Alzheimer & Parkinson

Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD) represent two major categories of neurodegenerative disorders-TAR DNA-binding protein 43 (TDP-43) and tau proteinopathies-for which the mechanisms driving neuronal death remain unclear. Single-cell whole-genome sequencing of 469 neurons from C9ORF72 ALS, C9ORF72 FTD, AD, and control brains revealed increased somatic single-nucleotide variants (sSNVs) and insertions/deletions (sIndels) in all three...

Type 2 diabetes (T2D) is traditionally viewed as a metabolic disease centered on insulin resistance and β-cell failure. However, growing evidence supports its reclassification as a systemic proteinopathy, in which the aggregation of amylin (islet amyloid polypeptide, IAPP) emerges as a key pathogenic event. In this review, we examine the shift toward an IAPP-centric model of disease, highlighting how IAPP misfolding and aggregation drive β-cell dysfunction independently of, and in parallel with,...

Alzheimer's disease and related dementia (ADRD) represents a growing public health burden, especially in low- and middle-income countries. Yet, most studies focus on Non-Hispanic white (NHW) populations from high-income countries. This study investigates plasma proteomic signatures associated with amyloid pathology in African populations. Nigerian older adults from the VALIANT study and participants from a Tanzanian study, with available biomarker quantification in plasma are employed. For...

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Detection of Alzheimer's disease (AD) before the development of clinical symptoms is critical for enabling the use of new treatments. Circular RNAs (circRNAs) are highly stable non-coding RNAs enriched in the brain that can cross the blood-brain barrier. Here, analyzing blood data from 1,221 individuals with AD and healthy individuals, we identified 34 circRNAs associated with AD status. A predictive model including these 34 circRNAs was comparable to plasma phosphorylated Tau-217 (pTau217) in...

Mutations in the GBA1 gene, which encodes the lysosomal glucocerebrosidase enzyme GCase, cause the lysosomal storage disorder Gaucher disease and represent the most common genetic risk factor for Parkinson's disease (PD). These mutations deplete lysosomal GCase activity and cause accumulation of GCase substrate, glucosylceramide, and its pathological metabolite, glucosylsphingosine. Impaired GCase activity then drives immune and neuronal dysfunction in Gaucher disease and promotes pathogenic...

The rapid expansion of plasma proteomic data and protein quantitative trait loci (pQTLs) provides an opportunity to identify genes that confer disease risk through their effect on plasma protein abundance. We conducted an Alzheimer's disease (AD) proteome-wide association study (PWAS) integrating publicly available plasma cis-pQTL data (1348 European American and 1385 African American genetically determined protein models) with AD dementia GWAS summary statistics. Whereas the African American...

Lateralization is a hallmark of brain organization, yet the structural basis underlying this phenomenon remains a critical, unresolved question in cognitive and systems neuroscience. In this study, we applied multivariate machine learning techniques to investigate variations of global brain asymmetry and their associations with cognitive functions, aging, and aging-related diseases, using large-scale datasets. Our findings revealed substantial and previously unknown structural differences...

Recent studies suggest that copy number variants (CNVs) may contribute to the missing heritability of complex diseases such as Alzheimer's disease (AD) and related dementias (ADRD). We performed a CNV analysis using genotyping data (Axiom 815 K Spanish biobank array) from the GR@ACE/DEGESCO dementia dataset (n = 20,067) of the Spanish population. Applying PennCNV and extensive quality control, 8275 controls and 7818 dementia cases were selected for gene-level case/control associations. We...

The gut microbiome is emerging as a modifier of risk for neurodegenerative diseases, but underlying mechanisms remain poorly understood. Here, we show that the hTau.P301S mouse model for progressive tauopathy develops alterations in the composition and function of the gut microbiome that are not recapitulated in amyloid-based 5xFAD or 3xTg models for Alzheimer's disease. Disrupting the gut microbiome via chronic antibiotic treatment exacerbates cognitive deficits and tau pathology in hTau.P301S...

Immunotherapy against amyloid β-protein (Aβ) for Alzheimer's disease (AD) has been widely approved. Breakthrough disease-modifying treatments such as lecanemab and donanemab are often followed by drugs with improved efficacy. By immunizing Trianni mice with aggregated synthetic Aβ, we obtained B28, a fully human antibody specifically selected for its neutralization of tau neuritic dystrophy induced by AD brain-derived oligomers. In a blinded trial in mutant human APP^(NL-G-F) knock-in mice,...

Prion diseases represent a unique biological paradigm with mechanistic parallels to other neurodegenerative conditions like Alzheimer's and Parkinson's diseases. However, the study of human prion pathobiology and the development of effective therapeutics has been severely constrained by the inability to propagate human prions in dividing cells-forcing reliance on costly and slow animal bioassays. Here, we report the generation of EKV cells-a humanized cell model which supports the robust,...

Tau pathology spreads cell to cell, but the mechanisms of intercellular tau transmission remain unclear. We find that the neuronal gene Arc is critical for the release of tau in neuronal extracellular vesicles (EVs) via a direct protein-protein interaction. Brain EVs purified from transgenic rTg4510 mutant tau mice (rTg^(WT)) crossed with Arc knockout mice (rTg^(Arc KO)) contain less tau and reduced tau seeding potential. Both Arc and tau are co-packaged in mouse and human brain-derived EVs....

Tau is an intrinsically disordered protein that functions to support cytoskeletal stability by binding microtubules in neuronal axons. While tau is involved in healthy neuronal function, it can become pathogenic by forming protein aggregates leading to neurologic diseases collectively known as tauopathies, which include Alzheimer's disease, frontotemporal dementia, and chronic traumatic encephalopathy. Post-translational modifications, including phosphorylation, O-GlcNAcylation, acetylation,...

Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and others, are a group of neurological disorders characterized by progressive neuronal loss in the central nervous system (CNS) and the deterioration of CNS function. Multiple lines of evidence have highlighted activation of innate immune cells in the CNS, namely microglia and astrocytes, as hallmark pathological features in neurodegeneration and key drivers of disease progression....

Astrocytes, long considered supportive cells of the central nervous system (CNS), have critical roles in innate immunity. This Review explores immune signaling pathways in astrocytes, including pattern recognition through Toll-like receptors, nucleic acid sensors and inflammasomes. These pathways enable the detection of danger signals and initiate protective responses and endogenous innate immune functions. Downstream signaling pathways, including the interferon, NF-κB and STAT3 pathways,...

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The NLRP3 inflammasome has been implicated in a wide range of human diseases, including cardiovascular, metabolic, neurodegenerative (such as Alzheimer's disease), and other age-related conditions. This has positioned NLRP3 as a promising pharmacological target. Numerous studies have shown that complete NLRP3 ablation can prevent or mitigate these diseases. However, total elimination of NLRP3 is not a feasible therapeutic strategy for the millions of patients affected by these degenerative...

Growth/differentiation factor-15 (GDF15) is a secreted cytokine strongly associated with dementia risk. However, the extent to which GDF15 represents a biomarker and driver of dementia risk remains unclear. Across multiple cohorts, we demonstrated that plasma GDF15 is associated with greater dementia risk over 15- to 25-year follow-up periods when measured in midlife, with stronger associations observed for vascular, compared to Alzheimer's disease (AD), dementia. Two-sample Mendelian...

Lysophosphatidylinositol (LPI) is an endogenous GPR55 agonist, yet its role in Alzheimer's disease (AD) remains unclear. Here, we performed serum metabolomic profiling in 5xFAD mice and observed a reduction in multiple LPI species prior to the onset of overt Aβ pathology, and this decrease was further corroborated in human cohort samples. Exogenous LPI treatment reduced cerebral Aβ deposition, improved performance in learning and memory behavioral tasks, reduced pathological microglial...