Alzheimer & Parkinson

Genome-wide association studies have identified many loci for brain disorders, but most non-coding variants fail to colocalize with bulk expression quantitative trait loci. Single-cell expression quantitative trait loci studies capture cell-type-specific regulation but are often underpowered. We developed Bulk And Single cell expression quantitative trait loci Integration across Cell states (BASIC) to combine bulk and single-cell expression quantitative trait loci through "axis-quantitative...

Aging and age-related diseases share convergent pathways at the proteome level. Here, using plasma proteomics and machine learning, we developed organismal and ten organ-specific aging clocks in the UK Biobank (n = 43,616) and validated their high accuracy in cohorts from China (n = 3,977) and the USA (n = 800; cross-cohort r = 0.98 and 0.93). Accelerated organ aging predicted disease onset, progression and mortality beyond clinical and genetic risk factors, with brain aging being most strongly...

Intraneuronal aggregates of the microtubule-associated protein tau play a pivotal role in Alzheimer's disease and several other neurodegenerative syndromes. Anti-tau antibodies can reduce pathology in mouse models of neurodegeneration and are currently being tested in humans. Here, we performed a large-scale seroepidemiological search for anti-tau IgG autoantibodies (ατ) on 40,497 human plasma samples. High-titer ατ+ individuals were surprisingly prevalent, with hospital patients being three...

The abnormal protein degradation implicated in the pathogenesis of Parkinson's disease was previously attributed to defective H+ leakage from lysosomes via TMEM175 (https://doi.org/10.1016/j.cell.2022.05.021). In this issue, Riederer et al. (https://doi.org/10.1083/jcb.202501145) demonstrate that TMEM175 is instead a K+ channel, minimally permeable to H+.

Both microtubule-binding protein tau and RNA-binding protein TDP-43 have been associated with neurodegenerative diseases, such as Alzheimer’s disease, including in co-pathological deposition with each other, but how they interact biophysically and pathologically has been challenging to evaluate. In this issue of The EMBO Journal, Simonetti and colleagues show how tau and TDP-43 directly interact both in phase separation and pathologically associated seeding, resulting in enhanced TDP-43...

Parkinson's disease (PD) is an increasingly prevalent neurodegenerative disorder, largely sporadic in origin, with limited understanding of age- and region-specific lipid alterations in the human brain. Dysregulation of glycosphingolipid catabolism has been implicated in PD, yet comprehensive spatiotemporal profiling remains sparse. Here, we performed targeted lipidomics across eight anatomically distinct brain regions in post-mortem controls, mid-stage, and late-stage PD cases using...

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...