Alzheimer & Parkinson

Brain atrophy is a key factor behind episodic memory loss in aging, but the nature and ubiquity of this relationship remains poorly understood. This study leverages 13 longitudinal datasets, including 3737 cognitively healthy adults (10,343 MRI scans; 13,460 memory assessments), to determine whether brain change-memory change associations are more pronounced with age and genetic risk for Alzheimer's Disease. Both factors are associated with accelerated brain decline, yet it remains unclear...

Alzheimer's disease (AD) is characterized by the accumulation of amyloid beta, which is strongly associated with disease progression and cognitive decline. Despite the approval of monoclonal antibodies targeting Aβ, optimizing treatment strategies while minimizing side effects remains a challenge. This study develops a mathematical framework to model Aβ aggregation dynamics, capturing the transition from monomers to higher-order aggregates, including protofibrils, toxic oligomers, and fibrils,...

Impairment of axonal transport has been emphasized as a common feature in a series of neurodegenerative diseases (NDs). Variations in DCTN1 have been reported in NDs such as Parkinson's disease (PD), Perry syndrome (PS) and Amyotrophic lateral sclerosis (ALS). The overall objective of this study was to investigate the contribution of DCTN1 variants in different NDs and to explore the correlation between DCTN1 variants and disease phenotypes. We identified a previously published mutation p.G71E...

Patients with Alzheimer's disease (AD) initially show temporally graded retrograde amnesia, which gradually progresses into more severe retrograde amnesia. Although mouse models of AD have provided insight into neurobiological mechanisms contributing to impaired formation and retrieval of new memories, the process underlying the progressive loss of remote memories in AD has remained elusive. Here, we demonstrate age-dependent remote memory decline in APP/PS1 mice, which coincides with...

Alzheimer's disease(AD) is the most common cause of dementia and affects millions of people worldwide. The early and accurate diagnosis of AD is crucial for timely intervention and disease management. Magnetic resonance imaging (MRI) is a widely used noninvasive technique for assessing brain structure and function in patients with AD. However, conventional MRI analysis methods are often subjective, time-consuming, and depend on expert knowledge. Artificial intelligence (AI), particularly deep...

Damaged mitochondria can be cleared from the cell by mitophagy, using a pathway formed by the recessive Parkinson's disease genes PINK1 and Parkin. Whether the pathway senses diverse forms of mitochondrial damage via a common mechanism, however, remains uncertain. Here, using a novel Parkin reporter in genome-wide screens, we identified that diverse forms of mitochondrial damage converge on loss of mitochondrial membrane potential (MMP) to activate PINK1. Loss of MMP, but not the presequence...

The lack of safe, durable therapeutics that act against both biological aging and Alzheimer's disease is an unmet clinical need. To bridge this gap, we devised an artificial intelligence (AI)-enabled approach that pairs rapid compound triage with mechanistic target deconvolution. Our AI-driven screening highlighted melatonin (MLT) as a promising candidate. Serum profiling of 161 human individuals confirmed an age-related fall in circulating MLT level, while subsequent in vivo and in vitro...

Understanding the complex relationships among major clinical outcomes and the interplay among multiple organs remains a considerable challenge. By using imaging phenotypes, we can characterize the functional and structural architecture of major human organs. Mendelian randomization (MR) provides a valuable framework for uncovering robust relationships between phenotypes by leveraging genetic variants as instrumental variables. Here we conduct a systematic multi-organ MR analysis involving 402...

Type 2 diabetes is an established risk factor for dementia. However, how its genetic heterogeneity affects different dementia subtypes remains unclear. In this study, we investigate the associations between genetic risk of type 2 diabetes and dementia subtypes among 33,136 older Chinese adults from the KARE cohort. We find that a higher overall polygenic risk score for type 2 diabetes is significantly associated with an increased risk of vascular dementia, but not Alzheimer's disease. Further...

No abstract

Impulse control disorders, debilitating non-motor complications of Parkinson's disease, are linked to dopaminergic therapy and mesocorticolimbic dysfunction. This study aimed to characterize cortical sulcal depth, a sensitive morphometric index of cortical folding, and cortical thickness and subcortical volumetric alterations in Parkinson's disease patients with impulse control disorders. Sixty-eight Parkinson's disease patients (30 with impulse control disorders, 38 without impulse control...

Frailty influences the risk, phenotypic expression, and course of highly prevalent neurological conditions. However, the structural, functional, and pathological changes in the brain associated with frailty remain insufficiently explored. This narrative review examines existing evidence on the functional and pathological brain correlates of frailty in both healthy adults and patients with neurological conditions, encompassing findings from neuropathology, fluid biomarkers, neuroimaging, and...

Somatosensory processing has been shown to be correlated with brain development and cognitive function, but whether and how tactile sensory deficits affect cognition decline remains unclear. Here we show that tactile function is impaired in individuals with Alzheimer's disease (AD), and this impairment is inversely correlated with Montreal Cognitive Assessment scores and positively correlated with Tau pathology. We observed similar deficits in presymptomatic 3×Tg AD mice and find that...

Glycation, the nonenzymatic attachment of reactive dicarbonyls to proteins, lipids, or nucleic acids, contributes to the formation of advanced glycation end-products (AGEs). In Alzheimer's disease (AD), amyloid-beta (Aβ) undergoes posttranslational glycation to produce glycated Aβ (gAβ), yet its pathological role remains poorly understood. Here, we demonstrate that gAβ promotes neuronal mitochondrial DNA (mtDNA) efflux via a VDAC1-dependent mechanism, activating the innate immune cGAS-STING...

Alpha-Synuclein (αSyn) plays a central role in Parkinson's disease (PD), and the p.A53T mutation causes an early-onset familial form of PD with severe manifestations. While its effects on neurons are well studied, its consequences on astrocytes and astrocytic contribution to PD pathology are understudied. Here, we differentiated patient-derived p.A53T-αSyn induced pluripotent stem cells (iPSC) to ventral midbrain astrocytes and characterized them via comprehensive molecular, functional, and...

Despite the long interspersed nuclear element-1 (LINE1, L1) retrotransposons having been implicated in Alzheimer's disease (AD), a fundamental understanding of the AD-specific lifespan-long trajectory of L1 has been limited. Here, we characterize the content and expression of L1 covering four brain regions (hippocampus, prefrontal cortex, cerebellum, and the rest of brain tissue) of APP/PS1 mice, a murine model of AD, and their wild-type C57BL/6 littermates from 3 to 24 months of age. We report...

α-Synuclein (αSyn) aggregation is a prominent hallmark of Parkinson's disease (PD), yet the initial cellular mechanisms are not well understood. In this study, we show that a single day of αSyn preformed fibril (PFF) administration leads to prominent localization of phosphorylated αSyn (p-αSyn) within the pre-synapse of primary neurons. Overexpressing chromogranin A (CgA), which is found in large dense-core vesicles (LDCVs), enhances αSyn aggregation in various neuronal and PD mouse models....

Aging-associated neurodegeneration underlies various neurological diseases; however, the neurocrine basis remains poorly understood. Here, we investigate the role of parathymosin (PTMS), a secretory protein with nuclear functions that has recently been identified as a circulating factor in the brain. The results show that loss of PTMS is sufficient to cause severe, age-dependent neurodegeneration and reduced lifespan, whereas hypothalamic PTMS gain of function counteracts aging-associated brain...

High-resolution structure determination of ex vivo amyloid fibrils offers critical mechanistic insights into amyloid polymorphism and heterogeneity of neurodegenerative diseases. However, purifying amyloid fibrils from diseased brains may favor certain polymorphs over others. Here, instead of purifying fibrils, we used in situ amplification (ISA) of α-synuclein (α-syn) fibrils in brain homogenates. Cryoelectron microscopy (cryo-EM) structural analysis of the ISA fibrils from patients with...

Mitochondrial dysfunction is a hallmark of Parkinson's disease (PD), but the mechanisms by which it drives autosomal dominant and idiopathic forms of PD remain unclear. To investigate this, we generated and performed a comprehensive phenotypic analysis of a knock-in mouse model carrying the T61I mutation in the mitochondrial protein CHCHD2 (coiled-coil-helix-coiled-coil-helix domain-containing 2), which causes late-onset symptoms indistinguishable from idiopathic PD. We observed pronounced...