Alzheimer & Parkinson

Saliva is an accessible biofluid with potential for non-invasive disease diagnostics. This study explores how genetic susceptibility to common diseases is reflected in DNA methylation (DNAm) and gene expression profiles in saliva. We constructed cis-mQTL (n = 345) and cis-eQTL (n = 277) datasets and examined correlations between DNAm and gene expression. Saliva QTLs were integrated with summary statistics from 36 genome-wide association studies (GWAS) using Summary-based Mendelian Randomization...

Cortical tau deposition begins in higher-order association regions and spreads to lower-order primary sensory-motor networks in moderate/advanced Alzheimer's dementia. The neural mechanisms underlying this spatiotemporal pattern remain elusive. Initial evidence has shown that coupled dynamic, low-frequency (<0.1 Hz) brain activity in cerebrospinal fluid (CSF) flow and gray matter (global brain-CSF coupling) might be related to CSF clearance and thus β-amyloid accumulation. Here, we report that...

A polygenic score (PGS) for Alzheimer's disease (AD) was derived recently from data on genome-wide significant loci in European ancestry populations. We applied this PGS to populations in 17 European countries and observed a consistent association with the AD risk, age at onset and cerebrospinal fluid levels of AD biomarkers, independently of apolipoprotein E locus (APOE). This PGS was also associated with the AD risk in many other populations of diverse ancestries. A cross-ancestry polygenic...

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Mitochondria are essential for ATP production, calcium buffering, and apoptotic signaling, with mitophagy playing a critical role in removing dysfunctional mitochondria. This study demonstrates that PINK1-dependent mitophagy occurs more rapidly and is less spatially restricted in astrocytes compared to neurons. We identified hexokinase 2 (HK2) as a key regulator of mitophagy in astrocytes, forming a glucose-dependent complex with PINK1 in response to mitochondrial damage. Additionally, exposure...

The presence of α-synuclein (α-syn) aggregates, such as Lewy bodies in patients with Parkinson's disease (PD), contributes to dopaminergic cell death. Injection of PD patient-derived α-syn in nonhuman primates has illustrated the exquisite vulnerability of primate dopaminergic neurons. Here, we aimed to elucidate the temporal and spatial pathological changes induced by two distinct α-syn pathogenic structures, having large or small sizes. To unravel the underlying molecular pathways, we...

A scoping review of community health education studies for dementia prevention was conducted to clarify the form, content, outcome indicators, evaluation tools, and effects of community health education interventions for dementia prevention and to inform future research in this area. This scoping review of community-based health education interventions for Alzheimer's disease prevention across eight databases identified five intervention approaches-culturally adapted interventions, health...

Non-neuronal glial cells in the brain, such as astrocytes, play essential roles in maintaining the functional integrity of neuronal cells. A growing body of evidence suggests that cellular senescence of astrocytes, characterized by loss of proliferative potential and secretion of neurotoxic cytokines, makes significant contribution to neurotoxicity in Alzheimer's disease and a wide range of other neurodegenerative diseases. This review discusses the beneficial effects of Δ133p53α, a natural p53...

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Neurodegenerative disorders such as Alzheimer's and Parkinson's have captured researchers' attention regarding their connection to gut microbiota and dietary factors. Research has shown that changes in our regular dietary consumption can profoundly influence the composition of the gut microbiota, which possesses the capacity to influence brain functioning through a number of mechanisms, suggesting that dietary modifications may serve as promising therapeutic intervention for managing and...

Parkinson's disease (PD), the second most prevalent neurodegenerative disorder globally, is pathologically characterized by progressive degeneration of dopaminergic neurons in the substantia nigra (SN). Current therapeutic strategies primarily alleviate clinical symptoms but lack efficacy in halting or reversing neurodegeneration. Recent studies have highlighted the FGF21-ACE2 signaling axis-a synergistic interaction between fibroblast growth factor 21 (FGF21) and angiotensin-converting enzyme 2...

Light has a profound impact on non-visual functions, and clinical evidence suggests bright-light therapy's effectiveness in alleviating motor and non-motor symptoms of Parkinson's disease (PD). However, the neural mechanisms underlying these effects remain unclear. Here, we demonstrate that bright-light treatment alleviates PD symptoms in mice via distinct visual circuits. Specifically, bright-light signals transmitted by the ventral lateral geniculate nucleus alleviate non-motor symptoms, such...

Myelin ensheathment is essential for rapid axonal conduction, metabolic support and neuronal plasticity. In Alzheimer's disease (AD), disruptions in myelin and axonal structures occur, although the underlying mechanisms remain unclear. We implemented proximity labeling subcellular proteomics of the myelin-axon interface in postmortem human brains from AD donors and 15-month-old male and female 5XFAD mice. We uncovered multiple dysregulated signaling pathways and ligand-receptor interactions,...

The amyloid precursor protein (APP) family is ubiquitously expressed in the mammalian brain and implicated in Alzheimer's disease. APP family proteins participate in synaptic function and their absence impairs cognition. However, how these proteins regulate neural circuits and influence brain-behavior relationships remains unknown. Using in vivo two-photon Ca^(2+)-imaging and Neuropixels, we show that APP family knockout (KO) in excitatory neocortical and hippocampal neurons suppresses neuronal...

Effective memory formation declines in human aging. Diminished neural selectivity-reduced differential responses to preferred versus nonpreferred stimuli-may contribute to memory decline, but its drivers remain unclear. We investigated the effects of top-down attention and preclinical Alzheimer's disease (AD) pathology on neural selectivity in 166 cognitively unimpaired older participants using functional magnetic resonance imaging during a word-face/word-place associative memory task. During...

Exercise's protective effects in Alzheimer's disease (AD) are well recognized, but cell-specific contributions to this phenomenon remain unclear. Here we used single-nucleus RNA sequencing (snRNA-seq) to dissect the response to exercise (free-wheel running) in the neurogenic stem-cell niche of the hippocampal dentate gyrus in male APP/PS1 transgenic AD model mice. Transcriptomic responses to exercise were distinct between wild-type and AD mice, and most prominent in immature neurons. Exercise...

Here, we explore the potential involvement of fumarate, a metabolite generated from the TCA cycle, as a key regulator of PINK1-Parkin-mediated mitophagy. Fumarate engages in a process called succination, forming S-(2-succino) cysteine with protein cysteine residues. Our research demonstrates that this modification specifically targets the sulfhydryl group of cysteine 323 and 451 residues of human Parkin, leading to the inhibition of its mitochondrial localization and E3 ligase activity, thereby...

Amyloid aggregates are pathological hallmarks of many human diseases, but how soluble proteins nucleate to form amyloids is poorly understood. Here, we use combinatorial mutagenesis, a kinetic selection assay, and machine learning to massively perturb the energetics of the nucleation reaction of amyloid-β (Aβ42), the protein that aggregates in Alzheimer's disease. In total, we measure the nucleation rates of >140,000 variants of Aβ42 to accurately quantify the changes in free energy of...

Alzheimer's disease (AD) and hearing loss (HL) are major age-related public health challenges with emerging evidence suggesting their interconnection. This study aimed to investigate global research trends, shared molecular mechanisms, and clinical implications of AD and HL. A total of 349 articles published between 2004 and 2024 were retrieved from the Web of Science Core Collection and analyzed using VOSviewer and CiteSpace. GeneCards and STRING databases were used to explore molecular targets...

Protein misfolding and conformational instability drive protein conformational disorders, causing either accelerated degradation and loss-of-function, as in inherited metabolic disorders like lysosomal storage disorders, or toxic aggregation and gain-of-function, as in neurodegenerative diseases like Alzheimer's disease or amyotrophic lateral sclerosis. Classical homocystinuria (HCU), an inborn error of sulfur amino acid metabolism, results from cystathionine beta-synthase (CBS) deficiency. CBS...