Alzheimer & Parkinson

Losing track of personal experiences is a defining feature of Alzheimer disease (AD), arising from the spread of AD pathology through the brain circuits that support episodic memory. In this Review, we explore strategies to improve the function of episodic memory circuits in AD by leveraging the optimized use of neural resources. We introduce the circuit utilization framework, which builds on evidence that synaptic dysfunction, maladaptive responses and deficient adaptive plasticity contribute...

Parkinson's disease (PD) is a debilitating neurodegenerative condition that results in a loss of mobility and muscle control. A neuropathological hallmark of PD is the presence of aberrant inclusions, known as Lewy pathology, of which α-synuclein (α-Syn) is a major component. The accumulation of α-Syn may be due to an imbalance in the proteostasis system regulating α-Syn. To investigate this hypothesis, we delineated the proteostasis network (PN) of α-Syn in the human substantia nigra at the...

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Alzheimer's disease (AD), an age-associated neurodegenerative disorder, is characterized by progressive cognitive decline, amyloid-β (Aβ) accumulation (including soluble oligomers and deposited aggregates), lipid dysregulation, and neuroinflammation. Although mutations in the amyloid precursor protein (APP) and accumulation of Aβ42 are established drivers of pathology, the mechanisms connecting oligomeric amyloid toxicity with lipid metabolism and inflammatory responses remain poorly understood....

Neuroinflammation is a pathological feature of neurodegenerative diseases like Alzheimer's disease and ALS. Cytoplasmic dsRNA (cdsRNA) triggers a type-I interferon response in human neural cells, leading to their death, and is found in neurons of C9ORF72-ALS patients. Here, we report the spatial coincidence of cdsRNA and pTDP-43 inclusions in human postmortem tissue with Alzheimer's disease pathology, and upregulated interferon response genes in affected regions. CdsRNA also accumulates in a...

The connection between aging and immune dysfunction is uncovering how immunoaging processes contribute to disease. Recent data from Alzheimer’s disease, Parkinson’s disease, and adult and pediatric glioblastomas reveal a novel role for TIM3 in brain immune alteration. These findings highlight the role of TIM3 in promoting myeloid cell dysfunction toward an immunosuppressive profile. TIM3-blocking antibody treatments for central nervous system pathologies could be a new therapeutic window for...

Type 1 diabetes, particularly with childhood onset, is associated with altered neurocognitive traits, yet the underlying biological mechanisms are unclear. Here, we integrate genome-wide association results with single-cell epigenomic profiles and show that type 1 diabetes heritability is enriched in accessible chromatin of human brain-resident cells, most notably microglia, across neurodevelopment into adulthood. Bonferroni-corrected cross-trait genetic correlation analyses reveal negative...

Aging is the strongest risk factor for chronic diseases such as cardiovascular disease, Alzheimer's, and cancer. DNA methylation (DNAm) clocks offer a promising measure of biological age, but most rely on linear models that miss non-linear dynamics and CpG interactions. To address this, we developed a deep neural network (DNN)-based DNAm clock trained on 29,167 samples profiled on Illumina EPIC v1.0 and v2.0 arrays. Using 12,234 CpGs selected through sex- and age-stratified correlations, our...

Deep brain stimulation (DBS) is an effective treatment for Parkinson's disease (PD) but its neural mechanisms remain poorly understood. A mechanistic understanding requires precise characterization of functional responses to various stimulation conditions within the same individual. Here we use 3-T magnetic resonance imaging (MRI)-compatible DBS and precision imaging to collect extensive data from 14 patients with PD who received DBS. Across five timepoints spanning 1 year, each patient...

Neurofibrillary tangles (NFTs) formed from the protein tau disrupt neuronal function in Alzheimer's disease and are strongly associated with cognitive decline. Early events in tau aggregation are increasingly linked to the formation of biomolecular condensates, which lower the energetic barriers to pathological aggregation by acting as intermediates that transition into insoluble assemblies, a mechanism also implicated in other neurodegenerative diseases, such as amyotrophic lateral sclerosis...

Transcriptome-wide association studies (TWAS) have successfully identified genes associated with complex traits and diseases, but most have been performed using bulk gene expression data, which aggregate signals across heterogeneous cell types. Population-scale single-cell RNA sequencing data now make it possible to perform TWAS at the cell-type resolution, but present unique challenges due to strong noises, technical variations, and high sparsity. Here, we propose scTWAS, a statistical method...

Traditional Alzheimer's disease (AD) research has predominantly focused on neuronal pathology within the amyloid-tau-neurodegeneration (ATN) framework, emphasizing β-amyloid (Aβ) plaques, neurofibrillary tangles (NFTS), and neuroinflammation as primary drivers of disease progression. Recently, converging evidence suggests that oligodendrocytes (OLs) and myelin abnormalities are not merely downstream consequences of neuronal injury. Instead, OL dysfunction may emerge early and actively shape...

Recent advances suggest a correlation between gut dysbiosis and neurological diseases, however, relatively little is known about how gut bacteria impact the brain. Here, we reveal that bacteria can translocate directly from the gut to the brain in small numbers when mice are fed an atherogenic, high-fat diet (Paigen diet) that causes alterations in gut microbiome composition and gut barrier permeability. The bacteria were not found in other systemic sites or the blood, but were detected in the...

Acute stress triggers the release of cortisol, which broadly affects cognitive processes. Path integration, a specific navigational process, relies heavily on grid cells in the entorhinal cortex. The entorhinal cortex contains glucocorticoid receptors and is therefore likely to be influenced by cortisol, though little is known about this relationship. Given the role of the entorhinal cortex in neurological diseases such as Alzheimer's Disease, investigating the effects of cortisol on this brain...

Detecting small extracellular vesicles is critical for understanding disease biology and developing diagnostic tools, yet current methods require lengthy isolation steps and lack sensitivity owing to interference from abundant proteins. Here we report on an assay that uses Janus particles that enable rapid, isolation-free detection by exploiting Brownian rotation-induced blinking changes. When vesicles bind, their size significantly alters the blinking frequency, while smaller proteins produce...

Elevated blood levels of phosphorylated tau (p-tau) are diagnostic of Alzheimer disease and are associated with the deposition of amyloid-β in the cerebral neuropil. Elevated p-tau levels have also been associated with cerebral deposition of Danish amyloid and prion protein amyloid. Here we analyzed p-tau in serum from four different cohorts of people with the most common types of systemic amyloidosis, transthyretin (ATTR) amyloidosis and immunoglobulin light chain (AL) amyloidosis. We found...

Microglia are implicated in the progression of Alzheimer's disease (AD) pathology from its earliest stages, suggesting that cerebrospinal fluid (CSF) microglia profiling across clinical AD stages can aid in treatment development and monitoring. We analyzed two CSF cohorts (n = 834) that span from unimpaired controls to preclinical and dementia AD stages, identifying 109 dysregulated microglia-related proteins. Enrichment analyses revealed innate immune processes and cellular recruitment in...

Preclinical Alzheimer's disease (AD) is associated with distressing neuropsychiatric symptoms (NPSs) that may accelerate progression toward dementia. Existing approaches probe the symptom-level domain-general or domain-specific neural correlates of NPSs. However, the field lacks process-oriented models of symptom emergence for targeted treatment. We propose one pathway for symptom emergence involving the disruption of emotion regulation (ER) systems by early AD pathology. AD pathology in the...

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by β-amyloid (Aβ) deposition, tau hyperphosphorylation, neuroinflammation, and cholinergic dysfunction. Currently, no disease-modifying drugs are available, and existing symptomatic treatments offer limited efficacy while posing safety concerns, highlighting the urgent need for multi‑target therapeutic strategies. The natural β‑carboline alkaloid harmine has attracted considerable attention due to its favorable...

Extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated Tau are the two main pathological hallmarks of Alzheimer's disease (AD). Although the co-occurrence and synergistic effects of Aβ and Tau are well established, the mechanisms underlying their interplay in a biomolecular condensate environment remain unclear. Here we show that Aβ40 does not undergo liquid-liquid phase separation (LLPS) but significantly enhances Tau phase...