Alzheimer & Parkinson

Tauopathies, such as Alzheimer's disease, are neurodegenerative disorders characterized by the accumulation and propagation of toxic extracellular forms of the microtubule-associated protein tau across brain regions. Microglia, the resident macrophages of the brain, are known for clearing and degrading toxic proteins. However, emerging evidence suggests that microglia also enhance tau spreading. To dissect the molecular mechanisms underlying microglial responses to extracellular tau, we use...

Spatial multi-omic technologies measure multiple molecular layers within intact tissues. Two central challenges are vertical integration, which combines different molecular modalities, and horizontal integration, which aligns cell types across studies. Here we show domain invariant representation through adaptive calibration (DIRAC), a geometric deep learning model that unifies these tasks in a generalized domain adaptation framework. DIRAC learns task-discriminative features that are...

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and dementia with Lewy bodies have long been viewed through the lens of protein aggregation. Emerging evidence, however, highlights lipid transfer, load, metabolism, and cellular homeostasis as upstream drivers of pathology. This perspective integrates established neurobiological, genetic, and mechanistic evidence of lipid dysfunction and outlines how these pathways can guide patient stratification, biomarker discovery,...

CONCLUSIONS: This preliminary single-center cross-sectional study revealed significant differences in brain structure and function between PD-WO and PD-nWO patients. These findings provide a better understanding of the neural mechanisms behind the WO phenomenon in PD and suggest potential therapeutic targets.

Pharmacotherapies for obesity and type 2 diabetes are increasingly being evaluated for their effects on cognition and brain health. Evidence from preclinical models, observational cohorts, and clinical trials has intensified interest, but findings remain mixed. A central challenge is to determine whether potential cognitive effects arise from direct actions on neural circuits, indirect consequences of improved cardiometabolic health, or both. This Review examines the evidence across...

While the accumulation of Aβ peptides, derived by proteolytic cleavage from the amyloid precursor protein APP, constitutes a hallmark of Alzheimer's disease, the question of whether endogenous, physiological APP processing serves an essential role for normal brain function(s) has remained elusive. Here, we modified the mouse APP locus to delete the endogenous α- and β-secretase sites (APP residues S592-G621) while preserving the transmembrane topology and the APP C-terminus. These novel knockin...

The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer's disease (AD), influencing amyloid-β (Aβ) aggregation, clearance, and glial function. While APOE4 promotes Aβ pathology and APOE2 is protective, how these opposing alleles interact in the heterozygous APOE2/4 state remains unknown. Here, using littermate-controlled heterozygous APOE mice (APOE2/3, APOE3/4, and APOE2/4) alongside APOE3/3 controls crossed with 5xFAD mice, we show that APOE3/4 mice exhibit...

No abstract

Parkinson's disease (PD) is a growing public health challenge as populations age. Current diagnosis relies on motor symptoms and invasive procedures, making early detection difficult. Here we present Quest2Dx, a generalized artificial intelligence model that analyzes health questionnaires to enable low-cost, non-invasive PD screening. Conventional models are built for each questionnaire, and missing responses degrade their performance. Quest2Dx uses language modeling to encode the meaning of...

No abstract

No abstract

No abstract

No abstract

No abstract

No abstract

No abstract

No abstract

No abstract

P2X purinoreceptor 7 (P2RX7), an ATP-gated ion channel, contributes to Alzheimer's disease (AD) progression, but its molecular mechanisms remain unclear. Here, we show that genetic disruption of P2rx7 mitigates brain atrophy, tau accumulation, and cognitive impairment in PS19 mice. Microglia-specific, but not astrocyte-specific, deletion of P2rx7 suppresses tau propagation. Single-cell RNA sequencing identifies a previously unrecognized first-responding microglial state (FRM) with prominent...

Early sleep disruption is a hallmark of preclinical Alzheimer's disease (AD), but its underlying mechanisms are unclear. The locus coeruleus (LC) dopamine-β-hydroxylase noradrenergic (LC^(DBH)) neurons are vulnerable to early tau pathology in AD. Using P301S transgenic mice and cell-type-specific tau overexpression models, we show that pathological tau accumulation selectively increases the intrinsic excitability of LC^(DBH) neurons. Tau-induced neuronal hyperactivity disrupts sleep homeostasis,...