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Meditation is becoming increasingly practiced, especially for stress-related medical conditions. Meditation may improve cellular health; however, studies have not separated out effects of meditation from vacation-like effects in a residential randomized controlled trial. We recruited healthy women non-meditators to live at a resort for 6 days and randomized to either meditation retreat or relaxing on-site, with both groups compared with 'regular meditators' already enrolled in the retreat. Blood drawn at baseline and post intervention was assessed for transcriptome-wide expression patterns and aging-related biomarkers. Highly significant gene expression changes were detected across all groups (the 'vacation effect') that could accurately predict (96% accuracy) between baseline and post-intervention states and were characterized by improved regulation of stress response, immune function and amyloid beta (Aβ) metabolism. Although a smaller set of genes was affected, regular meditators showed post-intervention differences in a gene network characterized by lower regulation of protein synthesis and viral genome activity. Changes in well-being were assessed post intervention relative to baseline, as well as 1 and 10 months later. All groups showed equivalently large immediate post-intervention improvements in well-being, but novice meditators showed greater maintenance of lower distress over time compared with those in the vacation arm. Regular meditators showed a trend toward increased telomerase activity compared with randomized women, who showed increased plasma Aβ42/Aβ40 ratios and tumor necrosis factor alpha (TNF-α) levels. This highly controlled residential study showed large salutary changes in gene expression networks due to the vacation effect, common to all groups. For those already trained in the practice of meditation, a retreat appears to provide additional benefits to cellular health beyond the vacation effect.

Airong Li, Rudolph E Tanzi Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USACorrespondence: Airong Li; Rudolph E TanziGenetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114, 16th Street, Charlestown, MA 02129, USATel +617 724 9397; +617 726 6845Fax +617 724 1823Email ali3@mgh.harvard.edu; rtanzi@mgh.harvard.eduAbstract: Optogenetics combines the biological techniques of optics and genetics and uses light to control the activities of living tissues such as neurons and heart. Optogenetic actuators like channelrhodopsin (ChR), halorhodopsin (NpHR), and archaerhodopsin (bacterio-opsin) provide specificity for neuronal or cardiac controls, and the field has made much progress in heart research since its introduction almost a decade ago. This review will provide information about the history, research highlights and clinical applications of optical coherence tomography (OCT) technology. The clinical translation of cardiac optogenetics will be towards human and larger mammalian animal model applications and ultimately optogenetics may have the power to restore normal heart rhythm and greatly improve quality of life.Keywords: optical coherence tomography, channelrhodopsin, halorhodopsin, archaerhodopsin, Drosophila, heart

Mounting evidence suggests that Alzheimer's disease (AD) is caused by the accumulation of the small peptide, amyloid-β (Aβ), a proteolytic cleavage product of amyloid-β protein precursor (AβPP). Aβ is generated through a serial cleavage of AβPP by β- and γ-secretase. Aβ40 and Aβ42 are the two main components of amyloid plaques in AD brains, with Aβ42 being more prone to aggregation. AβPP can also be processed by α-secretase, which cleaves AβPP within the Aβ sequence, thereby preventing the generation of Aβ. Little is currently known regarding the effects of cell density on AβPP processing and Aβ generation. Here we assessed the effects of cell density on AβPP processing in neuronal and non-neuronal cell lines, as well as mouse primary cortical neurons. We found that decreased cell density significantly increases levels of Aβ40, Aβ42, total Aβ, and the ratio of Aβ42: Aβ40. These results also indicate that cell density is a significant modulator of AβPP processing. Overall, these findings carry profound implications for both previous and forthcoming studies aiming to assess the effects of various conditions and genetic/chemical factors, e.g., novel drugs on AβPP processing and Aβ generation in cell-based systems. Moreover, it is interesting to speculate whether cell density changes in vivo may also affect AβPP processing and Aβ levels in the AD brain. [ABSTRACT FROM AUTHOR]

The posteromedial cortices and other regions of the "default network" are particularly vulnerable to the pathology of Alzheimer disease (AD). In this study, we performed functional magnetic resonance imaging (fMRI) to investigate whether the presence of apolipoprotein E (APOE) epsilon allele and degree of memory impairment were associated with the dysfunction of these brain regions. Seventy-five elderly subjects ranging from cognitively normal to mild AD, divided into epsilon carriers and noncarriers, underwent fMRI during a memory-encoding task. Across all subjects, posteromedial and ventral anterior cingulate cortices (key components of the default network) as well as right middle and inferior prefrontal regions demonstrated reduced task-induced deactivation in the epsilon carriers relative to noncarriers. Even among cognitively normal subjects, epsilon carriers demonstrated reduced posteromedial deactivation compared with the noncarriers in the same regions which demonstrated failure of deactivation in AD patients. Greater failure of posteromedial deactivation was related to worse memory performance (delayed recall) across all subjects and within the range of cognitively normal subjects. In summary, the posteromedial cortical fMRI response pattern is modulated both by the presence of APOE epsilon and episodic memory capability. Altered fMRI activity of the posteromedial areas of the brain default network may be an early indicator of risk for AD. [ABSTRACT FROM AUTHOR]

Objective: An estimated 200 million patients worldwide have surgery each year. Anesthesia and surgery have been reported to facilitate emergence of Alzheimer's disease. The commonly used inhalation anesthetic isoflurane has previously been reported to induce apoptosis, and to increase levels and aggregation of Alzheimer's disease-associated amyloid beta-protein (Abeta) in cultured cells. However, the in vivo relevance has not been addressed.Methods: We therefore set out to determine effects of isoflurane on caspase activation and levels of beta-site amyloid precursor protein-cleaving enzyme (BACE) and Abeta in naive mice, using Western blot, immunohistochemistry, and reverse transcriptase polymerase chain reaction.Results: Here we show for the first time that a clinically relevant isoflurane anesthesia (1.4% isoflurane for 2 hours) leads to caspase activation and modest increases in levels of BACE 6 hours after anesthesia in mouse brain. Isoflurane anesthesia induces caspase activation, and increases levels of BACE and Abeta up to 24 hours after anesthesia. Isoflurane may increase BACE levels by reducing BACE degradation. Moreover, the Abeta aggregation inhibitor, clioquinol, was able to attenuate isoflurane-induced caspase-3 activation in vivo.Interpretation: Given that transient insults to brain may lead to long-term brain damage, these findings suggest that isoflurane may promote Alzheimer's disease neuropathogenesis and, as such, have implications for use of isoflurane in humans, pending human study confirmation. [ABSTRACT FROM AUTHOR]

The authors evaluated whether there is an excess of statistically significant results in studies of genetic associations with Alzheimer's disease reflecting either between-study heterogeneity or bias. Among published articles on genetic associations entered into the comprehensive AlzGene database (www.alzgene.org) through January 31, 2007, 1,348 studies included in 175 meta-analyses with 3 or more studies each were analyzed. The number of observed studies (O) with statistically significant results (P = 0.05 threshold) was compared with the expected number (E) under different assumptions for the magnitude of the effect size. In the main analysis, the plausible effect size of each association was the summary effect presented in the respective meta-analysis. Overall, 19 meta-analyses (all with eventually nonsignificant summary effects) had a documented excess of O over E: Typically single studies had significant effects pointing in opposite directions and early summary effects were dissipated over time. Across the whole domain, O was 235 (17.4%), while E was 164.8 (12.2%) (P < 10(-6)). The excess showed a predilection for meta-analyses with nonsignificant summary effects and between-study heterogeneity. The excess was seen for all levels of statistical significance and also for studies with borderline P values (P = 0.05-0.10). The excess of significant findings may represent significance-chasing biases in a setting of massive testing. [ABSTRACT FROM AUTHOR]

Background: Recent analyses suggest that the known Alzheimer's disease genes account for less than half the genetic variance in this disease. The gene encoding ubiquilin 1 (UBQLN1) is one of several candidate genes for Alzheimer's disease located near a well-established linkage peak on chromosome 9q22.Methods: We evaluated 19 single-nucleotide polymorphisms in three genes within the chromosome 9q linkage region in 437 multiplex families with Alzheimer's disease from the National Institute of Mental Health (NIMH) sample (1439 subjects). We then tested the single-nucleotide polymorphisms showing a positive result in an independently identified set of 217 sibships discordant for Alzheimer's disease (Consortium on Alzheimer's Genetics [CAG] sample; 489 subjects) and assessed the functional effect of an implicated single-nucleotide polymorphism in brain tissue from 25 patients with Alzheimer's disease and 17 controls.Results: In the NIMH sample, we observed a significant association between Alzheimer's disease and various single-nucleotide polymorphisms in UBQLN1. We confirmed these associations in the CAG sample. The risk-conferring haplotype in both samples was defined by a single intronic single-nucleotide polymorphism located downstream of exon 8. The risk allele was associated with a dose-dependent increase in an alternatively spliced UBQLN1 (lacking exon 8) transcript in RNA extracted from brain samples of patients with Alzheimer's disease.Conclusions: Our findings suggest that genetic variants in UBQLN1 on chromosome 9q22 substantially increase the risk of Alzheimer's disease, possibly by influencing alternative splicing of this gene in the brain. [ABSTRACT FROM AUTHOR]

The blood-brain barrier (BBB) serves as a selective filter that prevents harmful substances from entering the healthy brain. Dysfunction of this barrier is implicated in several neurological diseases. In the context of Alzheimer's disease (AD), BBB breakdown plays a significant role in both the initiation and progression of the disease. This study introduces a three-dimensional (3D) self-assembled in vitro model of the human neurovascular unit to recapitulate some of the complex interactions between the BBB and AD pathologies. It incorporates primary human brain endothelial cells, pericytes and astrocytes, and stem cell-derived neurons and astrocytes harboring Familial AD (FAD) mutations. Over an extended co-culture period, the model demonstrates increased BBB permeability, dysregulation of key endothelial and pericyte markers, and morphological alterations mirroring AD pathologies. The model enables visualization of amyloid-beta (Aβ) accumulation in both neuronal and vascular compartments. This model may serve as a versatile tool for neuroscience research and drug development to provide insights into the dynamic relationship between vascular dysfunction and AD pathogenesis., Competing Interests: Declaration of competing interest R.D.K. is a co-founder of AIM Biotech, a company that markets microfluidic technologies and receives research support from Amgen, Abbvie, Boehringer-Ingelheim, Daiichi-Sankyo, Novartis, Roche, Takeda, Eisai, EMD Serono, and Visterra., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The adenosine triphosphate-binding cassette transporter A7 (ABCA7) gene is ranked as one of the top susceptibility loci for Alzheimer's disease (AD). While ABCA7 mediates lipid transport across cellular membranes, ABCA7 loss of function has been shown to exacerbate amyloid-β (Aβ) pathology and compromise microglial function. Our family-based study uncovered an extremely rare ABCA7 p.A696S variant that was substantially segregated with the development of AD in 3 African American families. Using the knockin mouse model, we investigated the effects of ABCA7-A696S substitution on amyloid pathology and brain immune response in 5xFAD transgenic mice. Importantly, our study demonstrated that ABCA7-A696S substitution reduces amyloid plaque-associated microgliosis and increases dystrophic neurites around amyloid deposits compared to control mice. We also found increased X-34-positive amyloid plaque burden in 5xFAD mice with ABCA7-A696S substitution, while there was no evident difference in insoluble Aβ levels between mouse groups. Thus, ABCA7-A696S substitution may disrupt amyloid compaction resulting in aggravated neuritic dystrophy due to insufficient microglia barrier function. In addition, we observed that ABCA7-A696S substitution disturbs the induction of proinflammatory cytokines interleukin 1β and interferon γ in the brains of 5xFAD mice, although some disease-associated microglia gene expression, including Trem2 and Tyrobp, are upregulated. Lipidomics also detected higher total lysophosphatidylethanolamine levels in the brains of 5xFAD mice with ABCA7-A696S substitution than controls. These results suggest that ABCA7-A696S substitution might compromise the adequate innate immune response to amyloid pathology in AD by modulating brain lipid metabolism, providing novel insight into the pathogenic mechanisms mediated by ABCA7. ONE SENTENCE SUMMARY: A rare Alzheimer's disease risk ABCA7 p.A696S variant compromises microglial response to amyloid pathology., Competing Interests: Declaration of competing interest T.K. serves on scientific advisory boards for Path Biotech LLC. and has consulted for Ono Pharma Inc. G.B. serves as a consultant for SciNeuro Pharmaceuticals and Kisbee Therapeutics. Other authors declare no competing interests., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Alzheimer's disease (AD) is the most prevalent form of dementia. While many AD-associated genetic determinants have been identified, few studies have analyzed individuals of non-European ancestry., Methods: We conducted a multi-ancestry genome-wide association study (GWAS) of clinically diagnosed AD and AD-by-proxy using whole genome sequencing data from the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS), National Institute of Mental Health, UK Biobank (UKB), and All of Us (AoU) consisting of 49,149 cases (12,074 clinically diagnosed and 37,075 AD-by-proxy) and 383,225 controls. Nearly half of NIAGADS and AoU participants were of non-European ancestry., Results: For clinically diagnosed AD, we identified 14 new loci-five common (FBN2/SCL27A6, AC090115.1, DYM, KCNG1/AL121785.1, TIAM1) and nine rare (VWA5B1, RNU6-755P/LMX1A, MOB1A, MORC1-AS1, LINC00989, PDE4D, RNU2-49P/CDO1, NEO1, and SLC35G3/AC022916.1). Meta-analysis of UKB and AoU AD-by-proxy cases yielded two new rare loci (RPL23/LASP1 and CEBPA/AC008738.6), also nominally significant in NIAGADS., Discussion: In summary, we provide evidence for 16 novel AD loci and advocate for more studies using whole genome sequencing-based GWAS of diverse cohorts., Highlights: We used whole-genome sequencing data from large and diverse cohorts. We found novel genome-wide association study findings based on whole-genome data. We performed a multiancestry meta-analysis and incorporated results from underrepresented groups., (© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Alzheimer's disease (AD) presents a complex pathological landscape, posing challenges to current therapeutic strategies that primarily target amyloid-β (Aβ). Using a novel integrative pathway activity analysis (IPAA), we identified 83 dysregulated pathways common between both post-mortem AD brains and three-dimensional AD cellular models showing robust Aβ42 accumulation. p38 mitogen-activated protein kinase (MAPK) was the most upregulated common pathway. Active p38 MAPK levels increased in the cellular models, human brains, and 5XFAD mice and selectively localized to presynaptic dystrophic neurites. Unbiased phosphoproteomics confirmed increased phosphorylation of p38 MAPK substrates. Downstream activation of MAPK-activated protein kinase 2 (MK2) plays a crucial role in Aβ42-p38 MAPK-mediated tau pathology. Therapeutic targeting of the p38 MAPK-MK2 axis with selective inhibitors significantly reduced Aβ42-driven tau pathology and neuronal loss. IPAA prioritizes the best models to derisk target-drug discovery by integrating human tissue gene expression with functional readouts from cellular models, enabling the identification and validation of high-confidence AD therapeutic targets., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is the most common form of dementia in elderly, affecting 6.9 million individuals in the United States. Some studies have suggested the prevalence of AD is greater in individuals who self-identify as Hispanic. Focused results are relevant for personalized and equitable clinical interventions. Ethnicity as a stratifying tool in genetic studies is often accompanied by genomic inflation due to heterogeneity. In this study, we report GWAS and meta-analyses conducted among NIAGADS subjects who self-identified as Hispanic and All of Us (AoU) sub-cohorts matched to that cohort, using projected genetically-derived principal components, with and without age and sex. In Hispanic NIAGADS subjects, we identified a common variant in PIEZO2 that was protective for AD with a p-value just beyond genome-wide significance (p = 5.4 * 10 -8 ). Meta-analyses with genetically-matched AoU participants yielded three (two novel) genome-wide significant AD-associated loci based on rare lead variants: rs374043832 ( RGS6/PSEN1 ), rs192423465 ( ASPSCR1 ), and rs935208076 ( GDAP2 ), which were also nominally significant in AoU sub-cohorts. We also show how genomic inflation can be mitigated in heterogeneous populations while increasing sample size and result generalizability.

Background: A significant proportion of individuals maintain healthy cognitive function despite having extensive Alzheimer's disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals can identify therapeutic targets for AD dementia. This study aims to define molecular and cellular signatures of cognitive resilience, protection and resistance, by integrating genetics, bulk RNA, and single-nucleus RNA sequencing data across multiple brain regions from AD, resilient, and control individuals., Methods: We analyzed data from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP), including bulk (n=631) and multi-regional single nucleus (n=48) RNA sequencing. Subjects were categorized into AD, resilient, and control based on β-amyloid and tau pathology, and cognitive status. We identified and prioritized protected cell populations using whole genome sequencing-derived genetic variants, transcriptomic profiling, and cellular composition distribution., Results: Transcriptomic results, supported by GWAS-derived polygenic risk scores, place cognitive resilience as an intermediate state in the AD continuum. Tissue-level analysis revealed 43 genes enriched in nucleic acid metabolism and signaling that were differentially expressed between AD and resilience. Only GFAP (upregulated) and KLF4 (downregulated) showed differential expression in resilience compared to controls. Cellular resilience involved reorganization of protein folding and degradation pathways, with downregulation of Hsp90 and selective upregulation of Hsp40, Hsp70, and Hsp110 families in excitatory neurons. Excitatory neuronal subpopulations in the entorhinal cortex (ATP8B1+ and MEF2C high ) exhibited unique resilience signaling through neurotrophin (modulated by LINGO1) and angiopoietin (ANGPT2/TEK) pathways. We identified MEF2C, ATP8B1, and RELN as key markers of resilient excitatory neuronal populations, characterized by selective vulnerability in AD. Protective rare variant enrichment highlighted vulnerable populations, including somatostatin (SST) inhibitory interneurons, validated through immunofluorescence showing co-expression of rare variant associated RBFOX1 and KIF26B in SST+ neurons in the dorsolateral prefrontal cortex. The maintenance of excitatory-inhibitory balance emerges as a key characteristic of resilience., Conclusions: We identified molecular and cellular hallmarks of cognitive resilience, an intermediate state in the AD continuum. Resilience mechanisms include preservation of neuronal function, maintenance of excitatory/inhibitory balance, and activation of protective signaling pathways. Specific excitatory neuronal populations appear to play a central role in mediating cognitive resilience, while a subset of vulnerable SST interneurons likely provide compensation against AD-associated dysregulation. This study offers a framework to leverage natural protective mechanisms to mitigate neurodegeneration and preserve cognition in AD., Competing Interests: Competing interests Authors declare that they have no competing interests.

Introduction: Age-associated depletion in nicotinamide adenine dinucleotide (NAD+) concentrations has been implicated in metabolic, cardiovascular, and neurodegenerative disorders. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), offers a potential therapeutic avenue against neurodegenerative pathologies in aging, Alzheimer's disease, and related dementias. A crossover, double-blind, randomized placebo (PBO) controlled trial was conducted to test the safety and efficacy of 8 weeks' active treatment with NR (1 g/day) on cognition and plasma AD biomarkers in older adults with subjective cognitive decline and mild cognitive impairment., Methods: The primary efficacy outcome was the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Secondary outcomes included plasma phosphorylated tau 217 (pTau 217 ), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Exploratory outcomes included Lumosity gameplay ( z -scores) for cognition and step counts from wearables. Mixed model for repeated measures was used for between-group comparisons; paired t -tests were used for within-individual comparisons., Results: Forty-six participants aged over 55 were randomized to NR-PBO or PBO-NR groups; 41 completed baseline visits, and 37 completed the trial. NR supplementation was safe and well tolerated with no differences in adverse events reported between NR and PBO treatment phases. For the between-group comparison, there was a 7% reduction in pTau 217 concentrations after taking NR, while an 18% increase with PBO ( p = 0.02). No significant between-group differences were observed for RBANS, other plasma biomarkers(GFAP and NfL), Lumosity gameplay scores or step counts. For the within-individual comparison, pTau 217 concentrations significantly decreased during the NR phase compared to the PBO ( p = 0.02), while step counts significantly increased during the NR phase than PBO ( p = 0.04)., Discussion: Eight weeks NR supplementation is safe and lowered pTau 217 concentrations but did not alter cognition as measured by conventional or novel digital assessments. Further research is warranted to validate NR's efficacy in altering pathological brain aging processes., Highlights: The integrated study design combines a two-arm parallel trial with a crossover phase, offering the opportunity to enhance sample size for within-individual analysis and assess carryover effects.NR is safe but did not alter cognition as measured by multi-modal assessments in SCD/MCI.For between-group comparison, pTau 217 levels decreased with NR and increased with PBO at 8-week follow-up.For within-individual comparison, step counts increased after NR and decreased after PBO.A larger, longer study with pharmacodynamic and pathophysiological biomarkers is needed to assess NR's disease-modifying effects., Competing Interests: C.Y.W., A.K., L.C., A.J.M., P.K., J.A.G., N.S., L.A.D., V.J.W., J.G., M.R., C.Y., E.G.V., H.H.D., and C.M.S. have no declarations of interest directly related to the contents of the work presented herein. S.E.A. has no declarations of conflict of interest directly related to the work presented here, but has consulted and/or served on advisory boards for Allyx Therapeutics, BioVie, Bob's Last Marathon, Daewoong Pharmaceuticals, Foster & Eldridge, LLP, Quince Therapeutics, Sage Therapeutics, and Vandria; received sponsored research grant support via his institution from the following commercial entities: AbbVie, Amylyx, Athira Pharma, Cyclerion Therapeutics, EIP Pharma, Ionis Pharmaceuticals, Janssen Pharmaceuticals, Inc., Novartis AG, Seer Biosciences, Inc. and vTv Therapeutics, Inc; and has received sponsored research grant support via his institution from the following non‐commercial entities: Alzheimer's Association, Alzheimer's Drug Discovery Foundation, Challenger Foundation, Cure Alzheimer's Fund, John Sperling Foundation, the National Institutes of Health and the Prion Alliance. R.E.T. is a paid consultant for, and holds equity in Chromadex, Inc and was not involved with the execution of the trial. Author disclosures are available in the supporting information., (© 2025 The Author(s). Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

A method to quantitate the stabilization of Mitochondria-Associated endoplasmic reticulum Membranes (MAMs) in a 3-dimensional (3D) neural model of Alzheimer's disease (AD) is presented here. To begin, fresh human neuro progenitor ReN cells expressing β-amyloid precursor protein (APP) containing familial Alzheimer's disease (FAD) or naïve ReN cells are grown in thin (1:100) Matrigel-coated tissue culture plates. After the cells reach confluency, these are electroporated with expression plasmids encoding red fluorescence protein (RFP)-conjugated mitochondria-binding sequence of AKAP1(34-63) (Mito-RFP) that detects mitochondria or constitutive MAM stabilizers MAM 1X or MAM 9X that stabilize tight (6 nm ± 1 nm gap width) or loose (24 nm ± 3 nm gap width) MAMs, respectively. After 16-24 h, the cells are harvested and enriched by a fluorescence-activated cell sorter (FACS). An equal number of FACS-enriched cells are seeded in the 3-dimensional matrix (1:1 Matrigel) and allowed to differentiate into mature neurons for 10 days. Live cell images of the 10-day differentiated cells expressing the RFP-conjugated MAM stabilizers are captured under a fluorescent microscope equipped with a live-cell imaging culture chamber maintaining the CO2 (5%), temperature (37 °C), and humidity (~90%). Toward this end, we performed live-cell imaging and kymographic analyses to measure the motility of free mitochondria labeled with Mito-RFP or ER-bound mitochondria of tight or loose gap widths stabilized by MAM 1X or MAM 9X, respectively, in the most extended neuronal process of each ReN GA neuron which is at least 500 nm long, considering these as axons.

The prediction of the susceptibility of an individual to a certain disease is an important and timely research area. An established technique is to estimate the risk of an individual with the help of an integrated risk model, that is, a polygenic risk score with added epidemiological covariates. However, integrated risk models do not capture any time dependence, and may provide a point estimate of the relative risk with respect to a reference population. The aim of this work is twofold. First, we explore and advocate the idea of predicting the time-dependent hazard and survival (defined as disease-free time) of an individual for the onset of a disease. This provides a practitioner with a much more differentiated view of absolute survival as a function of time. Second, to compute the time-dependent risk of an individual, we use published methodology to fit a Cox's proportional hazard model to data from a genetic SNP study of time to Alzheimer's disease (AD) onset, using the lasso to incorporate further epidemiological variables such as sex, APOE (apolipoprotein E, a genetic risk factor for AD) status, 10 leading principal components, and selected genomic loci. We apply the lasso for Cox's proportional hazards to a data set of 6792 AD patients (composed of 4102 cases and 2690 controls) and 87 covariates. We demonstrate that fitting a lasso model for Cox's proportional hazards allows one to obtain more accurate survival curves than with state-of-the-art (likelihood-based) methods. Moreover, the methodology allows one to obtain personalized survival curves for a patient, thus giving a much more differentiated view of the expected progression of a disease than the view offered by integrated risk models. The runtime to compute personalized survival curves is under a minute for the entire data set of AD patients, thus enabling it to handle datasets with 60,000-100,000 subjects in less than 1 h., (© 2024 Wiley Periodicals LLC.)

Irisin is a myokine that is generated by cleavage of the membrane protein fibronectin type III domain-containing protein 5 (FNDC5) in response to physical exercise. Studies reveal that irisin/FNDC5 has neuroprotective functions against Alzheimer's disease, the most common form of dementia in the elderly, by improving cognitive function and reducing amyloid-β and tau pathologies as well as neuroinflammation in cell culture or animal models of Alzheimer's disease. Although current and ongoing studies on irisin/FNDC5 show promising results, further mechanistic studies are required to clarify its potential as a meaningful therapeutic target for alleviating Alzheimer's disease. We recently found that irisin treatment reduces amyloid-β pathology by increasing the activity/levels of amyloid-β-degrading enzyme neprilysin secreted from astrocytes. Herein, we present an overview of irisin/FNDC5's protective roles and mechanisms against Alzheimer's disease., (Copyright © 2025 Copyright: © 2025 Neural Regeneration Research.)

Mast cells, which constitute tissue-resident immune cells, are distributed in the dural meninges. Here, we provide procedural guidelines for investigating mouse dural mast cells using two techniques. First, we outline the procedures for dural tissue dissection, single-cell isolation, and subsequent surface staining for mast cell identification via flow cytometry. We then describe the techniques employed for whole dura tissue staining to visualize mast cells using confocal and slide scanning microscopy, followed by analysis using Nikon's NIS-Elements Advanced Research software. For complete details on the use and execution of this protocol, please refer to Lin et al. 1 ., Competing Interests: Declaration of interests R.E.T. is an inventor on patents involving the use of the mast cell stabilizer, cromolyn and its analogs, for treatment of COVID (US20230149345A1), cytokine release syndrome (US20220218652A1), and inflammation in neurodegenerative disease (US-11679095-B2 and US-20220079914-A1). R.E.T. also holds equity in AZTherapies, which is developing mast cell stabilizers., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Peripheral immune cells play an important role in the pathology of Alzheimer's disease (AD), impacting processes such as amyloid and tau protein aggregation, glial activation, neuronal integrity, and cognitive decline. Here, we examine cutting-edge strategies - encompassing animal and cellular models - used to investigate the roles of peripheral immune cells in AD. Approaches such as antibody-mediated depletion, genetic ablation, and bone marrow chimeras in mouse models have been instrumental in uncovering T, B, and innate immune cell disease-modifying functions. However, challenges such as specificity, off-target effects, and differences between human and mouse immune systems underscore the need for more human-relevant models. Emerging multicellular models replicating critical aspects of human brain tissue and neuroimmune interactions increasingly offer fresh insights into the role of immune cells in AD pathogenesis. Refining these methodologies can deepen our understanding of immune cell contributions to AD and support the development of novel immune-related therapeutic interventions., Competing Interests: Declaration of interests The authors have no interests to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Alzheimer's disease (AD) is the most common form of dementia in the elderly. Given that AD neuropathology begins decades before symptoms, there is a dire need for effective screening tools for early detection of AD to facilitate early intervention., Methods: Here, we used tree-based and deep learning methods to train polyomic prediction models for AD affection status and age at onset, employing genomic, proteomic, metabolomic, and drug use data from UK Biobank. We used SHAP to determine the feature's importance., Results: Our best-performing polyomic model achieved an area under the receiver operating characteristics curve (AUROC) of 0.87. We identified GFAP and CXCL17 proteins to be the strongest predictors of AD, besides apolipoprotein E (APOE) alleles. Increasing the number of cases by including "AD-by-proxy" cases did not improve AD prediction., Discussion: Among the four modalities, genomics, and proteomics were the most informative modality based on AUROC (area under the receiver operating characteristic curve). Our data suggest that two blood-based biomarkers (glial fibrillary acidic protein [GFAP] and CXCL17) may be effective for early presymptomatic prediction of AD., Highlights: We developed a polyomic model to predict AD and age-at-onset using omics and medication use data from EHR. We identified GFAP and CXCL17 proteins to be the strongest predictors of AD, besides APOE alleles. "AD-by-proxy" cases, if used in training, do not improve AD prediction. Proteomics was the most informative modality overall for affection status and AAO prediction., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background and Objectives: The 21-point Brain Care Score (BCS) is an index that ranks behaviors and clinical measurements with the aim of encouraging lifestyle adjustments to lower the incidence of age-related brain disease, including stroke, late-life depression (LLD), and dementia. A higher BCS at baseline is associated with a lower risk of these outcomes. We aimed to investigate whether the associations between BCS and stroke, LLD, and dementia risks are independent of genetic predisposition for these conditions and quantify the effect of healthy lifestyle across genetic risk distributions for these outcomes., Methods: Using the UK Biobank (UKB) prospective cohort study, we computed baseline BCSs and polygenic scores to estimate genetic predisposition for stroke and LLD and APOE ε allele status to stratify dementia risk. As for outcomes again in UKB, we measured incidence of stroke, LLD, and dementia. We used multivariate Cox proportional hazard models to assess associations between BCS, genetic predisposition, and these outcomes. We also conducted stratified and interaction analyses to estimate the incidence of these outcomes across quartiles of genetic risk and BCS., Results: We included 368,340 UKB participants (median age 58 years (interquartile range 51-63 years), 46.3% male). Independent of genetic risk, a 5-point increase in BCS corresponded to lowered hazards of stroke (hazard ratio [HR] 0.70, 95% CI 0.68-0.73), LLD (HR 0.65, 95% CI 0.63-0.67), and dementia (HR 0.82, 95% CI 0.78-0.85). Incidences of all 3 outcomes were higher among participants with high genetic risk of these outcomes. However, these increased risks were offset for individuals with a higher BCS (incidence rates per 1,000 person-years were 2.76 vs 1.19 for stroke, 7.34 vs 4.46 for LLD, and 3.64 vs 2.05 for dementia, when comparing low and high BCS)., Discussion: Across different genetic predispositions for stroke, LLD, and dementia, healthier lifestyle behaviors are protective for brain health, demonstrating the nondeterminism of genetic risk. Furthermore, differences in BCS behave as aggregate risk estimators of all 3 outcomes. Further work is needed to prospectively investigate the utility and performance of the BCS as a targeted intervention in populations at elevated genetic risk of age-related brain disease.

Aims: Although the genetic locus of X-linked dystonia parkinsonism (XDP), a neurodegenerative disease endemic in the Philippines, is well-characterized, the exact mechanisms leading to neuronal loss are not yet fully understood. Recently, we demonstrated an increase in myeloperoxidase (MPO) levels in XDP postmortem prefrontal cortex (PFC), suggesting a role for inflammation in XDP pathogenesis. Therefore, we hypothesized that inhibiting MPO could provide a therapeutic strategy for XDP., Methods: MPO activity was measured by using an MPO-activatable fluorescent agent (MAFA) in human postmortem PFC. Reactive oxygen species (ROS) and MPO activity were measured in XDP-derived fibroblasts and SH-SY5Y cells following MPO inhibition., Results: MPO activity was significantly increased in XDP PFC. Additionally, treatment of cell lines with postmortem XDP PFC resulted in a significant increase in ROS levels. To determine whether increases in MPO activity caused increases in ROS, MPO content was immunodepleted from XDP PFC, which resulted in a significant decrease in ROS in SH-SY5Y cells. Consistently, the treatment with verdiperstat, a potent and selective MPO inhibitor, significantly decreased ROS in both XDP-derived fibroblasts and XDP PFC-treated SH-SY5Y cells., Conclusions: Collectively, our results suggest that MPO inhibition mitigates oxidative stress and may provide a novel therapeutic strategy for XDP treatment., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

The tauopathies are defined by pathological tau protein aggregates within a spectrum of clinically heterogeneous neurodegenerative diseases. The primary tauopathies meet the definition of rare diseases in the United States. There is no approved treatment for primary tauopathies. In this context, designing the most efficient development programs to translate promising targets and treatments from preclinical studies to early-phase clinical trials is vital. In September 2022, the Rainwater Charitable Foundation convened an international expert workshop focused on the translation of tauopathy therapeutics through early-phase trials. Our report on the workshop recommends a framework for principled drug development and a companion lexicon to facilitate communication focusing on reproducibility and achieving common elements. Topics include the selection of targets, drugs, biomarkers, participants, and study designs. The maturation of pharmacodynamic biomarkers to demonstrate target engagement and surrogate disease biomarkers is a crucial unmet need. HIGHLIGHTS: Experts provided a framework to translate therapeutics (discovery to clinical trials). Experts focused on the "5 Rights" (target, drug, biomarker, participants, trial). Current research on frontotemporal degeneration, progressive supranuclear palsy, and corticobasal syndrome therapeutics includes 32 trials (37% on biologics) Tau therapeutics are being tested in Alzheimer's disease; primary tauopathies have a large unmet need., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Chronic pain is a debilitating medical condition that lacks effective treatments. Increasing evidence suggests that microglia and neuroinflammation underlie pain pathophysiology, which therefore supports a potential strategy for developing pain therapeutics. Here, our study is testing the hypothesis that the promise of pain amelioration can be achieved using the small-molecule pexidartinib (PLX-3397), a previously food and drug administration (FDA)-approved cancer medicine and a colony-stimulating factor-1 receptor (CSF-1R) inhibitor that display microglia-depleting properties., Method: We used the previously reported chronic constriction injury (CCI) mouse model, in which PLX-3397 or vehicle was orally administrated to mice daily for 21 days, then applied to the CCI model, followed by PLX-3397 or vehicle administration for an additional 28 days. Additionally, we examined microglia-related neuroinflammation markers using positron emission tomography (PET) neuroimaging and immunofluorescence (IF)., Results: We showed that PLX-3397 significantly ameliorated pain-related behavioral changes throughout the entire experimental period after CCI (vehicle versus PLX-3397 at day 14, effect size: 2.57, P = .002). Microglia changes were first analyzed by live-animal PET neuroimaging, revealing PLX-3397-associated reduction of microglia by probing receptor-interacting serine/threonine-protein kinase 1 (RIPK1), a protein primarily expressed in microglia, which were further corroborated by postmortem immunohistochemistry (IHC) analysis using antibodies for microglia, including ionized Ca2+ binding adaptor molecule 1 (Iba-1) (somatosensory cortex, hindlimb area; vehicle versus PLX-3397, effect size 3.6, P = .011) and RIPK1 (somatosensory cortex, hindlimb area; vehicle versus PLX-3397, effect size 2.9, P = .023. The expression of both markers decreased in the PLX-3397 group. Furthermore, we found that PLX-3397 led to significant reductions in various proteins, including inducible nitric oxide synthase (iNOS) (somatosensory cortex, hindlimb area; vehicle versus PLX-3397, effect size: 2.3, P = .048), involved in neuroinflammation through IHC., Conclusions: Collectively, our study showed PLX-3397-related efficacy in ameliorating pain linked to the reduction of microglia and neuroinflammation in mice. Furthermore, our research provided new proof-of-concept data supporting the promise of testing PLX-3397 as an analgesic., Competing Interests: Conflicts of Interest, Funding: Please see DISCLOSURES at the end of this article., (Copyright © 2024 International Anesthesia Research Society.)