Distinct medical and substance use histories associate with cognitive decline in Alzheimer's Disease.

Introduction: Phenotype clustering reduces patient heterogeneity and could be useful when designing precision clinical trials. We hypothesized that the onset of early cognitive decline in patients would exhibit variance predicated on the clinical history documented prior to an Alzheimer's Disease (AD) diagnosis.

Methods: Self-reported medical and substance use history (i.

Multi-omics after O-GlcNAc alteration identified cellular processes promoting aneuploidy after loss of O-GlcNAc transferase.

Objective: Pharmacologic or genetic manipulation of O-GlcNAcylation, an intracellular, single sugar post-translational modification, are difficult to interpret due to the pleotropic nature of O-GlcNAc and the vast signaling pathways it regulates.

Method: To address the pleotropic nature of O-GlcNAc, we employed either OGT (O-GlcNAc transferase), OGA (O-GlcNAcase) liver knockouts, or pharmacological inhibition of OGA coupled with multi-Omics analysis and bioinformatics.

Results: We identified numerous genes, proteins, phospho-proteins, or metabolites that were either inversely or equivalently changed between conditions.

Inhibiting mtDNA transcript translation alters Alzheimer's disease-associated biology.

Introduction: Alzheimer's disease (AD) features changes in mitochondrial structure and function. Investigators debate where to position mitochondrial pathology within the chronology and context of other AD features.

Methods: To address whether mitochondrial dysfunction alters AD-implicated genes and proteins, we treated SH-SY5Y cells and induced pluripotent stem cell (iPSC)-derived neurons with chloramphenicol, an antibiotic that inhibits mtDNA-generated transcript translation.

Gene interactions analysis of brain spatial transcriptome for Alzheimer's disease.

Recent studies have explored the spatial transcriptomics patterns of Alzheimer's disease (AD) brain by spatial sequencing in mouse models, enabling the identification of unique genome-wide transcriptomic features associated with different spatial regions and pathological status. However, the dynamics of gene interactions that occur during amyloid-β accumulation remain largely unknown. In this study, we performed analyses on ligand-receptor communication, transcription factor regulatory network, and spot-specific network to reveal the dependence and the dynamics of gene associations/interactions on spatial regions and pathological status with mouse and human brains.

O-GlcNAc impacts mitophagy via the PINK1-dependent pathway.

Background: The accumulation of dysfunctional mitochondria is an early feature of Alzheimer's disease (AD). The impaired turnover of damaged mitochondria increases reactive oxygen species production and lowers ATP generation, leading to cellular toxicity and neurodegeneration. Interestingly, AD exhibits a disruption in the global post-translational modification β-N-acetylglucosamine (O-GlcNAc).

Proactive M2 blockade prevents cognitive decline in GRK5-deficient APP transgenic mice via enhancing cholinergic neuronal resilience.

Alzheimer's disease (AD) poses an immense challenge in healthcare, lacking effective therapies. This study investigates the potential of anthranilamide derivative (AAD23), a selective M2 receptor antagonist, in proactively preventing cognitive impairments and cholinergic neuronal degeneration in G protein-coupled receptor kinase-5-deficient Swedish APP (GAP) mice. GAP mice manifest cognitive deficits by 7 months and develop senile plaques by 9 months.

Adaptive and Maladaptive DNA Breaks in Neuronal Physiology and Alzheimer's Disease.

DNA strand breaks excessively accumulate in the brains of patients with Alzheimer's disease (AD). While traditionally considered random, deleterious events, neuron activity itself induces DNA breaks, and these "adaptive" breaks help mediate synaptic plasticity and memory formation. Recent studies mapping the brain DNA break landscape reveal that despite a net increase in DNA breaks in ectopic genomic hotspots, adaptive DNA breaks around synaptic genes are lost in AD brains, and this is associated with transcriptomic dysregulation.

Efficacy and Safety of Exogenous Ketones in People with Mild Neurocognitive Disorder and Alzheimer's Disease: A Systematic Literature Review.

Context: Mild neurocognitive disorder (NCD), formally known as mild cognitive impairment, is usually the clinical stage preceding the development of Alzheimer's disease (AD), the most prevalent major NCD, and other causes of dementia. Glucose is a major source of energy for human brain metabolism and the uptake of glucose is reduced in patients with mild NCD, AD, and other NCDs. Unlike glucose, the uptake of ketones remains normal in people with mild NCD and AD, suggesting that the use of ketone bodies may compensate for glucose energy deficiency in patients with mild NCD and AD.

Proteome profiling of cerebrospinal fluid using machine learning shows a unique protein signature associated with APOE4 genotype.

Introduction: Proteome changes associated with APOE4 variant carriage that are independent of Alzheimer's disease (AD) pathology and diagnosis are unknown. This study investigated APOE4 proteome changes in people with AD, mild cognitive impairment, and no impairment.

Methods: Clinical, APOE genotype, and cerebrospinal fluid (CSF) proteome and AD biomarker data was sourced from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database.

Hippocampal transcriptome-wide association study and pathway analysis of mitochondrial solute carriers in Alzheimer's disease.

The etiopathogenesis of late-onset Alzheimer's disease (AD) is increasingly recognized as the result of the combination of the aging process, toxic proteins, brain dysmetabolism, and genetic risks. Although the role of mitochondrial dysfunction in the pathogenesis of AD has been well-appreciated, the interaction between mitochondrial function and genetic variability in promoting dementia is still poorly understood. In this study, by tissue-specific transcriptome-wide association study (TWAS) and further meta-analysis, we examined the genetic association between mitochondrial solute carrier family (SLC25) genes and AD in three independent cohorts and identified three AD-susceptibility genes, including SLC25A10, SLC25A17, and SLC25A22.

Spatial Dissection of the Distinct Cellular Responses to Normal Aging and Alzheimer's Disease in Human Prefrontal Cortex at Single-Nucleus Resolution.

Aging significantly elevates the risk for Alzheimer's disease (AD), contributing to the accumulation of AD pathologies, such as amyloid-β (Aβ), inflammation, and oxidative stress. The human prefrontal cortex (PFC) is highly vulnerable to the impacts of both aging and AD. Unveiling and understanding the molecular alterations in PFC associated with normal aging (NA) and AD is essential for elucidating the mechanisms of AD progression and developing novel therapeutics for this devastating disease.

Multi-Omics after O-GlcNAc Alteration Identifies Cellular Processes Working Synergistically to Promote Aneuploidy.

Pharmacologic or genetic manipulation of O-GlcNAcylation, an intracellular, single sugar post-translational modification, are difficult to interpret due to the pleotropic nature of O-GlcNAc and the vast signaling pathways it regulates. To address this issue, we employed either OGT (O-GlcNAc transferase), OGA (O-GlcNAcase) liver knockouts, or pharmacological inhibition of OGA coupled with multi-Omics analysis and bioinformatics. We identified numerous genes, proteins, phospho-proteins, or metabolites that were either inversely or equivalently changed between conditions.

Late-Life Alcohol Exposure Does Not Exacerbate Age-Dependent Reductions in Mouse Spatial Memory and Brain TFEB Activity.

Alcohol consumption is believed to affect Alzheimer's disease (AD) risk, but the contributing mechanisms are not well understood. A potential mediator of the proposed alcohol-AD connection is autophagy, a degradation pathway that maintains organelle and protein homeostasis. Autophagy is in turn regulated through the activity of Transcription factor EB (TFEB), which promotes lysosome and autophagy-related gene expression.

Protocol for a single-arm, pilot trial of creatine monohydrate supplementation in patients with Alzheimer's disease.

Background: Impaired brain bioenergetics is a pathological hallmark of Alzheimer's disease (AD) and is a compelling target for AD treatment. Patients with AD exhibit dysfunction in the brain creatine (Cr) system, which is integral in maintaining bioenergetic flux. Recent studies in AD mouse models suggest Cr supplementation improves brain mitochondrial function and may be protective of AD peptide pathology and cognition.

Loss of Adaptive DNA Breaks in Alzheimer's Disease Brains.

Background: DNA breaks accumulate in Alzheimer's disease (AD) brains. While their role as true genomic lesions is recognized, DNA breaks also support cognitive function by facilitating the expression of activity-dependent immediate early genes. This process involves TOP2B, a DNA topoisomerase that catalyzes the formation of DNA double-strand breaks.

Traumatic Brain Injury Alters the Trajectory of Age-Related Mitochondrial Change.

Background: Some epidemiologic studies associate traumatic brain injury (TBI) with Alzheimer's disease (AD).

Objective: To test whether a TBI-induced acceleration of age-related mitochondrial change could potentially mediate the reported TBI-AD association.

Methods: We administered unilateral controlled cortical impact (CCI) or sham injuries to 5-month-old C57BL/6J and tau transgenic rTg4510 mice.

O-GlcNAc regulates the mitochondrial integrated stress response by regulating ATF4.

Background: Accumulation of mitochondrial dysfunctional is a hallmark of age-related neurodegeneration including Alzheimer's disease (AD). Impairment of mitochondrial quality control mechanisms leading to the accumulation of damaged mitochondria and increasing neuronal stress. Therefore, investigating the basic mechanisms of how mitochondrial homeostasis is regulated is essential.

Loss of Adaptive DNA Breaks in Alzheimer's Disease Brains.

Background: DNA breaks accumulate in Alzheimer's disease (AD) brains. While their role as true genomic lesions is recognized, DNA breaks also support cognitive function by facilitating the expression of activity-dependent immediate early genes (IEGs). This process involves TOP2B, a DNA topoisomerase that catalyzes the formation of DNA double-strand breaks (DSBs).

New cyclophilin D inhibitor rescues mitochondrial and cognitive function in Alzheimer's disease.

Mitochondrial dysfunction is an early pathological feature of Alzheimer disease and plays a crucial role in the development and progression of Alzheimer's disease. Strategies to rescue mitochondrial function and cognition remain to be explored. Cyclophilin D (CypD), the peptidylprolyl isomerase F (PPIase), is a key component in opening the mitochondrial membrane permeability transition pore, leading to mitochondrial dysfunction and cell death.

Protection against Aβ-induced neuronal damage by KU-32: PDHK1 inhibition as important target.

A feature of most neurodegenerative diseases is the presence of "mis-folded proteins" that form aggregates, suggesting suboptimal activity of neuronal molecular chaperones. Heat shock protein 90 (Hsp90) is the master regulator of cell responses to "proteotoxic" stresses. Some Hsp90 modulators activate cascades leading to upregulation of additional chaperones.

Mitochondria-sequestered Aβ renders synaptic mitochondria vulnerable in the elderly with a risk of Alzheimer disease.

Mitochondria are critical for neurophysiology, and mitochondrial dysfunction constitutes a characteristic pathology in both brain aging and Alzheimer disease (AD). Whether mitochondrial deficiency in brain aging and AD is mechanistically linked, however, remains controversial. We report a correlation between intrasynaptosomal amyloid β 42 (Aβ42) and synaptic mitochondrial bioenergetics inefficiency in both aging and amnestic mild cognitive impairment, a transitional stage between normal aging and AD.

FUS G559A Mutation in a Patient with a Frontotemporal Dementia-Motor Neuron Disease Compatible Syndrome: A Case Report.

Fused in sarcoma (FUS) mutations cause frontotemporal dementia (FTD) and motor neuron disease (MND). Here, we describe a 43-year-old man with progressive behavioral and cognitive change, myelopathy, clinical and electrophysiologic evidence of MND, and a FUS variant of unknown significance (VUS). This VUS, a heterozygous G559A transition (Gly187Ser), was previously reported in a patient with sporadic MND and affects important FUS biophysical properties.

Blood-Based Transcriptomic Biomarkers Are Predictive of Neurodegeneration Rather Than Alzheimer's Disease.

Alzheimer's disease (AD) is a growing global health crisis affecting millions and incurring substantial economic costs. However, clinical diagnosis remains challenging, with misdiagnoses and underdiagnoses being prevalent. There is an increased focus on putative, blood-based biomarkers that may be useful for the diagnosis as well as early detection of AD.

Alzheimer's disease cortical morphological phenotypes are associated with TOMM40'523-APOE haplotypes.

Both the APOE ε4 and TOMM40 rs10524523 ("523") genes have been associated with risk for Alzheimer's disease (AD) and neuroimaging biomarkers of AD. No studies have investigated the relationship of TOMM40'523-APOE ε4 on the structural complexity of the brain in AD individuals. We quantified brain morphology and multiple cortical attributes in individuals with mild cognitive impairment (MCI) and AD, then tested whether APOE ε4 or TOMM40 poly-T genotypes were related to AD morphological biomarkers in cognitively unimpaired (CU) and MCI/AD individuals.