Alzheimer & Parkinson

No abstract

Alzheimer disease (AD) is defined biologically by the presence of amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain; however, these pathologies do not affect all brain regions equally. Typical AD usually presents with memory impairment, whereas atypical forms of AD, including posterior cortical atrophy, logopenic variant primary progressive aphasia, behavioural and dysexecutive AD, and corticobasal syndrome, manifest with prominent non-memory symptoms. Aβ biomarkers usually...

Although women live longer, they paradoxically face heightened susceptibility to cognitive and systemic decline emerging in midlife-an underexplored transition from resilience to vulnerability. Here, we investigate biological processes associated with this female-biased vulnerability and their molecular regulation. Senescence-associated features were preferentially elevated in middle-aged females in human brain and spleen tissues, with similar changes in mice. In female mice, epigenetic...

Microglia, the brain's resident immune cells, rely on histone modifications and chromatin remodeling to sculpt their identity across the trajectory from development through aging. Recent studies have identified enhancer rewiring and metabolic-epigenetic coupling-exemplified by histone lactylation-as central drivers of microglial plasticity. Disruption of this regulatory balance drives the transition from homeostatic microglia toward disease-associated microglia (DAM) in Alzheimer's and...

APOE gene variants encoding the apolipoprotein E (ApoE) protein are strong genetic modifiers of risk of Alzheimer's disease (AD) with the APOE ε4 allele (APOE4) associated with substantially increased disease risk, APOE ε2 allele (APOE2) associated with decreased risk and APOE ε3 allele (APOE3) considered neutral. Recently the Christchurch variant of APOE3 (APOE3CH) has been shown to protect people from familial AD. Despite this strong evidence for APOE mediating AD risk, the exact biological...

Alzheimer's disease (AD) involves complex neuroimmune dysregulation, and the role of immune checkpoint pathways in regulating neuro-glial interactions and intrinsic glial homeostasis remains unclear. In AD, glial expression of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) is elevated in mouse models and human patients, suggesting involvement of immune checkpoint signaling in glial function. To define the role of this pathway in the AD brain, we locally modulated PD-1/PD-L1...

Toward development of an autologous, induced pluripotent stem cell (iPSC)-based cell therapy for Parkinson's disease (PD), we demonstrate successful, reproducible genomic and transcriptomic qualification of patient-derived dopaminergic neuron precursor cells (DANPCs) across multiple donors. Our analysis includes whole-genome sequencing data from fibroblasts, iPSCs, and DANPCs and the development of NeuriTest, an RNAseq-based bioinformatic analysis of DANPCs designed to predict cell quality based...

The role of physical fitness in cognitive reserve and brain maintenance remains unclear. We investigated the associations of muscular and aerobic fitness (VO(2)max) with markers of brain health and cognition in 353 cognitively unimpaired older adults (mean age = 72.77 ± 7.95 years; 177 females). Muscular fitness comprised handgrip strength, appendicular skeletal muscle mass, and Timed-Up-and-Go performance. Blood biomarkers of Alzheimer's pathology (Aβ(1-42)/Aβ(1-40), p-tau(217), GFAP) and...

Lipid droplets are dynamic cellular organelles that store neutral lipids and coordinate metabolic and stress-response pathways. In the brain, lipid droplets in glial cells, including astrocytes, have been implicated in Alzheimer's disease, but how genetic risk factors influence their composition and turnover remains poorly understood. APOE is the strongest genetic modulator of late-onset Alzheimer's disease and exists in common variants that confer decreased, neutral, or increased risk. Here we...

No abstract

Sex differentially shapes aging, neurodevelopment and neurodegenerative diseases such as Alzheimer's disease (AD). However, most biological aging clocks (artificial intelligence-predicted age minus chronological age) were trained on sex-pooled samples and implicitly assume sex invariance.Here we developed 38 sex-specific biological aging clocks across 15 organ systems. We first demonstrate the importance of sex-stratified training for constructing sex-specific healthy normative references and...

Mild cognitive impairment (MCI) is an important prodromal stage of Alzheimer's disease, and its early identification is critical for risk assessment and timely intervention. Resting-state functional magnetic resonance imaging (rs-fMRI) can noninvasively characterize brain functional activity and connectivity. However, most existing methods rely on static second-order functional connectivity, limiting their ability to capture dynamic coordination and high-order interactions among multiple brain...

Alzheimer's disease is widely depicted as a linear cascade from amyloid-β accumulation to Tau pathology and neurodegeneration. We propose instead that the disease unfolds through discrete molecular, cellular and network phases organized around biological inflection points. At these thresholds, stress-driven loss of homeostasis produces qualitative shifts in cellular behavior that alters disease progression. These altered states spread across local tissue-domains, accumulate as a mosaic across...

Dysregulated dopamine (DA) signaling and redox homeostasis contributes to multiple neuropsychiatric and neurodegenerative disorders. Polymorphisms that influence the activity of catechol-O-methyltransferase (COMT), an enzyme critical for degrading DA in the dorsolateral prefrontal cortex, have been implicated in behavioral and neuropsychiatric alterations associated with schizophrenia (SCZ). Adverse neuropsychiatric effects have also been reported in Parkinson's disease (PD) patients...

Identifying features that interact to trigger disease, while accounting for heterogeneity across diverse populations, is essential for the development of precision and targeted medicine. Despite the availability of vast and complex health-related datasets, most existing works focus on identifying disease-associated features at the population level or within a few subpopulations, often overlooking individual-level heterogeneity within these groups. To address this limitation, we propose a...

Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E (APOE) gene ɛ2/ɛ3/ɛ4 polymorphisms remain the longstanding benchmark for genetic disease risk with a consistently large effect across studies^(1-10). Despite this massive signal, the exact mechanisms by which ɛ4 increases and ɛ2 decreases dementia risk remain poorly understood. Notably, recent trials of anti-amyloid therapies suggest less efficacy and higher...

Understanding the molecular basis of neurodegeneration requires a comprehensive map of the genome's protein-coding output. Although thousands of small open reading frames (ORFs) are translated in the human brain, proteomic evidence for their encoded microproteins (MPs) (≤150 amino acids (aa)) remains limited. Here, we present a brain MP atlas that integrates transcriptomics, mass spectrometry and deep-learning-predicted spectra across more than 600 postmortem frontal cortex samples with and...

Parkinson's disease (PD) is a progressive neurodegenerative disorder influenced by both genetic and epigenetic mechanisms. Among these mechanisms, DNA methylation has emerged as a key regulatory process affecting gene expression without altering the DNA sequence. The synuclein alpha (SNCA) gene is a well-established contributor to Parkinson's disease pathogenesis, yet the extent and consistency of its methylation changes remain unclear. This scoping review aimed to map and summarise existing...

Dementia is a progressive neurodegenerative syndrome characterised by cognitive decline, synaptic dysfunction, and neuronal loss. In recent years, growing attention has been given to the role of the gut-brain axis in neurodegenerative disease. Emerging evidence indicates that changes in gut microbiota composition and metabolic activity may affect various systemic processes that contribute to dementia. This review examines the current evidence linking gut microbiota imbalance to dementia through...

Phosphorylation-targeting chimeras (PhosTACs) enable targeted protein dephosphorylation by recruiting phosphatases through induced proximity. However, the direct recruitment of phosphatase subunits or holoenzymes with small molecules remains challenging, as suitable ligands are scarce and often compromise enzymatic activity or cellular function. Here, we present togoPhosTAC, a hybrid modality that integrates a small-molecule PhosTAC, an engineered FKBP12^(F36V)-phosphatase, and a lipid...