Alzheimer & Parkinson

Dementia is a defining feature of Lewy body disease: its timing and onset distinguish different clinical diagnoses, and its effect on quality of life is profound. However, it remains unclear whether processes leading to cognitive and motor symptoms in Lewy body disease differ. To clarify this, we use in-vivo neuroimaging to assess spatial gradients of inter-regional differences in structural and functional connectivity in 108 people across the Lewy body disease spectrum (46 Parkinson's with...

Protein misfolding plays a central role in diseases such as Alzheimer's disease, Parkinson's disease, type 2 diabetes, and transthyretin amyloidosis (ATTR), often driven by specific aggregation-prone segments such as Aβ(17-23) and Aβ(37-42) of amyloid-β42 (Aβ42), α-Syn(66-74) and α-Syn(71-82) of α-synuclein (α-syn), hIAPP(22-27) of human islet amyloid polypeptide (hIAPP), and TTR(105-115) of transthyretin (TTR). Capturing the atomic-level structural features of these transient and dynamically...

Controversies over anti-amyloid immunotherapies underscore the need to elucidate their mechanisms of action. Here we demonstrate that Lecanemab, a leading anti-β-amyloid (Aβ) antibody, mediates amyloid clearance by activating microglial effector functions. Using a human microglia xenograft mouse model, we show that Lecanemab significantly reduces Aβ pathology and associated neuritic damage, while neither fragment crystallizable (Fc)-silenced Lecanemab nor microglia deficiency elicits this effect...

Alzheimer's disease causes progressive cognitive decline, yet some individuals remain resilient despite developing hallmark pathology. A subset of people with Down syndrome (DS), the most common genetic cause of Alzheimer's disease, demonstrates such resilience. Given the elevated risk of hematopoietic mutations in DS, we hypothesize that certain variants may confer microglial resilience. Here, we introduce a myeloid DS-linked CSF2RB A455D mutation into human pluripotent stem cell-derived...

Delirium is an acute change in cognition, common in hospitalized older adults, and associated with high healthcare and human cost; however, delirium's genetic and proteomic background remains poorly understood. Here we conducted a genetic meta-analysis on delirium using multi-ancestry data from the UK Biobank, FinnGen, All of Us Research Program and Michigan Genomics Initiative cohorts (n = 1,059,130; 11,931 cases), yielding the Apolipoprotein E (APOE) gene as a strong delirium risk factor...

No abstract

Parkinson's disease is a neurodegenerative condition, marked by a progressive deterioration in both motor and non-motor abilities, which can severely affect the quality of life of the elderly population. With no cure available, innovative tools in treatment development and drug discovery are necessary. For several years, traditional models have been essential; however, they face limitations in replicating the complex setting of Parkinson's disease. In this regard, in silico and in vitro models...

Alzheimer's disease, the leading cause of dementia in the elderly, is a neurodegenerative disorder that has been studied to uncover therapeutic pathways through its molecular and cellular hallmarks. Here, we present a comprehensive investigation of cellular heterogeneity from the temporal cortex region of 40 individuals, comprising healthy donors and individuals with differing AD pathology. Using single-nucleus transcriptomic analysis of 430,271 nuclei from both gray and white matter of these...

The human brain is one of the most metabolically active tissues in the body, due in large part to the activity of trillions of synaptic connections. Under normal conditions, macroautophagy/autophagy at the synapse plays a crucial role in synaptic pruning and plasticity, which occurs physiologically in the absence of disease- or aging-related stressors. Disruption of autophagy has profound effects on neuron development, structure, function, and survival. Neurons are dependent upon maintaining...

The amyloid precursor protein (APP) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). While the production of Amyloid beta (Aβ) has traditionally been considered the primary cause of AD, the role of the APP intracellular domain (AICD) remains largely elusive. In this study, we established a novel model in the adult fly wing by expressing human APP, recapitulating AD-associated axon degeneration. Using this model, we discovered that ectopic APP expression in Drosophila wing...

Type 2 diabetes mellitus (T2DM) is increasingly recognized as a shared pathological substrate for both sarcopenia and cognitive decline, particularly Alzheimer's disease (AD). This review synthesizes current evidence on the converging molecular pathways linking insulin resistance, hyperglycaemia, mitochondrial dysfunction, oxidative stress, and chronic inflammation to muscle wasting and neurodegeneration. Central to this interplay is the muscle-brain axis, a bidirectional communication network...

Blood biomarkers of Alzheimer's disease (AD) are promising for dementia prediction, but their association with progression across intermediate stages of cognitive decline in the general population remains unclear. We followed 2148 dementia-free individuals from a Swedish population-based cohort for up to 16 years. Associations between baseline AD blood biomarkers and transitions between normal cognition, mild cognitive impairment (MCI), and dementia were examined. Lower amyloid-β42/40 ratio and...

Spatial disorientation is emerging as an early cognitive biomarker of dementia, but the underlying neural mechanisms remain undefined. The anterodorsal nucleus of the thalamus (ADn) exhibits early and selective vulnerability to pathological misfolded forms of tau, a major hallmark of Alzheimer's disease. As the ADn contains a high density of head direction (HD) cells, we hypothesized that ptau disrupts HD cell activity, promoting spatial disorientation. To test this, we virally expressed human...

Astrocytes play essential roles in the brain, and their dysfunction is associated with nearly every form of neurological disease. Despite their ubiquity, knowledge of how astrocytes contribute to disease pathogenesis is incomplete; accordingly, harnessing their biology toward therapeutics remains a major challenge. Here we show that the transcription factor Sox9 plays a context-specific role in maintaining astrocyte function and circuit activity in the aging hippocampus and Alzheimer's disease...

Sex-biased differences in Alzheimer's disease (AD) are well documented, but the mechanisms underlying increased vulnerability in postmenopausal women remain unclear. This study aimed to model the effects of perimenopausal hormonal fluctuations on AD pathophysiology. Using a VCD-induced accelerated ovarian failure model in young female C57BL/6 J and 3xTg mice, we simulated a perimenopausal state with hormonal changes characterised by elevated oestradiol levels and reduced progesterone levels....

Cell type-specific analysis is crucial for uncovering biological insights hidden in bulk tissue data, yet single-cell or single-nuclei approaches are often cost-prohibitive for large samples. We introduce EPIC-unmix, a novel two-step empirical Bayesian method combining reference single-cell/single-nuclei and bulk RNA-seq data to improve cell type-specific inference, accounting for the difference between reference and target datasets. Under comprehensive simulations, we demonstrate that...

Expressed in the entorhinal cortex (EC), the cholecystokinin (CCK) B receptor (CCKBR) plays an important role in memory and learning. Here, we identify that CCKBR-Gs and -Gq signaling, rather than CCKBR-Gi signaling, are beneficial for Alzheimer's disease (AD) treatment. Clinically, patients with more severe AD associated with lower CCKBR-Gq activity. The cryo-electron microscopy (cryo-EM) structures of CCKBR in complex with the endogenous agonist sulfated CCK8 (CCK8s) and 3 different G protein...

Alzheimer's disease (AD), a leading neurodegenerative disorder, involves blood-brain barrier (BBB) dysfunction as a critical contributor to its pathogenesis. This review synthesizes current advancements in in vivo magnetic resonance imaging (MRI) and positron emission tomography (PET) techniques for imaging BBB breakdown in AD. The BBB, a dynamic neurovascular interface, regulates amyloid-beta (Aβ) and tau clearance through specialized transporters and cellular interactions. BBB dysfunction,...

Alzheimer's disease (AD) is a complex neurodegenerative disorder driven by multilayered molecular and cellular mechanisms that cannot be fully elucidated through single-omics approaches. Consequently, large-scale multi-omics integration-encompassing transcriptomics, epigenomics (e.g., methylation), and genetic association studies (GWAS/eQTL/mQTL)-has uncovered critical genetic and epigenetic networks underlying disease risk and progression.Based on these integrative insights, this review...

Alzheimer's disease (AD), the most prevalent neurodegenerative disorder, remains a global health crisis due to the lack of early diagnostic tools, dynamic monitoring strategies, and effective therapies. Current diagnostic methods such as cerebrospinal fluid (CSF) analysis and neuroimaging, while accurate, are invasive, expensive, and unsuitable for routine screening, highlighting the pressing need for alternative approaches. This review comprehensively examines the transformative role of...