Alzheimer's Disease Pathogenesis Research Articles

Palmitoylation-related gene ZDHHC22 as a potential diagnostic and immunomodulatory target in Alzheimer’s disease: insights from machine learning analyses and WGCNA

BackgroundThe mechanism of palmitoylation in the pathogenesis of Alzheimer's disease (AD) remains unclear.MethodsThis study retrieved AD data sets from the GEO database to identify palmitoylation-associated genes (PRGs). This study applied WGCNA along with three machine learning algorithms—random forest, LASSO regression, and SVM–RFE—to further select key PRGs (KPRGs). The diagnostic performance of KPRGs was evaluated using Receiver Operating Characteristic (ROC) curve analysis. Immune cell infiltration analysis was conducted to assess correlations between KPRGs and immune cell types, and a competing endogenous RNA (ceRNA) regulatory network was constructed to explore their potential regulatory mechanisms.Results17 PRGs were identified from the AD data sets, with 7 genes showing increased expression and 10 showing decreased expression. Through WGCNA and machine learning analyses, ZDHHC22 was selected as a KPRG. The ROC curve analysis demonstrated that ZDHHC22 had an area under the curve value of 0.659, indicating moderate diagnostic potential. Immune cell infiltration analysis revealed significant associations between ZDHHC22 expression and the infiltration of several immune cell types, including naïve B cells, CD8 + T cells, and M1 macrophages. In addition, 25 miRNAs and 55 lncRNAs were predicted to potentially target ZDHHC22, forming the basis for a lncRNA–miRNA–mRNA ceRNA network.ConclusionsThis study is the first to use bioinformatics methods to identify ZDHHC22 as a key KPRG in AD, highlighting its potential role in disease diagnosis and immune regulation. The regulatory network of ZDHHC22 provides new insights into the molecular mechanisms of AD and lays the foundation for future targeted therapeutic strategies.

Akkermansia muciniphila and its metabolite propionic acid maintains neuronal mitochondrial division and autophagy homeostasis during Alzheimer’s disease pathologic process via GPR41 and GPR43

BackgroundAlzheimer’s disease (AD) is a prevalent neurodegenerative disease (ND). In recent years, multiple clinical and animal studies have shown that mitochondrial dysfunction may be involved in the pathogenesis of AD. In addition, short-chain fatty acids (SCFA) produced by intestinal microbiota metabolism have been considered to be important factors affecting central nervous system (CNS) homeostasis. Among the main mediators of host-microbe interactions, volatile fatty acids play a crucial role. Nevertheless, the influence and pathways of microorganisms and their metabolites on Alzheimer’s disease (AD) remain uncertain.ResultsIn this study, we present distinctions in blood and fecal SCFA levels and microbiota composition between healthy individuals and those diagnosed with AD. We found that AD patients showed a decrease in the abundance of Akkermansia muciniphila and a decrease in propionic acid both in fecal and in blood. In order to further reveal the effects and the mechanisms of propionic acid on AD prevention, we systematically explored the effects of propionic acid administration on AD model mice and cultured hippocampal neuronal cells. Results showed that oral propionate supplementation ameliorated cognitive impairment in AD mice. Propionate downregulated mitochondrial fission protein (DRP1) via G-protein coupled receptor 41 (GPR41) and enhanced PINK1/PARKIN-mediated mitophagy via G-protein coupled receptor 43 (GPR43) in AD pathophysiology which contribute to maintaining mitochondrial homeostasis both in vivo and in vitro. Administered A. muciniphila to AD mice before disease onset showed improved cognition, mitochondrial division and mitophagy in AD mice.ConclusionsTaken together, our results demonstrate that A. muciniphila and its metabolite propionate protect against AD-like pathological events in AD mouse models by targeting mitochondrial homeostasis, making them promising therapeutic candidates for the prevention and treatment of AD.2Eefw-diaDYPDEcqvaR2iqVideo

Current Status of Plant-Based Bioactive Compounds as Therapeutics in Alzheimer's Diseases.

Alzheimer's disease (AD) is a common central neurodegenerative disease disorder characterized primarily by cognitive impairment and non-cognitive neuropsychiatric symptoms that significantly impact patients' daily lives and behavioral functioning. The pathogenesis of AD remains unclear and current Western medicines treatment are purely symptomatic, with a singular pathway, limited efficacy, and substantial toxicity and side effects. In recent years, as research into AD has deepened, there has been a gradual increase in the exploration and application of medicinal plants for the treatment of AD. Numerous studies have shown that medicinal plants and their active ingredients can potentially mitigate AD by regulating various molecular mechanisms, including the production and aggregation of pathological proteins, oxidative stress, neuroinflammation, apoptosis, mitochondrial dysfunction, neurogenesis, neurotransmission, and the brain-gut microbiota axis. In this review, we analyzed the pathogenesis of AD and comprehensively summarized recent advancements in research on medicinal plants for the treatment of AD, along with their underlying mechanisms and clinical evidence. Ultimately, we aimed to provide a reference for further investigation into the specific mechanisms through which medicinal plants prevent and treat AD, as well as for the identification of efficacious active ingredients derived from medicinal plants.

CHIT1 regulates the neuroinflammation and phagocytosis of microglia and suppresses Aβ plaque deposition in Alzheimer's disease.

Chitinase 1 (CHIT1), as a chitin-specific hydrolase, significantly influences the progression of Alzheimer's disease (AD) through microglia-associated inflammation and amyloid beta (Aβ) plaque accumulation. However, the precise mechanism of CHIT1 action in AD remains uncertain. The effects of CHIT1 on cerebral blood flow (CBF), hippocampal volume, and cognitive function were investigated in APP/PS1 mice. Protein alterations resulting from CHIT1 overexpression were analyzed using four-dimensional (4D) label-free quantitative (LFQ) protein spectrometry. Additionally, the influence of CHIT1 on microglial electrophysiology was assessed using patch clamp measurements, and its effects on neuroinflammation, phagocytosis, microglia migration, and neuronal apoptosis under AD-like conditions were examined using the cell lines N9, BV-2, and HT-22. CHIT1 ameliorated hippocampal atrophy, hypoperfusion, and cognitive function deficits in the APP/PS1 mouse. CHIT1 regulates microglial function and neuronal protection through its interactions in AD. Increased levels of CHIT1/IDH1 contributed to an anti-inflammatory phenotype in microglia via the Ca2+-activated K+ channel, enhanced microglial phagocytosis, and promoted Aβ clearance. Conversely, knocking down IDH1 reduced the secretion of anti-inflammatory agents and increased the production of inflammatory factors, as well as diminishing the expression of phagocytic factors and inhibiting Aβ endocytosis. Moreover, CHIT1 reduced neuronal apoptosis by diminishing the expression of apoptotic factors. However, IDH1 knockdown abrogated the protective effect of CHIT1 on neurons. CHIT1 exerts a protective role in AD pathogenesis through its interaction with IDH1. The CHIT1/IDH1 pathway promotes Aβ clearance via a shift in microglia toward an anti-inflammatory state and prevents neuronal apoptosis and dysfunction caused by Aβ toxicity. © 2025 The Pathological Society of Great Britain and Ireland.

The Role of Air Pollution and Olfactory Dysfunction in Alzheimer's Disease Pathogenesis.

The escalating issue of air pollution contributes to an alarming number of premature fatalities each year, thereby posing a significant threat to global health. The focus of recent research has shifted towards understanding its potential association with neurodegenerative diseases, specifically Alzheimer's disease (AD). AD is recognised for its characteristic deposition of toxic proteins within the brain, leading to a steady deterioration of cognitive capabilities, memory failure, and, ultimately, death. There is burgeoning evidence implying that air pollution may be a contributing factor to this protein build up, thereby intensifying the course of AD. It has been demonstrated that the olfactory system, responsible for smell perception and processing, acts as a potential gateway for airborne pollutants to inflict brain damage. This review aims to elucidate the relationship between air pollution, olfactory deterioration, and AD. Additionally, this review aims to highlight the potential mechanisms through which pollutants might instigate the development of AD and the role of the olfactory system in disease pathogenesis. Moreover, the diverse model systems employed in exploring the correlation, public health policy ramifications, and prospective directions for future research will be discussed.

KIF9 Ameliorates Neuropathology and Cognitive Dysfunction by Promoting Macroautophagy in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder affecting the elderly. The imbalance of protein production and degradation processes leads to the accumulation of misfolded and abnormally aggregated amyloid-beta (Aβ) in the extracellular space and forms senile plaques, which constitute one of the most critical pathological hallmarks of AD. KIF9, a member of the kinesin protein superfamily, mediates the anterograde transport of intracellular cargo along microtubules. However, the exact role of KIF9 in AD pathogenesis remains largely elusive. In this study, we reported that the expression of kinesin family member 9 (KIF9) in the hippocampus of APP23/PS45 double-transgenic AD model mice declined in an age-dependent manner, concurrent with macroautophagy dysfunction. Furthermore, we found that KIF9 mediated the transport of lysosomes through kinesin light chain 1 (KLC1), thereby participating in the degradation of amyloidogenic pathway-related proteins of Aβ precursor protein (APP) in AD model cells through promoting the macroautophagy pathway. Importantly, genetic upregulation of KIF9 via adeno-associated virus (AAV) diminished Aβ deposition and alleviated cognitive impairments in AD model mice by enhancing macroautophagy function. Collectively, our findings underscore the ability of KIF9 to promote macroautophagy through KLC1-mediated anterograde transport of lysosomes, effectively ameliorating cognitive dysfunction in AD model mice. These discoveries suggest that KIF9 may represent a novel therapeutic target for the treatment of AD.

Alterations of amino acids in older adults with Alzheimer’s Disease and Vascular Dementia

Metabolomics provide a promising tool for understanding dementia pathogenesis and identifying novel biomarkers. This study aimed to identify amino acid biomarkers for Alzheimer’s Disease (AD) and Vascular Dementia (VD). By amino acid metabolomics, the concentrations of amino acids were determined in the serum of AD and VD patients as well as age-matched healthy controls. Several differences in the concentration of amino acids were observed in AD patients compared to both healthy controls and VD patients. However, no significant distinction was found between healthy controls and VD patients. Considering comorbidities, cystine levels were higher in AD than in VD among non-diabetic patients, but not in those with diabetes. Notably, creatine, spermidine, cystine, and tyrosine demonstrated favorable results in decision curve analyses and good discriminative performances, suggesting their potential for clinical application. These fundings give novel perspectives of serum amino acids for predicting metabolic pathways in AD and VD pathogenesis.

Comparison of the amyloid plaque proteome in Down syndrome, early-onset Alzheimer’s disease, and late-onset Alzheimer’s disease

Down syndrome (DS) is strongly associated with Alzheimer’s disease (AD) due to APP overexpression, exhibiting Amyloid-β (Aβ) and Tau pathology similar to early-onset (EOAD) and late-onset AD (LOAD). We evaluated the Aβ plaque proteome of DS, EOAD, and LOAD using unbiased localized proteomics on post-mortem paraffin-embedded tissues from four cohorts (n = 20/group): DS (59.8 ± 4.99 y/o), EOAD (63 ± 4.07 y/o), LOAD (82.1 ± 6.37 y/o), and controls (66.4 ± 13.04). We identified differentially abundant proteins when comparing Aβ plaques and neighboring non-plaque tissue (FDR < 5%, fold-change > 1.5) in DS (n = 132), EOAD (n = 192), and LOAD (n = 128), with 43 plaque-associated proteins shared across all groups. Positive correlations were observed between plaque-associated proteins in DS and EOAD (R2 = .77), DS and LOAD (R2 = .73), and EOAD and LOAD (R2 = .67). Top gene ontology biological processes (GOBP) included lysosomal transport (p = 1.29 × 10−5) for DS, immune system regulation (p = 4.33 × 10−5) for EOAD, and lysosome organization (p = 0.029) for LOAD. Protein networks revealed a plaque-associated protein signature involving APP metabolism, immune response, and lysosomal functions. In DS, EOAD, and LOAD non-plaque vs. control tissue, we identified 263, 269, and 301 differentially abundant proteins, with 65 altered proteins shared across all cohorts. Non-plaque proteins in DS showed modest correlations with EOAD (R2 = .59) and LOAD (R2 = .33) compared to the correlation between EOAD and LOAD (R2 = .79). Top GOBP term for all groups was chromatin remodeling (p < 0.001), with additional terms for DS including extracellular matrix, and protein–DNA complexes and gene expression regulation for EOAD and LOAD. Our study reveals key functional characteristics of the amyloid plaque proteome in DS, compared to EOAD and LOAD, highlighting shared pathways in endo/lysosomal functions and immune responses. The non-plaque proteome revealed distinct alterations in ECM and chromatin structure, underscoring unique differences between DS and AD subtypes. Our findings enhance our understanding of AD pathogenesis and identify potential biomarkers and therapeutic targets.

Mitochondrial dysfunction in Alzheimer's disease: Guiding the path to targeted therapies.

Alzheimer's disease (AD) is characterized by progressive neurodegeneration, marked by the accumulation of amyloid-β (Aβ) plaques and tau tangles. Emerging evidence suggests that mitochondrial dysfunction plays a pivotal role in AD pathogenesis, driven by impairments in mitochondrial quality control (MQC) mechanisms. MQC is crucial for maintaining mitochondrial integrity through processes such as proteostasis, mitochondrial dynamics, mitophagy, and precise communication with other subcellular organelles. In AD, disruptions in these processes lead to bioenergetic failure, gene dysregulation, the accumulation of damaged mitochondria, neuroinflammation, and lipid homeostasis impairment, further exacerbating neurodegeneration. This review elucidates the molecular pathways involved in MQC and their pathological relevance in AD, highlighting recent discoveries related to mitochondrial mechanisms underlying neurodegeneration. Furthermore, we explore potential therapeutic strategies targeting mitochondrial dysfunction, including gene therapy and pharmacological interventions, offering new avenues for slowing AD progression. The complex interplay between mitochondrial health and neurodegeneration underscores the need for innovative approaches to restore mitochondrial function and mitigate the onset and progression of AD.

Neuron-derived extracellular vesicles as a liquid biopsy for brain insulin dysregulation in Alzheimer's disease and related disorders.

Extracellular vesicles (EVs) have emerged as novel blood-based biomarkers for various pathologies. The development of methods to enrich cell-specific EVs from biofluids has enabled us to monitor difficult-to-access organs, such as the brain, in real time without disrupting their function, thus serving as liquid biopsy. Burgeoning evidence indicates that the contents of neuron-derived EVs (NDEs) in blood reveal dynamic alterations that occur during neurodegenerative pathogenesis, including Alzheimer's disease (AD), reflecting a disease-specific molecular signature. Among these AD-specific molecular changes is brain insulin-signaling dysregulation, which cannot be assessed clinically in a living patient and remains an unexplained co-occurrence during AD pathogenesis. This review is focused on delineating how NDEs in the blood may begin to close the gap between identifying molecular changes associated with brain insulin dysregulation reliably in living patients and its connection to AD. This approach could lead to the identification of novel early and less-invasive diagnostic molecular biomarkers for AD. HIGHLIGHTS: Neuron-derived extracellular vesicles (NDEs) could be isolated from peripheral blood. NDEs in blood reflect the molecular signature of Alzheimer's disease (AD). Brain insulin-signaling dysregulation plays a critical role in AD. NDEs in blood could predict brain insulin-signaling dysregulation. NDEs offer novel early and less-invasive diagnostic biomarkers for AD.

Cerebrospinal Fluid (CSF) Proteomic Signature in Preclinical and Clinical Alzheimer's disease (AD): Role of Adhesion Molecules.

Although Amyloid-beta and Tau are the hallmarks of Alzheimer's Disease (AD), other protein pathways such as endothelial dysfunction may be involved and may precede cognitive symptoms. Our objective was to characterize the cerebrospinal fluid (CSF) proteomic profiles focusing on cardiometabolic-related protein pathways in individuals on the AD spectrum. We performed CSF and plasma-targeted proteomics (276 proteins) from 354 participants of the Brain Stress Hypertension and Aging Program (BSHARP), of which 8% had preclinical AD, and 24% had MCI due to AD. We instituted a bioinformatic pipeline to generate data-driven protein modules, used "Hub" and "Critical" proteins within each module to describe protein signatures for each AD stage and then assessed their associations with clinical and biological AD traits. Finally, we completed pathway enrichment analysis to get insight into pathways that might be implicated in AD pathogenesis. The 276 measured proteins clustered into five modules that were associated with CSF Amyloid-β42, Tau, and pTau. (all p-value <0.05). A CSF protein AD signature was characterized by elevated levels of CSF Hepatocyte Growth Factor (HGF), Intercellular and Vascular Cell Adhesion Molecule 1 (ICAM-1, VCAM-1), Neuropilin 1 and 2 (NRP-1, NRP-2), Scavenger Receptor Class B Member 2(SCARB2), Plasminogen Activator, Urokinase (PLAU). (all <0.05) We also found a significant difference in the CSF/Plasma ratio for the proteins associated with Cognitive Status and the Tau/Aβ42 ratio (TAR) in the CSF. Pathway enrichment analysis revealed that cell adhesion and endothelial dysfunction (all p-value <0.05) were key mechanisms involved in AD pathogenesis, especially in the preclinical stage. Our results suggest a proteomic signature in the CSF of individuals with preclinical AD that is driven by adhesion molecules and might be implicated in the pathogenesis of AD. Future studies investigating these pathways may provide insights into novel AD biomarkers and therapeutic targets.

Fatty-acid amide hydrolase inhibition mitigates Alzheimer's disease progression in mouse models ofamyloidosis.

The endocannabinoid N-arachidonoylethanolamine (AEA) is a pro-homeostatic bioactive lipid known for its anti-inflammatory, anti-oxidative, immunomodulatory, and neuroprotective properties, which may contrast/mitigate Alzheimer's disease (AD) pathology. This study explores the therapeutic potential of targeting fatty acid amide hydrolase (FAAH), the major enzyme degrading AEA, in mouse models of amyloidosis (APP/PS1 and Tg2576). Enhancing AEA signaling by genetic deletion of FAAH delayed cognitive deficits in APP/PS1 mice and improved cognitive symptoms in 12-month-old AD-like mice. Chronic pharmacological FAAH inhibition fully reverted neurocognitive decline, attenuated neuroinflammation, and promoted neuroprotective mechanisms in Tg2576 mice. Additionally, pharmacological FAAH inhibition robustly suppressed β-amyloid production and accumulation, associated with decreased expression of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), possibly through a cannabinoid receptor 1-dependent epigenetic mechanism. These findings improve our understanding of AEA signaling in AD pathogenesis and provide proof of concept that selective targeting of FAAH activity could be a promising therapeutic strategy against AD.

Deciphering the Role of Adrenergic Receptors in Alzheimer's Disease: Paving the Way for Innovative Therapies.

Neurodegenerative diseases are currently among the most devastating diseases with no effective disease-modifying drugs in the market, with Alzheimer's disease (AD) being the most prevalent. AD is a complex multifactorial neurodegenerative disorder characterized by progressive and severe cognitive impairment and memory loss. It is the most common cause of progressive memory loss (dementia) in the elderly, and to date, there is no effective treatment to cure or slow disease progression substantially. The role of adrenergic receptors in the pathogenesis of Alzheimer's disease and other tauopathies is poorly understood or investigated. Recently, some studies indicated a potential benefit of drugs acting on the adrenergic receptors for AD and dementias, although due to the heterogeneity of the drug classes used, the results on the whole remain inconclusive. The scope of this review article is to comprehensively review the literature on the possible role of adrenergic receptors in neurodegenerative diseases, stemming from the use of agonists and antagonists including antihypertensive and asthma drugs acting on the adrenergic receptors, but also from animal models and in vitro models where these receptors have been studied. Ultimately, we hope to obtain a better understanding of the role of these receptors, identify the gaps in knowledge, and explore the possibility of repurposing such drugs for AD, given their long history of use and safety.

Dysregulation of the molecular clock by blood-borne factors in Alzheimer's disease patients.

Circadian disruptions are increasingly recognized in Alzheimer's disease (AD) patients and may influence disease onset and progression. This study examines how AD pathology affects blood-borne factors that regulate circadian rhythms. Eighty-five participants from the Sino Longitudinal Study on Cognitive Decline were enrolled: 35 amyloid-beta negative normal controls (Aβ- NCs), 23 amyloid-beta positive normal controls (Aβ+ NCs), 15 patients with amnestic mild cognitive impairment (aMCI), and 12 with Alzheimer's disease dementia (ADD). Patients with aMCI and ADD were grouped as cognitively impaired (CI). Cellular circadian period length was assessed using a serum-based assay. Expression levels of clock genes in serum-treated cells and in leukocytes of participants were measured via real-time PCR. Plasma biomarkers were quantified using a single-molecule array immunoassay. Pineal parenchymal and hippocampal volumes were determined by magnetic resonance imaging. The cellular circadian period length was significantly extended by serum from CI patients than by that from Aβ- NCs (p < 0.01). Treatment of cells with serum from the CI patients resulted in suppressed expression of the clock genes Bmal1 and Nr1d1. Strong relationships between the expression levels of clock genes observed in leukocytes of the Aβ- NC group did not appear in those of the Aβ+ NC or CI groups. The significant correlation of cellular circadian period length and the pineal volume was only observed in the Aβ- NC group, but not in the Aβ+ NC or CI groups. This study indicates the presence of significant changes in blood-borne factors that could affect the circadian rhythms in AD, starting even at preclinical stages. These alterations could precede cognitive decline and contribute to AD pathogenesis. The cohort is registered at ClinicalTrials.gov (SILCODE: NCT03370744; Registered on Mar 15th, 2017).

Phytomedicine Potential of Oroxylum indicum Root and Its Constituents: Targeting Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative condition characterized by a gradual decline in cognitive function, for which few effective treatments exist. This study investigated the neuroprotective potential of Oroxylum indicum root extract and its key constituents (baicalein, chrysin, oroxylin A) against AD hallmarks. The extract and its constituents exhibited antioxidant activity in the DPPH assay. They inhibited β-amyloid aggregation as measured by the thioflavin T assay and acetylcholinesterase activity using the Ellman method. In cell culture models, O. indicum extract showed an ability to protect neurons from the toxic effects of H2O2. Western blot analysis revealed the extract and its major active component, baicalein, downregulated pro-apoptotic markers (cleaved caspase-3, and BAX) upon H2O2 exposure. Furthermore, they reduced the expression of amyloidogenic proteins (BACE1) and phosphorylated tau. These findings suggest that O. indicum root extract, particularly baicalein, possesses multifaceted neuroprotective properties, targeting various aspects of AD pathogenesis, including oxidative stress, cholinergic dysfunction, β-amyloid formation, aggregation, and apoptosis. O. indicum root thus warrants further investigation as a promising source of therapeutic agents for AD.

Alzheimer's Disease and Porphyromonas gingivalis: Exploring the Links.

Recent research highlights compelling links between oral health, particularly periodontitis, and systemic diseases, including Alzheimer's disease (AD). Although the biological mechanisms underlying these associations remain unclear, the role of periodontal pathogens, particularly Porphyromonas gingivalis, has garnered significant attention. P. gingivalis, a major driver of periodontitis, is recognized for its potential systemic effects and its putative role in AD pathogenesis. This review examines evidence connecting P. gingivalis to hallmark AD features, such as amyloid β accumulation, tau hyperphosphorylation, neuroinflammation, and other neuropathological features consistent with AD. Virulence factors, such as gingipains and lipopolysaccharides, were shown to be implicated in blood-brain barrier disruption, neuroinflammation, and neuronal damage. P. gingivalis-derived outer membrane vesicles may serve to disseminate virulence factors to brain tissues. Indirect mechanisms, including systemic inflammation triggered by chronic periodontal infections, are also supposed to exacerbate neurodegenerative processes. While the exact pathways remain uncertain, studies detecting P. gingivalis virulence factors and its other components in AD-affected brains support their possible role in disease pathogenesis. This review underscores the need for further investigation into P. gingivalis-mediated mechanisms and their interplay with host responses. Understanding these interactions could provide critical insights into novel strategies for reducing AD risk through periodontal disease management.

Lower slow wave sleep and rapid eye-movement sleep are associated with brain atrophy of AD-vulnerable regions.

Sleep deficiency is associated with Alzheimer's disease (AD) pathogenesis. We examined the association of sleep architecture with anatomical features observed in AD: (1) atrophy of hippocampus, entorhinal, inferior parietal, parahippocampal, precuneus, and cuneus regions ("AD-vulnerable regions") and (2) cerebral microbleeds. In 271 participants of the Atherosclerosis Risk in the Communities Study, we examined the association of baseline sleep architecture with anatomical features identified on brain MRI 13~17 years later. Sleep architecture was quantified as the proportion of slow wave sleep (SWS), proportion of rapid eye-movement sleep (REM), and arousals index using polysomnography. Outcomes included (1) volumetric measurements of each AD-vulnerable region and (2) the presence of any cerebral microbleeds (CMBs) and that of lobar CMBs, which are more specifically associated with AD. We analyzed the association of each sleep predictor with each MRI outcome, adjusting for covariates. Having less SWS was associated with smaller inferior parietal region (β=-44.19 mm3 [95%CI=76.63, -11.76]) and cuneus (β=-11.99 mm3 [-20.93, -3.04]) after covariate adjustment. Having less REM was associated with smaller inferior parietal region (β=-75.52 mm3 [-129.34, -21.70]) and precuneus (β=-31.93 mm3 [-63.79, -0.07]). After FDR adjustments, lower SWS and REM, respectively, were associated with smaller inferior parietal region. Arousal index was not associated with the volumes of AD-vulnerable regions. None of the sleep architecture variables were associated with CMBs or lobar CMBs. Sleep deficiency is associated with the atrophy of the inferior parietal region, which is observed in early AD. Sleep architecture may be a modifiable risk factor for AD.

Evolution of Human Susceptibility to Alzheimer's Disease: A Review of Hypotheses and Comparative Evidence.

Primates rely on memory to navigate both physical and social environments and in humans, loss of memory function leads to devastating consequences. Alzheimer's disease (AD) is a neurodegenerative disease which begins by impacting memory functioning and is ultimately fatal. AD is common across human populations and its prevalence is predicted to rise with increases in the aging population. Despite this, the full AD phenotype has not been observed in any other nonhuman primate species. While a significant amount of research has been devoted to understanding the immediate mechanisms involved in AD pathogenesis in humans, less research has focused on why humans are particularly vulnerable to neurodegenerative diseases like AD. Here we explore hypotheses on the evolution of distinct human susceptibility to AD and place these in the context of findings from comparative neuroanatomical and molecular studies and discuss recent evidence for evolutionary changes protective against AD in the primate lineage.

Neurotrophic factor-α1/carboxypeptidase E controls progression and reversal of Alzheimer's disease pathogenesis in mice

Neurotrophic factor-α1/carboxypeptidase E controls progression and reversal of Alzheimer's disease pathogenesis in mice

Systematic review of amyloid-beta clearance proteins from the brain to the periphery: implications for Alzheimer's disease diagnosis and therapeutic targets.

Amyloid-beta clearance plays a key role In the pathogenesis of Alzheimer's disease. However, the variation in functional proteins involved in amyloid-beta clearance and their correlation with amyloid-beta levels remain unclear. In this study, we conducted meta-analyses and a systematic review using studies from the PubMed, Embase, Web of Science, and Cochrane Library databases, including journal articles published from inception to June 30, 2023. The inclusion criteria included studies comparing the levels of functional proteins associated with amyloid-beta clearance in the blood, cerebrospinal fluid, and brain of healthy controls, patients with mild cognitive impairment, and patients with Alzheimer's disease. Additionally, we analyzed the correlation between these functional proteins and amyloid-beta levels in patients with Alzheimer's disease. The methodological quality of the studies was assessed via the Newcastle-Ottawa Scale.Owing to heterogeneity, we utilized either a fixed-effect or random-effect model to assess the 95% confidence interval (CI) of the standard mean difference (SMD) among healthy controls, patients with mild cognitive impairment, and patients with Alzheimer's disease. The findings revealed significant alterations in the levels of insulin-degrading enzymes, neprilysin, matrix metalloproteinase-9, cathepsin D, receptor for advanced glycation end products, and P-glycoprotein in the brains of patients with Alzheimer's disease, patients with mild cognitive impairment, and healthy controls. In cerebrospinal fluid, the levels of triggering receptor expressed on myeloid cells 2 and ubiquitin C-terminal hydrolase L1 are altered, whereas the levels of TREM2, CD40, CD40L, CD14, CD22, cathepsin D, cystatin C, and α2 M in peripheral blood differ. Notably, TREM2 and cathepsin D showed changes in both brain (SMD = 0.31, 95% CI: 0.16-0.47, P < 0.001, I2 = 78.4%; SMD = 1.24, 95% CI: 0.01-2.48, P = 0.048, I2 = 90.1%) and peripheral blood (SMD = 1.01, 95% CI: 0.35-1.66, P = 0.003, I2 = 96.5%; SMD = 7.55, 95% CI: 3.92-11.18, P < 0.001, I2 = 98.2%) samples. Furthermore, correlations were observed between amyloid-beta levels and the levels of TREM2 (r = 0.16, 95% CI: 0.04-0.28, P = 0.009, I2 = 74.7%), neprilysin (r = -0.47, 95% CI: -0.80-0.14, P = 0.005, I2 = 76.1%), and P-glycoprotein (r = -0.31, 95% CI: -0.51-0.11, P = 0.002, I2 = 0.0%) in patients with Alzheimer's disease. These findings suggest that triggering receptor expressed on myeloid cells 2 and cathepsin D could serve as potential diagnostic biomarkers for Alzheimer's disease, whereas triggering receptor expressed on myeloid cells 2, neprilysin, and P-glycoprotein may represent potential therapeutic targets.