Alzheimer & Parkinson

Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E (APOE) gene ɛ2/ɛ3/ɛ4 polymorphisms remain the longstanding benchmark for genetic disease risk with a consistently large effect across studies^(1-10). Despite this massive signal, the exact mechanisms by which ɛ4 increases and ɛ2 decreases dementia risk remain poorly understood. Notably, recent trials of anti-amyloid therapies suggest less efficacy and higher...

Understanding the molecular basis of neurodegeneration requires a comprehensive map of the genome's protein-coding output. Although thousands of small open reading frames (ORFs) are translated in the human brain, proteomic evidence for their encoded microproteins (MPs) (≤150 amino acids (aa)) remains limited. Here, we present a brain MP atlas that integrates transcriptomics, mass spectrometry and deep-learning-predicted spectra across more than 600 postmortem frontal cortex samples with and...

Parkinson's disease (PD) is a progressive neurodegenerative disorder influenced by both genetic and epigenetic mechanisms. Among these mechanisms, DNA methylation has emerged as a key regulatory process affecting gene expression without altering the DNA sequence. The synuclein alpha (SNCA) gene is a well-established contributor to Parkinson's disease pathogenesis, yet the extent and consistency of its methylation changes remain unclear. This scoping review aimed to map and summarise existing...

Dementia is a progressive neurodegenerative syndrome characterised by cognitive decline, synaptic dysfunction, and neuronal loss. In recent years, growing attention has been given to the role of the gut-brain axis in neurodegenerative disease. Emerging evidence indicates that changes in gut microbiota composition and metabolic activity may affect various systemic processes that contribute to dementia. This review examines the current evidence linking gut microbiota imbalance to dementia through...

Phosphorylation-targeting chimeras (PhosTACs) enable targeted protein dephosphorylation by recruiting phosphatases through induced proximity. However, the direct recruitment of phosphatase subunits or holoenzymes with small molecules remains challenging, as suitable ligands are scarce and often compromise enzymatic activity or cellular function. Here, we present togoPhosTAC, a hybrid modality that integrates a small-molecule PhosTAC, an engineered FKBP12^(F36V)-phosphatase, and a lipid...

Memory markedly declines with age, exaggerated in those with Alzheimer's disease, yet the mechanisms are still not resolved. Here we show that frontal lobe tau pathology in humans is associated with impaired en masse unity and cortical traveling propagation of nonrapid eye movement slow waves, linked to impaired memory retention. We elucidate these findings using positron-emission tomography tau brain imaging, and then replicate and extend them using Alzheimer's disease pathology markers derived...

Alzheimer's disease (AD) is conventionally framed as a consequence of progressive amyloid-β and tau pathology, yet substantial heterogeneity in cognitive outcome at any given level of pathological burden indicates that cognitive resilience constitutes a parallel determinant of disease risk. Here we test whether pathology and resilience function as independent and synergistic dimensions of incident AD dementia. In 3,119 older adults from the China Cognition and Aging Study, followed for a median...

Blood-brain barrier (BBB) dysfunction is an early feature of Alzheimer's disease (AD) and is particularly pronounced in individuals carrying the APOE ε4 allele, but the mechanisms linking APOE ε4 to BBB failure remain unclear. Here we show that astrocyte-derived fibronectin (FN1) is a key mediator of apolipoprotein E4 (APOE4)-driven BBB dysfunction in AD. Using postmortem human brain tissue, human three-dimensional vascular models and in vivo models, we demonstrate that APOE4, amyloid-β42 and...

Cellular senescence is increasingly recognized as a fundamental driver of aging and age-related diseases. Studies in peripheral tissues have revealed that senescence is not a uniform cellular state, but a highly heterogeneous phenotype shaped by distinct combinations of DNA damage, mitochondrial dysfunction, chromatin remodeling, impaired proteostasis, and diverse senescence-associated secretory phenotype. This heterogeneity critically influences both the identification and therapeutic targeting...

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder in which neuroinflammation, vascular dysfunction, metabolic disturbances, and impaired tissue resilience contribute to disease progression. Aerobic exercise is a widely applicable lifestyle intervention that has been increasingly investigated in AD; however, the mechanisms linking peripheral exercise adaptations to brain outcomes remain incompletely understood. This review evaluates the potential contribution of gut-derived...

CONCLUSION: Deep learning models hold considerable potential for predicting MCI-to-AD conversion, yet substantial barriers remain to their translation into routine clinical practice. Greater emphasis on longitudinal analysis, intelligent multimodal fusion, and interpretable architectures is essential for clinical impact. Future research should prioritize the development of diverse, multicenter datasets, advancement of explainable AI (XAI) techniques, and the design of personalized time-to-event...

Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose global prevalence is rapidly increasing, highlighting the urgent need to identify modifiable risk factors. Chronic alcohol consumption has emerged as one such significant factor contributing to the risk and progression of AD. Importantly, alcohol metabolism impacts cellular acetylation pathways, creating an environment that promotes protein dysregulation and disrupts cellular functions. Among these alterations, tau...

Blood phosphorylated tau at threonine 217 (p-tau217) has shown considerable potential for the diagnosis of Alzheimer's disease (AD). For successful implementation in clinical practice, its applicability must be established across representative populations and settings. In this systematic review, we aimed to characterize participants included in p-tau217 research in AD, focusing on study setting, and sociodemographic and clinical features relevant to biomarker interpretation, and to assess how...

Study in mice strengthens T cells' ties to neurodegenerative conditions like Alzheimer's.

With the acceleration of global aging, the relationship between Alzheimer's disease (AD) and the glymphatic system (GS) has become a research hotspot in the field of neuroscience in recent years. Traditionally, the central nervous system was thought to lack a lymphatic system; however, research over the past decade has overturned this view. Studies have revealed the existence of GS and meningeal lymphatic vessels (mLVs) in the brain, which clear metabolic waste (such as amyloid-β and tau...

Yu and colleagues¹ demonstrate that α-synuclein pathology within the dorsal motor nucleus of the vagus (DMV) compromises neuronal excitability and drives Parkinson's disease-related gastrointestinal dysmotility through alteration of a fundamental DMV-gut circuit. Electroacupuncture reactivates this circuit ameliorating this functional deficit.

This year's Lasker~Bloomberg Public Service Award honors the singular achievement of Michael J. Fox, who has devoted much of his life to a philanthropic effort to conquer Parkinson's Disease (PD), a progressive neurodegenerative disorder that afflicts many millions of patients world-wide. Just a few years after his diagnosis of PD at the tender age of 29, Fox pivoted in part from his enormous success in acting [leading roles in the Back to the Future trilogy (1985-1989) and in the hit National...

Bone marrow-derived macrophages were shown to play an important role in coping with Alzheimer's disease (AD). Boosting their spontaneous recruitment reduces inflammation and disease pathology and slows cognitive decline in mouse models of amyloidosis. However, the factors limiting their spontaneous homing to the diseased brain remain unclear. In this study, we discovered that monocyte development is impaired in mouse models and in patients. In the 5×FAD mouse model, monocyte differentiation was...

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Primary cultures from fetal or postnatal rodent brain are widely used to study alpha-synuclein (aSyn)-associated mechanisms but poorly reflect age-dependent neurodegenerative processes. We established primary whole-brain cultures from adult Thy1-aSyn (Line 61) mice overexpressing human aSyn and compared them with postnatal and wild-type cultures. Cultures were maintained for 21 days and characterized by electrophysiology, immunohistochemistry, gene expression analysis, and protein biochemistry....