Exposure to repetitive head impacts (RHI) is associated with increased risk for chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy, and other neuropathological changes. Biological drivers of RHI-related neurodegeneration are not well understood. We interrogated the plasma proteome in aging adults with prior RHI compared to healthy controls (CTL) and individuals with Alzheimer’s disease

Edward H. Koo, MD, left us on April 22, 2025. At the age of 70, he was gone too soon, but he lived a full life and left a lasting legacy: He was a devoted husband to his wife Nancy, a loving father to his son Jeremy and daughter Allison (both followed his path to Amherst College), an accomplished scientist, and a celebrated mentor. To many of us, he was an extraordinary human being, a wonderful colleague

Myelin is a multilamellar membrane that surrounds axons in the vertebrate nervous system. Properly functioning myelin is essential for the rapid conduction of nerve impulses, and it metabolically supports axonal integrity. Emerging evidence indicates that myelin is also involved in various aspects of cognition, with adaptive myelination playing a critical role in memory consolidation and motor learning

Extracellular vesicles (EVs) are membrane-enclosed nanoparticles released by most cell types, and from multiple sub-cellular compartments. They carry a range of cargo biomolecules, including protein and RNA that reflect the type and status of their cell of origin. EVs are associated with the 43 kDa trans-active response DNA binding protein (TDP-43), aggregates of which are a key pathological feature

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by macroscopic features such as cortical atrophy, narrowing of the gyri, widening of the sulci, and enlargement of the ventricles. At the cellular level, the pathological characteristics include the extracellular aggregation of β-amyloid (Aβ) forming senile plaques, and the intracellular accumulation of hyperphosphorylated tau proteins

Alzheimer’s disease (AD) is a complex neurodegenerative disorder that is characterized by the accumulation of pathologic tau and beta-amyloid proteins. UFMylation is an emerging ubiquitin-like post-translational modification that is crucial for healthy brain development. The UFM1 cascade was recently identified as a major modifier of tau aggregation in vitro and in vivo. Moreover, post-mortem AD brain

Alzheimer’s disease (AD) is characterized by amyloid plaques, neurofibrillary tangles, and synaptic and neuronal loss. Recently, a rare autosomal dominant coding mutation, T835M, in the Un-coordinated 5c (UNC5C) netrin receptor gene was segregated with late-onset AD (LOAD). Overexpression of T835M in primary hippocampal neurons increased cell death in response to neurotoxic stimuli including beta-amyloid

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative disorders with overlapping clinical, genetic and pathological features. A large body of evidence highlights the critical role of RNA-binding proteins (RBPs) – in particular TAR DNA-binding protein 43 (TDP-43) and Fused in sarcoma (FUS) – in the pathogenesis of these diseases. These RBPs normally

Polymorphisms in the gene encoding CD2-associated protein (CD2AP) are associated with an increased risk for developing Alzheimer’s disease (AD). Intriguingly, variants in the gene also cause a pattern of kidney injury termed focal segmental glomerulosclerosis. Recent studies have investigated the cell types and mechanisms by which CD2AP gene dosage contributes to the key pathological features of AD

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β plaques, tau hyperphosphorylation, and neuroinflammation. The choroid plexus (ChP), serving as the blood-cerebrospinal fluid-brain barrier, plays essential roles in immune response to stress and brain homeostasis. However, the cellular and molecular contributions of the ChP to AD progression

Alzheimer’s disease (AD) is increasingly recognized as a systemic disorder with a substantial metabolic disorder component, where the liver significantly impacts the brain via the liver-brain axis. Key mechanisms include the liver’s role in clearing peripheral β-amyloid (Aβ), the influence of hepatic enzymes and metabolites on cognitive decline, and the systemic effects of metabolic disorders on AD

Asparagine endopeptidase (AEP) is implicated in the pathogenesis of Alzheimer’s disease (AD) by cleaving Tau at residue N368, accelerating its hyperphosphorylation and aggregation. The Tau N368/t-Tau ratio in cerebrospinal fluid (CSF) serves as a superior biomarker compared to established biomarkers (p-Tau 181/217) for correlating with tau pathology and synaptic dysfunction in patients with AD, highlighting

Neuronal primary cilia, vital for signaling and cell-cycle regulation, have been implicated in maintaining neuronal identity. While a link between primary ciliary defects and neurodegenerative diseases is emerging, the precise pathological mechanisms remain unclear. We studied the genetic contribution of NEK1 to ALS pathogenesis by analyzing the exome sequences of 920 Korean patients with ALS. To understand

Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease involving loss of motor neurons, typically results in death within 3–5 years of disease onset. Although roughly 10% of cases can be linked to a specific inherited mutation (e.g., C9orf72 hexanucleotide repeat expansion or SOD1 mutation), the cause(s) of most cases are unknown. Consequently, there is a critical need for biomarkers that

The development of anti-amyloid-beta (Aβ) immunotherapies as the first disease modifying therapy for Alzheimer’s Disease (AD) is a breakthrough of basic research and translational science. Genetically modified mouse models developed to study AD neuropathology and physiology were used for the discovery of Aβ immunotherapies and helped ultimately propel therapies to FDA approval. Nonetheless, the combination

Tau protein plays a critical role in the physiological functioning of the central nervous system by providing structural integrity to the cytoskeletal architecture of neurons and glia through microtubule assembly and stabilization. Under certain pathological conditions, tau is aberrantly phosphorylated and aggregates into neurotoxic fibrillary tangles. The aggregation and cell-to-cell propagation of

While APP is largely neuonally expressed, Aβ amyloid is largely produced by microglia as the clearance mechanisms for damaged membranes becomes overwhelmed.

In the recent decade, there has been a surge of efforts to develop scalable, specific and cost-effective biomarkers in blood to diagnose neurodegenerative diseases and prognose their progress even before overt symptoms manifest. Among an array of brain-associated proteins, glial fibrillary acidic protein (GFAP) has emerged as a compelling biomarker candidate, often in conjunction with other biomarkers

Increased phosphorylation of TDP-43 is a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the regulation and roles of TDP-43 phosphorylation remain incompletely understood. A variety of techniques have been utilized to understand TDP-43 phosphorylation, including kinase/phosphatase manipulation, phosphomimic

While the temporal profile of amyloid (Aβ) and tau cerebrospinal fluid (CSF) biomarkers along the Alzheimer’s disease (AD) continuum is well-studied, chronological changes of CSF proteins reflecting other disease-relevant processes, denoted ‘X’ in the ATX(N) framework, remain poorly understood. Using an untargeted mass spectrometric approach termed tandem mass tag (TMT), we quantified over 1500 CSF

Genome-wide association studies (GWAS) of Alzheimer’s disease (AD) have identified a plethora of risk loci. However, the disease variants/genes and the underlying mechanisms have not been extensively studied. Bulk ATAC-seq was performed in induced pluripotent stem cells (iPSCs) differentiated various brain cell types to identify allele-specific open chromatin (ASoC) SNPs. CRISPR-Cas9 editing generated

Biallelic loss-of-function variants in TYROBP and TREM2 cause autosomal recessive presenile dementia with bone cysts known as Nasu-Hakola disease (NHD, alternatively polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL). Some other TREM2 variants contribute to the risk of Alzheimer’s disease (AD) and frontotemporal dementia, while deleterious TYROBP variants are globally

In recent years, the seed amplification assay (SAA) has enabled the identification of pathological TDP-43 in the cerebrospinal fluid (CSF) and olfactory mucosa (OM) of patients with genetic forms of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we investigated the seeding activity of TDP-43 in OM samples collected from patients with sporadic ALS. OM samples were collected

Autosomal Dominant Alzheimer's Disease (ADAD), caused by mutations in Presenilins (PSEN1/2) and Amyloid Precursor Protein (APP) genes, typically manifests with early onset (< 65 years). Age at symptom onset (AAO) is relatively consistent among carriers of the same PSEN1 mutation, but more variable for PSEN2 and APP variants, with these mutations associated with later AAOs than PSEN1. Understanding

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects the motor neurons, causing progressive muscle weakness and paralysis. While research has focused on understanding pathological mechanisms in the motor cortex and spinal cord, there is growing evidence that extra-motor brain regions may also play a role in the pathogenesis or progression of ALS. We generated 165

Apolipoprotein E (APOE- gene; apoE- protein) is the strongest genetic modulator of late-onset Alzheimer’s disease (AD), with its three major isoforms conferring risk for disease ε2 < ε3 < ε4. Emerging protective gene variants, such as APOE Christchurch and the COLBOS variant of REELIN, an alternative target of certain apoE receptors, offer novel insights into resilience against AD. In recent years

Lewy body dementia (LBD) encompasses neurodegenerative dementias characterized by cognitive fluctuations, visual hallucinations, and parkinsonism. Clinical differentiation of LBD from Alzheimer’s disease (AD) remains complex due to symptom overlap, yet approximately 25% of dementia cases are diagnosed as LBD postmortem, primarily identified by the presence of α-synuclein aggregates, tau tangles, and

Genetic variation in Transmembrane protein 106B (TMEM106B) is known to influence the risk and presentation in several neurodegenerative diseases and modifies healthy aging. While evidence from human studies suggests that the risk allele is associated with higher levels of TMEM106B, the contribution of elevated levels of TMEM106B to neurodegeneration and aging has not been assessed and it remains unclear

The epoxyeicosatrienoic acids (EETs) are derivatives of the arachidonic acid metabolism with anti-inflammatory activities. However, their efficacy is limited due to the rapid hydrolysis by soluble epoxide hydrolase (sEH). Inhibition of sEH has been shown to stabilize the EETs and reduce neuroinflammation in Aβ mouse models of Alzheimer’s disease (AD). However, the role of the sEH-EET signaling pathway

Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor predominantly expressed by microglia in the brain. Recent studies have established TREM2 as a central immune signaling hub in neurodegeneration, where it triggers immune responses upon sensing pathological development and tissue damages. TREM2 binds diverse ligands and activates downstream pathways that regulate microglial

There is currently no effective therapy for prion diseases. The glymphatic system is an organized system of perivascular spaces that facilitates the removal of metabolic waste from the brain. This study demonstrates the therapeutic potential of a combination therapy of adipose-derived mesenchymal stem cells (AdMSCs) and a glymphatic system-activated drug, clonidine, against prion disease. The therapy

GPNMB has been discussed as a potential therapeutic target in GRN-mediated neurodegeneration, based on the observed reproducible upregulation in FTD-GRN cerebrospinal fluid (CSF) and post-mortem brain. However, the functional impacts of up-regulated GPNMB are currently unknown, and it is currently unclear if targeting GPNMB will be protective or deleterious. Increases in GPNMB seen in FTD-GRN are reproduced

Immune mechanisms play a fundamental role in Alzheimer’s disease (AD) pathogenesis, suggesting that approaches which target immune cells and immunologically relevant molecules can offer therapeutic opportunities beyond the recently approved amyloid beta monoclonal therapies. In this review, we provide an overview of immunomodulatory therapeutics in development, including their preclinical evidence

Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are overwhelmingly linked to TDP-43 dysfunction. Mutations in TDP-43 are rare, indicating that the progressive accumulation of exogenous factors – such as cellular stressors – converge on TDP-43 to play a key role in disease pathogenesis. Post translational modifications such as SUMOylation play essential roles in response to such

Alzheimer’s disease (AD) involves a dynamic interaction between neuroinflammation and metabolic dysregulation, where microglia play a central role. These immune cells undergo metabolic reprogramming in response to AD-related pathology, with key genes such as TREM2, APOE, and HIF-1α orchestrating these processes. Microglial metabolism adapts to environmental stimuli, shifting between oxidative phosphorylation

Parkinson’s disease (PD) is a multi-system disorder characterized histopathologically by degeneration of dopaminergic neurons in the substantia nigra pars compacta. While the etiology of PD remains multifactorial and complex, growing evidence suggests that cellular metabolic dysfunction is a critical driver of neuronal death. Defects in cellular metabolism related to energy production, oxidative stress

Alzheimer’s disease (AD) is the most common form of dementia globally and is characterised by reduced mitochondrial respiration and cortical deposition of amyloid-β plaques and neurofibrillary tangles comprised of hyper-phosphorylated tau. Despite its characterisation more than 110 years ago, the mechanisms by which AD develops are still unclear. Dysregulation of microglial phagocytosis of amyloid-β

DNA damage and DNA damage repair (DDR) dysfunction are insults with broad implications for cellular physiology and have been implicated in various neurodegenerative diseases. Alpha-synuclein (aSyn), a pre-synaptic and nuclear protein associated with neurodegenerative disorders known as synucleinopathies, has been associated with DNA double strand break (DSB) repair. However, although nuclear aSyn pathology

Aggregated alpha-Synuclein (αSyn) is a hallmark pathology in Parkinson’s disease but also one of the most common co-pathologies in Alzheimer’s disease (AD). Preclinical studies suggest that αSyn can exacerbate tau aggregation, implying that αSyn co-pathology may specifically contribute to the Aβ-induced aggregation of tau that drives neurodegeneration and cognitive decline in AD. To investigate this

Alzheimer’s disease (AD) is neuropathologically characterized by the extracellular deposition of the amyloid-β peptide (Aβ) and the intraneuronal accumulation of abnormal phosphorylated tau (τ)-protein (p-τ). Most frequently, these hallmark lesions are accompanied by other co-pathologies in the brain that may contribute to cognitive impairment, such as vascular lesions, intraneuronal accumulation of

Tauopathies represent a diverse group of neurodegenerative disorders characterized by the abnormal aggregation of the microtubule-associated protein tau. Despite extensive research, the mechanisms underlying the diversity of neuronal and glial tau pathology in different tauopathies are poorly understood. While there is a growing understanding of tauopathy-specific differences in tau isoforms and fibrillar

Therapeutic development for frontotemporal dementia (FTD) is hindered by the lack of biomarkers that inform susceptibility/risk, prognosis, and the underlying causative pathology. Blood glial fibrillary acidic protein (GFAP) has garnered attention as a FTD biomarker. However, investigations of GFAP in FTD have been hampered by symptomatic and histopathologic heterogeneity and small cohort sizes contributing

Recent studies highlight the critical role of microglia in neurodegenerative disorders, and emphasize the need for humanized models to accurately study microglial responses. Human-mouse microglia xenotransplantation models are a valuable platform for functional studies and for testing therapeutic approaches, yet currently those models are only available for academic research. This hampers their implementation

Axon regeneration within the mammalian central nervous system is extremely limited. In optic neuropathy conditions like glaucoma, the inability of retinal ganglion cell (RGC) axons to regenerate is a major impediment to functional recovery. In contrast, adult teleost fish such as zebrafish can fully regenerate RGC axons enabling visual recovery from optic nerve (ON) injury making it an ideal model

Parkinson’s disease (PD) is a leading neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons, contributing to considerable disability worldwide. Current treatments offer only symptomatic relief, highlighting the need for novel therapeutic strategies targeting disease progression. Neuroinflammation plays a pivotal role in PD pathogenesis, with the NLRP3 inflammasome

Cytoplasmic alpha-synuclein (αSyn) aggregates are a typical feature of Parkinson’s disease (PD). Extracellular insoluble αSyn can induce pathology in healthy neurons suggesting that PD neurodegeneration may spread through cell-to-cell transfer of αSyn proteopathic seeds. Early pro-homeostatic reaction of microglia to toxic forms of αSyn remains elusive, which is especially relevant considering the

The relationship between Alzheimer's disease (AD) and neuroimmunity has gradually begun to be unveiled. Emerging evidence indicates that cyclic GMP-AMP synthase (cGAS) acts as a cytosolic DNA sensor, recognizing cytosolic damage-associated molecular patterns (DAMPs), and inducing the innate immune response by activating stimulator of interferon genes (STING). Dysregulation of this pathway culminates

The parkin-interacting substrate (PARIS, also known as ZNF746) is a transcriptional repressor, whose accumulation and phosphorylation play central pathological roles in Parkinson’s disease (PD). PARIS-induced transcriptional repression of PGC-1α or MDM4 contributes to mitochondrial dysfunction and p53-dependent neuron loss in PD. Despite the important role of PARIS in PD pathogenesis, unbiased transcriptomic

Molecular biomarkers of chronic traumatic encephalopathy (CTE) are lacking. We evaluated 18F-MK-6240 tau PET as a biomarker for CTE. Two studies were done: (1) 3H-MK-6240 autoradiography and an in-vitro brain homogenate binding studies on postmortem CTE tissue, (2) an in-vivo 18F-MK-6240 tau PET study in former American football players. Autoradiography and in-vitro binding studies were done using

Alzheimer’s disease (AD) poses a growing global health challenge as populations age. Recent research highlights the crucial role of peripheral immunity in AD pathogenesis. This review explores how blood-brain barrier disruption allows peripheral immune cells to infiltrate the central nervous system (CNS), worsening neuroinflammation and disease progression. We examine recent findings on interactions

Normal aging alters brain functions and phenotypes. However, it is not well understood how astrocytes are impacted by aging, nor how they contribute to neuronal dysfunction and disease risk as organisms age. Here, we examine the transcriptional, cell biology, and functional differences in astrocytes across normal aging. Astrocytes at baseline are heterogenous, responsive to their environments, and

The integrated stress response (ISR) is a conserved network in eukaryotic cells that mediates adaptive responses to diverse stressors. The ISR pathway ensures cell survival and homeostasis by regulating protein synthesis in response to internal or external stresses. In recent years, the ISR has emerged as an important regulator of the central nervous system (CNS) development, homeostasis and pathology

Parkinson disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy are synucleinopathies, characterized by neuronal loss, gliosis and the abnormal deposition of α-synuclein in vulnerable areas of the nervous system. Neurodegeneration begins however several years before clinical onset of motor, cognitive or autonomic symptoms. The isolated form of REM sleep behavior disorder (RBD),

Axon regeneration after injury to the central nervous system (CNS) is limited by an inhibitory environment but also because injured neurons fail to initiate expression of regeneration associated genes (RAGs). The potential of strong RAG expression to promote regeneration in the CNS is exemplified by the conditioning lesion model, whereby peripheral nerve injury promotes regeneration of centrally projecting

Cortical atrophy is a common manifestation in behavioral variant frontotemporal degeneration (bvFTD), exhibiting spatial heterogeneity across various genetic subgroups, which may be driven by distinct biological mechanisms. We employed an integrative imaging transcriptomics approach to identify both disparate and shared transcriptomic signatures associated with cortical thickness in bvFTD with C9orf72

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the loss of both upper and lower motor neurons, leading to progressive paralysis. Both genetic alterations and epigenetic modifications contribute to neuronal dysfunction in the pathogenesis of ALS. However, the mechanism behind genetic mutations in the non-coding region of genes that affect epigenetic modifications

Cellular senescence, a hallmark of aging, has been implicated in Alzheimer’s disease (AD) pathogenesis. Cholesterol accumulation is known to drive cellular senescence; however, its underlying mechanisms are not fully understood. ATP-binding cassette transporter A1 (ABCA1) plays an important role in cholesterol homeostasis, and its expression and trafficking are altered in APOE4 and AD models. However

Gastrointestinal (GI) involvement in Lewy body diseases (LBDs) has been observed since the initial descriptions of patients by James Parkinson. Recent experimental and human observational studies raise the possibility that pathogenic alpha-synuclein (⍺-syn) might develop in the GI tract and subsequently spread to susceptible brain regions. The cellular and mechanistic origins of ⍺-syn propagation in

Many diseases and disorders of the nervous system suffer from a lack of adequate therapeutics to halt or slow disease progression, and to this day, no cure exists for any of the fatal neurodegenerative diseases. In part this is due to the incredible diversity of cell types that comprise the brain, knowledge gaps in understanding basic mechanisms of disease, as well as a lack of reliable strategies

Alzheimer’s disease (AD) is a debilitating neurodegenerative disease that is marked by profound neurovascular dysfunction and significant cell-specific alterations in the brain vasculature. Recent advances in high throughput single-cell transcriptomics technology have enabled the study of the human brain vasculature at an unprecedented depth. Additionally, the understudied niche of cerebrovascular