Alzheimer & Parkinson

Healthy aging is shaped by the exposome-the accumulation of exposures experienced across the life course arising from intersections of the natural, physical, social, community and policy environments in which people age. This Consensus Statement reports recommendations from the Gateway Exposome Coordinating Center to accelerate life-course research on the exposome's impacts on healthy aging, including Alzheimer's disease and related dementias. Recommendations centered on five themes are...

Aging is the major risk factor for neurodegenerative disease, yet how it affects different cells in the primate brain remains unclear. In this issue of Cell, Yang et al. present a single-nucleus atlas of the aging macaque brain that, together with recent work by Zhang et al., reveals context-dependent aging programs, sex-biased transcriptional aging, and molecular links to Alzheimer's disease.

The basal ganglia (BG) underlie motor control, reward processing, and many neurological and psychiatric disorders, yet cell-type-resolved epigenomic and 3D genome maps of the human BG remain limited. Here, we present a multimodal single-cell atlas of DNA methylation (261,331 nuclei) and 3D chromatin conformation (229,286 nuclei) from eight subregions, harmonized under the BG consensus taxonomy and integrated with matched data across multiple regulatory layers. We identify millions of...

Brain aging is a complex process with profound health and societal consequences. However, the molecular and cellular pathways that govern its progression, and inter- and intra-individual variation, remain poorly defined. We present a transcriptomic atlas of 5.3 million cells from 582 samples spanning 11 brain regions of 55 rhesus macaques (aged 0.5-21 years). We identify age-depleted and vulnerable neuronal populations and subtle, age-associated compositional differences in glia-detectable only...

The anterior caudate shows a pattern of Alzheimer's disease pathology that differs from the more extensively studied cortex. Across 41 donors, we found mostly diffuse amyloid beta plaques in gray matter and phosphorylated tau threads associated with white matter. Combining digital pathology with single-nucleus and spatial gene expression data, we detected no significant loss or gain in neuronal cell-type abundance with increasing pathology. However, we did observe increases in an FLT1+/IL1B+...

Spatial omics enables the integration of high-dimensional molecular organization with clinical outcomes, yet incorporating spatial single-cell information into predictive models at the population scale remains challenging. We introduce SPIN (spatial predictive integration network), which integrates subject-specific, cell-type level, spatially informed co-expression or co-abundance networks for population-scale clinical prediction. Current implementation of SPIN includes three key modules:...

Degeneration of dopamine (DA) neurons and reduced DA levels in the brain is recognized as an underlying cause of Parkinson's Disease (PD). Levodopa (L-DOPA) is the standard treatment, but its effectiveness wanes over time and prolonged use can cause L-DOPA-induced dyskinesia (LID). AAV-mediated aromatic L-amino acid decarboxylase (AADC) expression in the striatum combined with L-DOPA shows promise for symptomatic improvement but requires invasive delivery. Here, we generate enhancer-driven AAVs...

Single-cell reference mapping is increasingly central to translating heterogeneous datasets into consistent representations of cell identity. As cell-type atlases expand in scale and complexity, mapping new data to shared references enables reproducible annotation, cross-study integration, and accumulation of biological knowledge. We present MapMyCells, an open-source, high-performance framework for mapping diverse single-cell omics datasets to hierarchical reference taxonomies with minimal...

Single-cell RNA technologies enable the routine acquisition of transcriptomic atlases. However, these molecular profiles are influenced by overlapping sources of variation. Since these covariates confound comparisons, data integration is the first step in most analyses. Three challenges remain: correcting strong batch effects, scaling to millions of cells, and modeling how covariates influence gene expression. To address these challenges, we developed PIANO, probabilistic inference autoencoder...

How an unpopular hypothesis linking Alzheimer's disease to the loss of crucial neurons made a comeback.

Parkinson's disease (PD) is marked by progressive dopamine neuron degeneration, but the phagocytic receptors and cells that clear neuronal corpses remain ill-defined. Moreover, while other cell types like glia, epithelia, and muscle are also impacted in PD, their roles in disease progression are unclear. We report that multiple nonneuronal cell types modulate dopamine neurodegeneration in Caenorhabditis elegans. Astrocyte-like CEPsh glia respond to neuronal stress and regulate dopamine...

Although cerebellum is neuropathologically affected in Alzheimer's disease (AD) and AD-related dementia (ADRD), the cell type-specific genomic and epigenomic changes remain poorly understood. Here, we present single-nucleus multiome (RNA-seq and ATAC-seq) analysis of 103,861 nuclei isolated from both the cerebellum and frontal cortex of diseased individuals and cognitively healthy controls. We identify 431,834 significant peak-to-gene linkages across cell subtypes, revealing cis-regulatory...

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The blood-brain barrier (BBB) has been defined primarily by what it excludes, yet the scale and function of physiological blood-to-brain protein transport remain largely unknown. Using bioorthogonal proteomics, we find that the healthy BBB samples 191 plasma proteins and permits 92 into the brain parenchyma. Enriched for carrier and metabolic functions, these proteins home to distinct brain cell types, such as apolipoprotein A1 (APOA1) to astrocytes and alpha-1 antitrypsin (SERPINA1) to...

Alzheimer's disease (AD), the leading cause of dementia, is increasingly recognized as a metabolic disorder characterized by disrupted insulin and insulin-like growth factor-1 signaling in the brain, a concept now referred to as type 3 diabetes. Central to this perspective is the insulin receptor substrate-1/phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (IRS-1/PI3K/Akt/mTOR) cascade, which acts as the primary convergence point linking systemic insulin resistance to...

Cholinergic dysfunction is a hallmark of Alzheimer's disease and other memory disorders. Yet, the neurophysiological mechanisms linking cholinergic signaling to memory remain poorly understood. In this study, we administered scopolamine, a muscarinic cholinergic antagonist, to neurosurgical patients with intracranial electrodes as they performed an associative recognition memory task. When scopolamine was present at encoding, we observed disruptions to hippocampal slow theta oscillations (2-4...

White matter free water (FW-WM), quantified using diffusion MRI, reflects extracellular water content and microstructural alterations within water matter, but its genetic architecture and clinical relevance remain largely uncharted. We conducted a multi-omics study integrating 42,039 individuals from the UK Biobank and Alzheimer's Disease Neuroimaging Initiative cohorts to characterize tract-specific FW-WM across genetic, phenotypic, and proteomic dimensions. Genome-wide association analyses...

Slow waves during sleep are fundamental for neural homeostasis, metabolic regulation, and waste clearance and are known to be altered in neurodegenerative diseases. Sleep-like slow waves (SLSWs) have been observed in awake, healthy individuals, where they are linked to fluctuations in vigilance and mind-wandering. Whether SLSWs are altered in Parkinson's disease (PD), and whether such alterations contribute to psychiatric or cognitive complications, remains unknown. In a cohort of 84 nondemented...

Lewy body dementia (LBD), encompassing Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB), is defined by widespread α-synuclein (αSyn) aggregation and frequently exhibits coexistent tau and amyloid-β (Aβ) pathologies. However, whether αSyn pathology is sufficient to drive endogenous tau and Aβ aggregation has remained unclear due to a lack of in vivo models that recapitulate the full spectrum of LBD-associated proteinopathies and neurodegeneration. AIMP2, a parkin substrate...

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