytes, and decreased synaptophysin expression. AD mice with extracted teeth also had a shorter lifespan than the control mice. Discussion: These findings revealed that long-term tooth loss is a chronic stressor, activating the recruitment of microglia and astrocytes; exacerbating neuroinflammation, Aβ deposition, phosphorylated tau accumulation, and synaptic dysfunction; and leading to spatial learning and memory impairments in AD model mice. [ABSTRACT FROM AUTHOR]

Collapsin response mediator protein 1 (CRMP1) is involved in semaphorin 3A signaling pathway, promoting neurite extension and growth cone collapse. It is highly expressed in the nervous system, especially the hippocampus. The crmp1 knockout (KO) mice display impaired spatial learning and memory, and this phenomenon seemingly tends to deteriorate with age. Here we investigated whether CRMP1 is involved in age-related cognitive decline in WT and crmp1 KO mice at adult, middle-aged and older stages. The results revealed that cognitive dysfunction in the Morris water maze task became more severe and decreased glutamate and glutamine level in middle-aged crmp1 KO mice. Additionally, increasing levels of extrasynaptic NMDA receptors and phosphorylation of Tau were observed in middle-aged crmp1 KO mice, leading to synaptic and neuronal loss in the CA3 regions of hippocampus. These findings suggest that deletion of CRMP1 accelerates age-related cognitive decline by disrupting the balance between synaptic and extrasynaptic NMDA receptors, resulting in the loss of synapses and neurons. [Display omitted] ● Depletion of CRMP1 accelerated aging-related cognitive decline. ● Depletion of CRMP1 increased extrasynaptic NMDA receptors. ● Depletion of CRMP1 induced hyperphosphorylation of Tau. ● Depletion of CRMP1 resulted in synaptic and neuronal loss. [ABSTRACT FROM AUTHOR]

INTRODUCTION: We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases. METHODS: Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p‐tau)181 and amyloid beta (Aβ)42/40 were measured using ultra‐sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD). RESULTS: GFAP, NfL, and/or p‐tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p‐tau181 were highly predictive across diseases, p‐tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aβ42/40. DISCUSSION: GFAP, NfL, and p‐tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials. [ABSTRACT FROM AUTHOR]

Background: Cardiometabolic multimorbidity is associated with an increased risk of dementia, but the pathogenic mechanisms linking them remain largely undefined. We aimed to assess the associations of cardiometabolic multimorbidity with cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathology to enhance our understanding of the underlying mechanisms linking cardiometabolic multimorbidity and AD. Methods: This study included 1464 cognitively intact participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database. Cardiometabolic diseases (CMD) are a group of interrelated disorders such as hypertension, diabetes, heart diseases (HD), and stroke. Based on the CMD status, participants were categorized as CMD-free, single CMD, or CMD multimorbidity. CMD multimorbidity is defined as the coexistence of two or more CMDs. The associations of cardiometabolic multimorbidity and CSF biomarkers were examined using multivariable linear regression models with demographic characteristics, the APOE ε4 allele, and lifestyle factors as covariates. Subgroup analyses stratified by age, sex, and APOE ε4 status were also performed. Results: A total of 1464 individuals (mean age, 61.80 years; age range, 40–89 years) were included. The markers of phosphorylated tau-related processes (CSF P-tau181: β = 0.165, P = 0.037) and neuronal injury (CSF T-tau: β = 0.065, P = 0.033) were significantly increased in subjects with CMD multimorbidity (versus CMD-free), but not in those with single CMD. The association between CMD multimorbidity with CSF T-tau levels remained significant after controlling for Aβ42 levels. Additionally, significantly elevated tau-related biomarkers were observed in patients with specific CMD combinations (i.e., hypertension and diabetes, hypertension and HD), especially in long disease courses. Conclusions: The presence of cardiometabolic multimorbidity was associated with tau phosphorylation and neuronal injury in cognitively normal populations. CMD multimorbidity might be a potential independent target to alleviate tau-related pathologies that can cause cognitive impairment. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) can initiate progressive injury responses, which are linked to increased risk of neurodegenerative diseases known as "tauopathies." Increased post-TBI tau hyperphosphorylation has been reported in brain tissue and biofluids. Acute-to-chronic TBI total (T)-tau and phosphorylated (P)-tau temporal profiles in the cerebrospinal fluid (CSF) and serum and their relationship to global outcome is unknown. Our multi-site longitudinal study examines these concurrent profiles acutely (CSF and serum) and also characterizes the acute- to-chronic serum patterns. Serial serum and CSF samples from individuals with moderate-to-severe TBI were obtained from two cohorts (acute, subacute, and chronic samples from University of Pittsburgh [UPitt] [n = 286 unique subjects] and acute samples from Baylor College of Medicine [BCM] [n = 114 unique subjects]) and assayed for T-tau and P-tau using the Rolling Circle Amplification-Surround Optical Fiber ImmunoAssay platform. Biokinetic analyses described serum T-tau and P-tau temporal patterns. T-tau and P-tau levels are compared with those in healthy controls (n = 89 for both CSF and serum), and univariate/multivariable associations are made with global outcome, including the Disability Rating Scale (DRS) and the Glasgow Outcome Scale-Extended (GOS-E) scores at 3 and 6 months post-TBI (BCM cohort) and at 6 and 12 months post-TBI (UPitt cohort). For both the UPitt and BCM cohorts, temporal increases in median serum and CSF T-tau and P-tau levels occurred over the first 5 days post-injury, while the initial increases of P-tau:T-tau ratio plateaued by day 4 post-injury (UPitt: n = 99, BCM: n = 48). Biokinetic analyses with UPitt data showed novel findings that T-tau (n = 74) and P-tau (n = 87) reached delayed maximum levels at 4.5 and 5.1 days, while exhibiting long serum half-lives (152 and 123 days), respectively. The post-TBI rise in acute (days 2–6) serum P-tau (up to 276-fold) far outpaced that of T-tau (7.3-fold), leading to a P-tau:T-tau increase of up to 267-fold, suggesting a shift toward tau hyperphosphorylation. BCM analyses showed that days 0–6 mean CSF T-tau and P-tau levels and P-tau:T-tau ratios were associated with greater disability (DRS) (n = 48) and worse global outcome (GOS-E) (n = 48) 6 months post-injury. Days 0–6 mean serum T-tau, P-tau, and P-tau:T-tau ratio were not associated with outcome in either cohort (UPitt: n = 145 [DRS], n = 154 [GOS-E], BCM: n = 99 [DRS and GOS-E]). UPitt multivariate models showed that higher chronic (months 1–6) mean P-tau levels and P-tau:T-tau ratio, but not T-tau levels, are associated with greater disability (DRS: n = 119) and worse global outcomes (GOS-E: n = 117) 12 months post-injury. This work shows the potential importance of monitoring post-TBI T-tau and P-tau levels over time. This multi-site longitudinal study features concurrent acute TBI T-tau and P-tau profiles in CSF and serum, and also characterizes acute-to-chronic serum profiles. Longitudinal profiles, along with no temporal concordance between trajectory groups over time, imply a sustained post-TBI shift in tau phosphorylation dynamics that may favor tauopathy development chronically. [ABSTRACT FROM AUTHOR]

Objective: Neurofibrillary tangles are present in a proportion of people with dementia with Lewy bodies and may be associated with worse cognition. Recent advances in biomarkers for Alzheimer's disease include second-generation tau positron emission tomography as well as the detection of phosphorylated tau at threonine 181 (p-tau181) in plasma. This study aimed to investigate tau in people with dementia with Lewy bodies using a second-generation tau positron emission tomography tracer as well as plasma p-tau181. Methods: Twenty-seven participants (mean age 74.7 ± 5.5) with clinically diagnosed probable dementia with Lewy bodies underwent comprehensive clinical assessment and positron emission tomography imaging (18F-MK6240 and 18F-NAV4694). Plasma p-tau181 levels were measured using Simoa technology. Results: Five dementia with Lewy bodies participants (18.5%) had an abnormal tau positron emission tomography (increased tau uptake in the temporal meta-region-of-interest). Higher plasma p-tau181 concentrations correlated with higher tau deposition in the temporal region (ρ = 0.46, 95% confidence interval = [0.10, 0.72]) and classified abnormal tau positron emission tomography in dementia with Lewy bodies with an area under the curve of 0.95 (95% confidence interval = [0.86, 0.99]). Plasma p-tau181 also correlated positively with cortical amyloid-beta binding (ρ = 0.68, 95% confidence interval = [0.40, 0.84]) and classified abnormal amyloid-beta positron emission tomography in dementia with Lewy bodies with an area under the curve of 0.91 (95% confidence interval = [0.79, 0.99]). There was no association found between tau deposition and any of the clinical variables. Conclusions: Tau is a common co-pathology in dementia with Lewy bodies. Plasma p-tau181 correlated with abnormal tau and amyloid-beta positron emission tomography and may potentially be used as a marker to identify co-morbid Alzheimer's disease-related pathology in dementia with Lewy bodies. The clinical implications of tau in dementia with Lewy bodies need to be further evaluated in larger longitudinal studies. [ABSTRACT FROM AUTHOR]

Background Subjective cognitive decline (SCD) has gained recent interest as a potential harbinger of neurodegenerative diseases such as Alzheimer's disease (AD) and cerebrovascular disease (CVD). In addition, SCD can be related to depressive symptomatology. However, the association between AD and CVD biomarkers, depressive symptomatology, and SCD is still unclear. We investigated the association of AD and CVD biomarkers and depressive symptomatology with SCD in individuals with subjective memory complaints (SCD-memory group) and individuals with subjective concentration complaints (SCD-concentration group). Methods We recruited a population-based cohort of 217 individuals (all aged 70 years, 53% female participants, 119 SCD-memory individuals, 23 SCD-concentration individuals, and 89 controls). AD and CVD were assessed through cerebrospinal fluid levels of the Aβ42/40 ratio and phosphorylated tau, and white matter signal abnormalities on magnetic resonance imaging, respectively. Associations between biomarkers, depressive symptomatology, and SCD were tested via logistic regression and correlation analyses. Results We found a significant association between depressive symptomatology with SCD-memory and SCD-concentration. Depressive symptomatology was not associated with AD and CVD biomarkers. Both the phosphorylated tau biomarker and depressive symptomatology predicted SCD-memory, and the Aβ42/40 ratio and depressive symptomatology predicted SCD-concentration. Conclusions The role of depressive symptomatology in SCD may differ depending on the stage within the spectrum of preclinical AD (as determined by amyloid-beta and tau positivity), and does not seem to reflect AD pathology. Our findings contribute to the emerging field of subclinical depressive symptomatology in SCD and clarify the association of different types of subjective complaints with distinct syndromic and biomarker profiles. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Blood biomarkers have proven useful in Alzheimer's disease (AD) research. However, little is known about their biological variation (BV), which improves the interpretation of individual‐level data. METHODS: We measured plasma amyloid beta (Aβ42, Aβ40), phosphorylated tau (p‐tau181, p‐tau217, p‐tau231), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) in plasma samples collected weekly over 10 weeks from 20 participants aged 40 to 60 years from the European Biological Variation Study. We estimated within‐ (CVI) and between‐subject (CVG) BV, analytical variation, and reference change values (RCV). RESULTS: Biomarkers presented considerable variability in CVI and CVG. Aβ42/Aβ40 had the lowest CVI (≈ 3%) and p‐tau181 the highest (≈ 16%), while others ranged from 6% to 10%. Most RCVs ranged from 20% to 30% (decrease) and 25% to 40% (increase). DISCUSSION: BV estimates for AD plasma biomarkers can potentially refine their clinical and research interpretation. RCVs might be useful for detecting significant changes between serial measurements when monitoring early disease progression or interventions. Highlights: Plasma amyloid beta (Aβ42/Aβ40) presents the lowest between‐ and within‐subject biological variation, but also changes the least in Alzheimer's disease (AD) patients versus controls.Plasma phosphorylated tau variants significantly vary in their within‐subject biological variation, but their substantial fold‐changes in AD likely limits the impact of their variability.Plasma neurofilament light chain and glial fibrillary acidic protein demonstrate high between‐subject variation, the impact of which will depend on clinical context.Reference change values can potentially be useful in monitoring early disease progression and the safety/efficacy of interventions on an individual level.Serial sampling revealed that unexpectedly high values in heathy individuals can be observed, which urges caution when interpreting AD plasma biomarkers based on a single test result. [ABSTRACT FROM AUTHOR]

Plasma-to-autopsy studies are essential for validation of blood biomarkers and understanding their relation to Alzheimer’s disease (AD) pathology. Few such studies have been done on phosphorylated tau (p-tau) and those that exist have made limited or no comparison of the different p-tau variants. This study is the first to use immunoprecipitation mass spectrometry (IP-MS) to compare the accuracy of eight different plasma tau species in predicting autopsy-confirmed AD. The sample included 123 participants (AD = 69, non-AD = 54) from the Boston University Alzheimer’s disease Research Center who had an available ante-mortem plasma sample and donated their brain. Plasma samples proximate to death were analyzed by targeted IP-MS for six different tryptic phosphorylated (p-tau-181, 199, 202, 205, 217, 231), and two non-phosphorylated tau (195–205, 212–221) peptides. NIA-Reagan Institute criteria were used for the neuropathological diagnosis of AD. Binary logistic regressions tested the association between each plasma peptide and autopsy-confirmed AD status. Area under the receiver operating curve (AUC) statistics were generated using predicted probabilities from the logistic regression models. Odds Ratio (OR) was used to study associations between the different plasma tau species and CERAD and Braak classifications. All tau species were increased in AD compared to non-AD, but p-tau217, p-tau205 and p-tau231 showed the highest fold-changes. Plasma p-tau217 (AUC = 89.8), p-tau231 (AUC = 83.4), and p-tau205 (AUC = 81.3) all had excellent accuracy in discriminating AD from non-AD brain donors, even among those with CDR < 1). Furthermore, p-tau217, p-tau205 and p-tau231 showed the highest ORs with both CERAD (ORp-tau217 = 15.29, ORp-tau205 = 5.05 and ORp-tau231 = 3.86) and Braak staging (ORp-tau217 = 14.29, ORp-tau205 = 5.27 and ORp-tau231 = 4.02) but presented increased levels at different amyloid and tau stages determined by neuropathological examination. Our findings support plasma p-tau217 as the most promising p-tau species for detecting AD brain pathology. Plasma p-tau231 and p-tau205 may additionally function as markers for different stages of the disease. [ABSTRACT FROM AUTHOR]

Introduction: The exclusion of affected populations from Alzheimer's disease (AD) clinical research limits our understanding of disease heterogeneity and its impact on clinical care. While micro sampling with dried plasma spots (DPS) can promote inclusivity by enabling sample collection in remote areas, current techniques lack the sensitivity required for the quantification of phosphorylated tau at Thr181 (pTau‐181) in DPS extracts. Methods: We developed an assay for pTau‐181 with reduced bead count and improved bead read efficiency (BRE) using a prototype Simoa instrument. This novel assay's performance was evaluated against standard pTau‐181 assays on two Simoa platforms, and DPS extracts were tested for pTau‐181 quantification feasibility. Results: The novel assay quantifies pTau‐181 at concentrations up to 16x lower than traditional pTau‐181 assays on HD‐X and SR‐X platforms. DPS extracts tested with our low‐bead assay were quantified considerably above the lower limit of quantification (LLOQ), indicating the suitability of this assay for future DPS extract measurements. Discussion: Implementing DPS sampling and pTau‐181 quantification could increase participation from underrepresented groups in AD research. However, additional assay optimization and an in‐depth study of preanalytical sample stability are essential for the transition to clinical applicability. [ABSTRACT FROM AUTHOR]

The relation between cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) and magnetic resonance imaging (MRI) measures is poorly understood in cognitively healthy individuals from the general population. Participants' (n = 226) mean age was 70.9 years (SD = 0.4). CSF concentrations of amyloid beta (Aβ)1‐42, total tau (t‐tau), phosphorylated tau (p‐tau), neurogranin, and neurofilament light, and volumes of hippocampus, amygdala, total basal forebrain (TBF), and cortical thickness were measured. Linear associations between CSF biomarkers and MRI measures were investigated. In Aβ1‐42 positives, higher t‐tau and p‐tau were associated with smaller hippocampus (P = 0.001 and P = 0.003) and amygdala (P = 0.005 and P = 0.01). In Aβ1‐42 negatives, higher t‐tau, p‐tau, and neurogranin were associated with larger TBF volume (P = 0.001, P = 0.001, and P = 0.01). No associations were observed between the CSF biomarkers and an AD signature score of cortical thickness. AD‐specific biomarkers in cognitively healthy 70‐year‐olds may be related to TBF, hippocampus, and amygdala. Lack of association with cortical thickness might be due to early stage of disease. [ABSTRACT FROM AUTHOR]

IntroductionAlzheimer’s disease (AD), the most common neurodegenerative disease, is characterized by accumulated amyloid-β (Aβ) plaques, aggregated phosphorylated tau protein, gliosis-associated neuroinflammation, synaptic dysfunction, and cognitive impairment. Many cohort studies indicate that tooth loss is a risk factor for AD. The detailed mechanisms underlying the association between AD and tooth loss, however, are not yet fully understood.MethodsWe explored the involvement of early tooth loss in the neuropathogenesis of the adult AppNL-G-F mouse AD model. The maxillary molars were extracted bilaterally in 1-month-old male mice soon after tooth eruption.ResultsPlasma corticosterone levels were increased and spatial learning memory was impaired in these mice at 6 months of age. The cerebral cortex and hippocampus of AD mice with extracted teeth showed an increased accumulation of Aβ plaques and phosphorylated tau proteins, and increased secretion of the proinflammatory cytokines, including interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α), accompanied by an increased number of microglia and astrocytes, and decreased synaptophysin expression. AD mice with extracted teeth also had a shorter lifespan than the control mice.DiscussionThese findings revealed that long-term tooth loss is a chronic stressor, activating the recruitment of microglia and astrocytes; exacerbating neuroinflammation, Aβ deposition, phosphorylated tau accumulation, and synaptic dysfunction; and leading to spatial learning and memory impairments in AD model mice.

Abstract Introduction The exclusion of affected populations from Alzheimer's disease (AD) clinical research limits our understanding of disease heterogeneity and its impact on clinical care. While micro sampling with dried plasma spots (DPS) can promote inclusivity by enabling sample collection in remote areas, current techniques lack the sensitivity required for the quantification of phosphorylated tau at Thr181 (pTau‐181) in DPS extracts. Methods We developed an assay for pTau‐181 with reduced bead count and improved bead read efficiency (BRE) using a prototype Simoa instrument. This novel assay's performance was evaluated against standard pTau‐181 assays on two Simoa platforms, and DPS extracts were tested for pTau‐181 quantification feasibility. Results The novel assay quantifies pTau‐181 at concentrations up to 16x lower than traditional pTau‐181 assays on HD‐X and SR‐X platforms. DPS extracts tested with our low‐bead assay were quantified considerably above the lower limit of quantification (LLOQ), indicating the suitability of this assay for future DPS extract measurements. Discussion Implementing DPS sampling and pTau‐181 quantification could increase participation from underrepresented groups in AD research. However, additional assay optimization and an in‐depth study of preanalytical sample stability are essential for the transition to clinical applicability.

Glaucoma, a group of diseases characterized by progressive optic nerve degeneration that results in irreversible blindness, can be considered a neurodegenerative disorder of both the eye and the brain. Increasing evidence from human and animal studies have shown that glaucoma shares some common neurodegenerative pathways with Alzheimer's disease (AD) and other tauopathies, such as chronic traumatic encephalopathy (CTE) and frontotemporal dementia. This hypothesis is based on the focal adhesion pathway hypothesis and the spreading hypothesis of tau. Not only has the Apolipoprotein E (APOE) gene been shown to be associated with AD, but also with primary open angle glaucoma (POAG). This review will highlight the relevant literature in the past 20 years from PubMed that show the pathogenic overlap between POAG and AD. Neurodegenerative pathways that contribute to transsynaptic neurodegeneration in AD and other tauopathies might also be similar to those in glaucomatous neurodegeneration.

Although type 2 diabetes is a well-known risk factor for Alzheimer's disease (AD), little is known about how its precursor-prediabetes-impacts neuropsychological function and brain health. Thus, we examined the relationship between prediabetes and AD-related biological and cognitive/clinical markers in a well-characterized sample drawn from the Alzheimer's Disease Neuroimaging Initiative. Additionally, because women show higher rates of AD and generally more atherogenic lipid profiles than men, particularly in the context of diabetes, we examined whether sex moderates any observed associations. The total sample of 911 nondemented and non-diabetic participants [normal control = 540; mild cognitive impairment (MCI) = 371] included 391 prediabetic (fasting blood glucose: 100-125 mg/dL) and 520 normoglycemic individuals (age range: 55-91). Linear mixed effects models, adjusted for demographics and vascular and AD risk factors, examined the independent and interactive effects of prediabetes and sex on 2-6 year trajectories of FDG-PET measured cerebral metabolic glucose rate (CMRglu), hippocampal/intracranial volume ratio (HV/IV), cerebrospinal fluid phosphorylated tau-181/amyloid-β1-42 ratio (p-tau181/Aβ1-42), cognitive function (executive function, language, and episodic memory) and the development of dementia. Analyses were repeated in the MCI subsample. In the total sample, prediabetic status had an adverse effect on CMRglu across time regardless of sex, whereas prediabetes had an adverse effect on executive function across time in women only. Within the MCI subsample, prediabetic status was associated with lower CMRglu and poorer executive function and language performance across time within women, whereas these associations were not seen within men. In the total sample and MCI subsample, prediabetes did not relate to HV/IV, p-tau181/Aβ1-42, memory function or dementia risk regardless of sex; however, among incident dementia cases, prediabetic status related to earlier age of dementia onset in women but not in men. Results suggest that prediabetes may affect cognition through altered brain metabolism, and that women may be more vulnerable to the negative effects of glucose intolerance.

Investigating interindividual variability is a major field of interest in neuroscience. The entorhinal cortex (EC) is essential for memory and affected early in the progression of Alzheimer's disease (AD). We combined histology ground‐truth data with ultrahigh‐resolution 7T ex vivo MRI to analyze EC interindividual variability in 3D. Further, we characterized (1) entorhinal shape as a whole, (2) entorhinal subfield range and midpoints, and (3) subfield architectural location and tau burden derived from 3D probability maps. Our results indicated that EC shape varied but was not related to demographic or disease factors at this preclinical stage. The medial intermediate subfield showed the highest degree of location variability in the probability maps. However, individual subfields did not display the same level of variability across dimensions and outcome measure, each providing a different perspective. For example, the olfactory subfield showed low variability in midpoint location in the superior–inferior dimension but high variability in anterior–posterior, and the subfield entorhinal intermediate showed a large variability in volumetric measures but a low variability in location derived from the 3D probability maps. These findings suggest that interindividual variability within the entorhinal subfields requires a 3D approach incorporating multiple outcome measures. This study provides 3D probability maps of the individual entorhinal subfields and respective tau pathology in the preclinical stage (Braak I and II) of AD. These probability maps illustrate the subfield average and may serve as a checkpoint for future modeling. [ABSTRACT FROM AUTHOR]