Alzheimer & Parkinson

CONCLUSIONS: The anti-ASC N-terminal and C-terminal antibodies may have neuroprotective effects, which are manifested as reducing cell apoptosis, improving cognitive function, and alleviating AD-like pathology in AD mice. Immunotherapies targeting ASC are promising for treating AD.

Mitochondrial dysfunction is increasingly recognized as a central driver of Alzheimer's disease (AD), contributing to neuroinflammation, synaptic failure, and energy collapse.Emerging preclinical evidence suggests that classic hallucinogens, such as psilocybin, lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), mescaline, may restore mitochondrial integrity by activating Serotonin 2A (5-HT2A) and sigma-1(Sig-1R) receptors. In experimental models, these pathways are associated with...

Formation of new amyloid fibrils and oligomers from monomeric protein on the surfaces of existing fibrils is an important driver of many disorders such as Alzheimer's and Parkinson's diseases. The structural basis of this secondary nucleation process, however, is poorly understood. Here, we ask whether secondary nucleation sites are found predominantly at rare growth defects: irregularities in the fibril core structure incorporated during their original assembly. We first demonstrate using the...

Redox dysregulation, characterized by an imbalance in the NAD^(+) [nicotinamide adenine dinucleotide (oxidized form)]/NADH (reduced form of NAD^(+)) ratio, is implicated in neurodegenerative and psychiatric disorders such as Alzheimer's disease and schizophrenia. This imbalance contributes to mitochondrial dysregulation, oxidative stress, and inflammation. Despite promising preclinical studies supporting therapeutic strategies aimed at restoring redox balance and thereby rescuing brain...

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CONCLUSIONS: Our findings suggest that PM2.5 exposure was associated with increased AD risk, primarily through direct rather than comorbidity-mediated pathways. Stroke may modestly increase susceptibility. These findings highlight the need for air quality interventions as part of dementia prevention strategies in aging populations, especially those facing overlapping environmental and clinical vulnerabilities.

Pathological progression in sporadic Alzheimer's disease (sAD) initiates with an early rise in soluble amyloid-β (Aβ), preceding plaque formation and neurodegeneration. However, the molecular event triggering this initial accumulation remains unknown. We report that phosphoglycerate dehydrogenase (PHGDH), a consistent biomarker of prodromal sAD, drives Aβ production through a previously unrecognized RNA-binding function. Specifically, PHGDH binds the 3'UTR of EIF2AK1 mRNA, enabling the physical...

Accurate diagnosis of dementia with Lewy bodies (DLB) remains challenging, with misdiagnosis potentially leading to harmful treatment decisions. DOPA decarboxylase (DDC) shows promise as a cerebrospinal fluid (CSF) biomarker for DLB and Parkinson's disease (PD), but quantitative assays are needed for its clinical implementation. Here we report on the development of two DDC immunoassays and the extensive clinical validation of DDC across three clinical cohorts (n = 740), one biologically defined...

Effective treatments for age-related chronic neurodegenerative diseases such as Alzheimer's disease remain limited, in part because the molecular drivers of cognitive decline are still not fully understood. Human genetic studies, together with detailed analysis of disease pathology, indicate that the immune system has an important influence on disease progression. Research to date has focused largely on microglia - specialized innate immune cells that reside within the central nervous system...

Understanding the development of midbrain dopaminergic (mesDA) neurons is essential for advancing cell replacement therapies for Parkinson's disease. In the developing ventral midbrain (VM), radial glia (Rgl) cells are the progenitors of mesDA neurons. However, distinct Rgl subtypes have recently been identified, and their individual roles are unclear. Here we analyze transcriptomic data from mouse and human VM Rgl to define their contributions to mesDA neuron development. We identify Rgl1 as...

Idebenone (IDE), an analog of ubiquinone, has demonstrated therapeutic potential across various neurodegenerative disorders. Clinically, IDE has been shown to exert neuroprotective effects in Parkinson's disease (PD), being capable of alleviating motor symptoms as well as reducing depressive and anxious moods. However, the mechanism of action of IDE in PD has not been fully elucidated. Thus, the present study aims to investigate the potential effects of IDE on...

Aging is the primary cause of cognitive decline. Despite extensive study, the molecular mechanisms driving aging-associated cognitive decline remain unclear. Here, we describe a proteostasis-independent function of SEC61A1 and its involvement in aging-associated cognitive decline. SEC61A1 regulates ER-mitochondria contact sites, affecting mitochondrial DNA and RNA synthesis and subsequently leading to changes in innate immune signaling mediated by mitochondrial double-stranded RNA (mt-dsRNA)....

Repurposing existing medicines to target disease-associated genes represents a promising strategy for developing effective treatments for complex diseases. However, progress has been hindered by a lack of viable candidate drug targets identified through genome-wide association studies. Gene-based association tests provide a more powerful alternative to traditional SNP-based methods, yet current approaches often fail to leverage shared heritability across populations and to effectively integrate...

Alzheimer's disease (AD) has a strong genetic predisposition. Genome-wide association studies have identified multiple risk loci, yet many non-coding variants remain uncharacterized. Machine learning-based polygenic risk scores (PRS) enhance prediction by modeling genetic epistasis and sex-specific risks. This review summarizes AD genetic risk factors, PRS methodologies, and ML-based AD risk prediction. It also highlights challenges such as population bias, functional validation, and integrating...

CONCLUSIONS: Our framework establishes a powerful new paradigm for epigenetic research that can be extended to other complex diseases, offering both a valuable tool for variant effect interpretation and a promising strategy for uncovering novel disease mechanisms through epigenetic profiling.

Glutamate accumulation linked to Parkinson's disease (PD) pathogenesis. While glutamate chemical exchange saturation transfer (GluCEST) imaging has been applied in various CNS disorders, its utility in PD remains underexplored. This study investigated the clinical relevance of dentate nucleus and cerebellar hemisphere glutamate levels across PD motor subtypes. We enrolled 36 resting-tremor predominant PD (PDRT), 33 akinetic-rigid predominant PD (PDAR), and 40 healthy controls (HCs). GluCEST data...

The current clinical diagnostic criteria for Parkinson disease (PD) have limitations and are inherently insensitive to the earliest stages of disease, when classical motor signs can be absent. Imaging and genetic tests are currently used to support or establish a diagnosis of PD, but no validated biomarker-based diagnostic framework currently exists. Substantial progress has been made in the field of molecular disease markers, most notably with the development and validation of seed...

Dementia diagnosis increasingly relies on blood-based biomarkers, yet their performance in diverse populations remains insufficiently characterized. Latin America, with substantial genetic and environmental heterogeneity, is particularly underrepresented in biomarker research. Here we show that plasma AT(N) biomarkers can distinguish Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) in a multinational Latin American cohort (N = 605). Aβ(42)/Aβ(40) amyloid-β ratios were...

Decoding human movement from invasive neural signals has traditionally relied on complex machine learning algorithms using data collected from short-term laboratory tasks, limiting understanding of brain function during natural behavior and hindering development of clinically viable closed-loop neuromodulation. Here, we demonstrate the first in-human, at-home classification of a specific movement state-walking-using a fully implantable, bidirectional neurostimulator. In four individuals with...

Cerebrospinal fluid (CSF) continuously circulates through the brain and surrounding tissues to remove metabolic waste, a process that becomes less efficient with ageing and in neurodegenerative disease. Visualizing this drainage in living animals has been difficult because existing imaging tools either lack depth, require radioactive tracers, or are too slow to capture dynamic flow. Here, we show that whole-body photoacoustic computed tomography (PACT) enables three-dimensional, real-time...