Alzheimer's Disease Pathology Research Articles

Detection and staging of Alzheimer's disease by plasma pTau217 on a high throughput immunoassay platform

Plasma phospho-tau 217 (pTau217) assays can accurately detect Alzheimer's disease (AD) pathology, but clinical application is limited by the need for specialised equipment. This study tests the performance of a plasma pTau217 assay performed on the Lumipulse-G® platform, that is in widespread clinical use, for selecting patients for therapy based on β-amyloid (Aβ) status and tau staging. Participants included 388 individuals with 18F-NAV4694 Aβ-PET and 18F-MK6240 tau-PET. Association of pTau217 with PET was examined using Spearman's correlation. Discriminative performance for Aβ and tau PET status as well as tau staging was assessed using Receiver Operating Characteristic analysis. Plasma pTau217 had a high correlation with both Aβ Centiloid (r=0.76) and tau SUVRmeta-temporal (r=0.78). Area under curve (AUC) was 0.93 for Aβ- vs Aβ+ and 0.94 for tau- vs tau+. Applying one threshold (Youden's index), pTau217 was 87% accurate in classification of participants to Aβ- vs Aβ+. Applying two thresholds to classify participants into Low, Indeterminate, and High zones, 17.8% had Indeterminate results and among Low/High zone participants, 92% were correctly classified as Aβ- or Aβ+. The assay accurately discriminated moderate/high neocortical tau from no tau or tau limited to mesial-temporal lobe (AUC 0.97) and high neocortical tau from all others (AUC 0.94). Plasma pTau217, measured by the widely-available, fully-automated Lumipulse®, was a strong predictor of both Aβ and tau PET status and demonstrated strong predictive power in identifying individuals likely to benefit the most from anti-Aβ treatments. NHMRC grants 1132604, 1140853, 1152623 and AbbVie.

Pharmacological Approaches and Herbal Interventions for Alzheimer's Disease

Abstract: This comprehensive review extensively examines the utilization of herbal remedies and pharmacological techniques for managing Alzheimer's disease (AD). It delves deeply into the active constituents and modes of operation of diverse herbal medications such as Withania somnifera, Bacopa monnieri, Ginkgo biloba, and Curcuma longa, emphasizing their qualities in reducing inflammation, acting as antioxidants, and safeguarding neural tissue. Additionally, it assesses conventional pharmaceuticals like cholinesterase inhibitors (Donepezil, rivastigmine) and memantine, investigating their mechanisms of action and potential adverse effects. The study also encompasses non-pharmacological therapies like interventions aimed at cognition, physical exercise, and methods of stimulating the brain, all of which exhibit potential in enhancing cognitive capacity and neural adaptability. Furthermore, it delves into the amalgamation of therapies to tackle numerous facets of AD pathology. In essence, this review furnishes valuable insights into alternative strategies for managing AD, underscoring the potential of herbal interventions in enhancing cognitive function and addressing the underlying issues of AD. Additionally, it presents a fresh avenue for exploring the collaborative impacts of combining conventional pharmaceuticals with herbal remedies.

On the Therapeutic Use of Monoclonal Antibodies Against Amyloid Plaques in Older Adults with Down Syndrome: A Narrative Review and Perspective

Down syndrome (DS) is a genetic disorder caused by an extra copy of chromosome 21 (trisomy 21 or T21) and is associated with an increased risk of early-onset Alzheimer’s disease (AD), also known as DS-associated AD (DSAD). Individuals with DS typically develop amyloid neuropathology in their late-thirties to early-forties and the mean age of onset of clinical dementia is approximately 55 years. Recent advances in AD clinical research have focused on monoclonal antibodies (mAbs) targeting amyloid-β (Aβ) plaques as a potential therapeutic approach. Therefore, there has been guarded enthusiasm about using anti-amyloid mAbs in the prevention/treatment of DSAD. This narrative review and perspective explores the current understanding of amyloid pathology in AD and DSAD, the rationale for using anti-amyloid mAbs in the treatment of DSAD, and the challenges and opportunities for research toward the application of this therapeutic strategy to older adults with DS.

Personality and Biomarkers of Neurodegeneration and Alzheimer’s Disease in Swedish Older Adults

Abstract Background Personality is associated with dementia risk. Neuroticism and conscientiousness may be involved in resistance and resilience to Alzheimer’s Disease (AD) pathology (ADP). These traits have also been associated with unspecific biomarkers of neurodegeneration; glial fibrillary acidic protein (GFAP) and neurofilament light (NfL). This study explores the role of personality in cognitive ageing. Methods We used data from the Swedish population-based studies H70 (individuals age 70 years only), and SNAC-K (individuals ages 60-104). Personality was assessed with the NEO-five-factor inventory. In H70, biomarkers of ADP were measured in cerebrospinal fluid (CSF, N = 305), except NfL which was also available in plasma (N = 1082). In SNAC-K (N = 1754), all biomarkers were measured in serum. We used multivariable regression models to evaluate the association between personality traits and ADP biomarkers, GFAP and NfL among individuals without dementia. We further examined if associations differed by age (SNAC-K only) and sex. Results In H70, higher neuroticism and was associated with lower Aβ42/Aβ40 ratio (B=-0.01, p = 0.02). In SNAC-K, higher openness was associated with lower NfL (B=-0.04, p = 0.03). For age 60-66, higher openness was associated with lower NfL (B=-0.09, p = 0.01), higher neuroticism was associated with higher GFAP (B = 0.09, p = 0.01), and NfL (B = 0.10, p = 0.003). For age >80, higher openness was associated with higher ptau-181, (B = 0.14, p = 0.01), and ptau-181/Aβ42 ratio (B = 0.15, p = 0.003). Conclusions Higher neuroticism and lower openness are associated with neurodegeneration. Higher openness may also be associated with resilience to AD-pathology. Key messages • Neuroticism may contribute to neurodegeneration in people <70. • Openness may contribute to cognitive resilience to ADP in people >80.

A comprehensive head-to-head comparison of key plasma phosphorylated tau 217 biomarker tests.

Plasma phosphorylated-tau 217 (p-tau217) is currently the most promising biomarker for reliable detection of Alzheimer's disease (AD) pathology. Various p-tau217 assays have been developed, but their relative performance is unclear. We compared key plasma p-tau217 tests using cross-sectional and longitudinal measures of amyloid-β (Aβ)-PET, tau-PET, and cognition as outcomes, and benchmarked them against cerebrospinal fluid (CSF) biomarker tests. Samples from 998 individuals (mean[range] age 68.5[20.0-92.5], 53% female) from the Swedish BioFINDER-2 cohort, including both cognitively unimpaired and cognitively impaired individuals, were analyzed. Plasma p-tau217 was measured with mass spectrometry (MS) assays (the ratio between phosphorylated and non-phosphorylated [%p-tau217WashU] and p-tau217WashU) as well as with immunoassays (p-tau217Lilly, p-tau217Janssen, p-tau217ALZpath). CSF biomarkers included p-tau217Lilly, the FDA-approved p-tau181/Aβ42Elecsys, and p-tau181Elecsys. All plasma p-tau217 tests exhibited a high ability to detect abnormal Aβ-PET (AUC range: 0.91-0.96) and tau-PET (AUC range: 0.94-0.97). Plasma %p-tau217WashU had the highest performance, with significantly higher AUCs than all the immunoassays (Pdiff<0.007). For detecting Aβ-PET status, %p-tau217WashU had an accuracy of 0.93 (immunoassays: 0.83-0.88), sensitivity of 91% (immunoassays: 84-87%), and a specificity of 94% (immunoassays: 85-89%). Among immunoassays, p-tau217Lilly and plasma p-tau217ALZpath had higher AUCs than plasma p-tau217Janssen for Aβ-PET status (Pdiff<0.006), and p-tau217Lilly outperformed plasma p-tau217ALZpath for tau-PET status (Pdiff=0.025). Plasma %p-tau217WashU exhibited stronger associations with all PET load outcomes compared to immunoassays; baseline Aβ-PET load (R2: 0.72; immunoassays: 0.47-0.58; Pdiff<0.001), baseline tau-PET load (R2: 0.51; immunoassays: 0.38-0.45; Pdiff<0.001), longitudinal Aβ-PET load (R2: 0.53; immunoassays: 0.31-0.38; Pdiff<0.001) and longitudinal tau-PET load (R2: 0.50; immunoassays: 0.35-0.43; Pdiff<0.014). Among immunoassays, plasma p-tau217Lilly was more associated with Aβ-PET load than plasma p-tau217Janssen (Pdiff<0.020) and with tau-PET load than both plasma p-tau217Janssen and plasma p-tau217ALZpath (all Pdiff<0.010). Plasma %p-tau217 also correlated more strongly with baseline cognition (Mini-Mental State Examination[MMSE]) than all immunoassays (R2 %p-tau217WashU: 0.33; immunoassays: 0.27-0.30; Pdiff<0.024). The main results were replicated in an external cohort from Washington University in St Louis (n =219). Finally, p-tau217NULISA showed similar performance to other immunoassays in subsets of both cohorts. In summary, both MS- and immunoassay-based p-tau217 tests generally perform well in identifying Aβ-PET, tau-PET, and cognitive abnormalities, but %p-tau217WashU performed significantly better than all the examined immunoassays. Plasma %p-tau217 may be considered as a stand-alone confirmatory test for AD pathology, while some immunoassays might be better suited as triage tests where positive results are confirmed with a second test, which needs to be determined by future reviews incorporating results from multiple cohorts.

Effects of Artemisia asiatica ex on Akkermansia muciniphila dominance for modulation of Alzheimer's disease in mice.

The gut microbiome influences neurological disorders through bidirectional communication between the gut and the brain, i.e., the gut-brain axis. Artemisia asiatica ex, an extract of Artemisia asiatica Nakai (Stillen®, DA-9601) has been reported to improve depression by increasing brain-derived neurotropic factor. Therefore, we hypothesized that DA-9601 can be a potential therapeutic candidate for Alzheimer's disease (AD) acting through the gut-brain axis. Four groups of Tg2576 mice were used as the animal model for AD: wild type mice (n = 6), AD mice (n = 6), and DA-9601-administered AD mice given dosages of 30mg/kg/day (DA_30mg; n = 6) or 100mg/kg/day (DA_100mg; n = 6). Microglial activation, blood‒brain barrier integrity, amyloid beta accumulation, cognitive behavior, and changes in the gut microbiome were analyzed. DA-9601 improved the cognitive behavior of mice (DA_30mg **p<0.01; DA_100mg **p<0.01) and reduced amyloid beta accumulation (DA_30mg ***p<0.001; DA_100mg **p<0.01). Increased Iba-1 and upregulation of claudin-5 (DA_30mg *p<0.05) and occludin (DA_30mg **p<0.01; DA_100mg ***p<0.001) indicated altered microglial activation and improved blood‒brain barrier integrity. Akkermansia muciniphila was dramatically increased by DA-9601 administration (DA_30mg 47%; DA_100mg 61%). DA-9601 improved AD pathology with Akkermansia muciniphila dominance in the gut microbiome in a mouse model of AD, inferring that DA-9601 can affect AD through the gut-brain axis.

The link between amyloid β and ferroptosis pathway in Alzheimer’s disease progression

Alzheimer’s disease (AD) affects millions of people worldwide and represents the most prevalent form of dementia. Treatment strategies aiming to interfere with the formation of amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs), the two major AD hallmarks, have shown modest or no effect. Recent evidence suggests that ferroptosis, a type of programmed cell death caused by iron accumulation and lipid peroxidation, contributes to AD pathogenesis. The existing link between ferroptosis and AD has been largely based on cell culture and animal studies, while evidence from human brain tissue is limited. Here we evaluate if Aβ is associated with ferroptosis pathways in post-mortem human brain tissue and whether ferroptosis inhibition could attenuate Aβ-related effects in human brain organoids. Performing positive pixel density scoring on immunohistochemically stained post-mortem Brodmann Area 17 sections revealed that the progression of AD pathology was accompanied by decreased expression of nuclear receptor co-activator 4 and glutathione peroxidase 4 in the grey matter. Differentiating between white and grey matter, allowed for a more precise understanding of the disease’s impact on different brain regions. In addition, ferroptosis inhibition prevented Aβ pathology, decreased lipid peroxidation and restored iron storage in human AD iPSCs-derived brain cortical organoids at day 50 of differentiation. Differential gene expression analysis of RNAseq of AD organoids compared to isogenic controls indicated activation of the ferroptotic pathway. This was also supported by results from untargeted proteomic analysis revealing significant changes between AD and isogenic brain organoids. Determining the causality between the development of Aβ plaques and the deregulation of molecular pathways involved in ferroptosis is crucial for developing potential therapeutic interventions.

Mechanisms of ozone-induced neurotoxicity in the development and progression of dementia: a brief review

Dementia encompasses a spectrum of neurodegenerative disorders significantly impacting global health, with environmental factors increasingly recognized as crucial in their etiology. Among these, ozone, has been identified as a potential exacerbator of neurodegenerative processes, particularly in Alzheimer’s disease (AD). Ozone exposure induces the production of reactive oxygen species (ROS), which penetrate the BBB, leading to oxidative damage in neuronal cells. This oxidative stress is closely linked with mitochondrial dysfunction and lipid peroxidation, processes that are foundational to the pathology observed in dementia, such as neuronal death and protein aggregation. Furthermore, ozone triggers chronic neuroinflammation, exacerbating these neurodegenerative processes and perpetuating a cycle of CNS damage. Recent studies highlight the role of peripheral biomarkers like High Mobility Group Box 1 (HMGB1) and Triggering Receptor Expressed on Myeloid cells 2 (TREM2) in mediating ozone’s effects. Disruption of these and other identified proteins by ozone exposure impairs microglial function and response to amyloid plaques, suggesting a novel pathway through which ozone may influence AD pathology via immune dysregulation. This review discusses the concept of a bidirectional lung-brain axis, illustrating that systemic responses to air pollutants like ozone may reflect and contribute to neurodegenerative processes in the CNS. By delineating these mechanisms, we emphasize the critical need for integrating environmental health management into strategies for the prevention and treatment of dementia.

Exploring the role of HIF-1α on pathogenesis in Alzheimer's disease and potential therapeutic approaches.

Hypoxia-inducible factor 1α (HIF-1α) is a crucial transcription factor that regulates cellular responses to low oxygen levels (hypoxia). In Alzheimer's disease (AD), emerging evidence suggests a significant involvement of HIF-1α in disease pathogenesis. AD is characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs), leading to neuronal dysfunction and cognitive decline. HIF-1α is implicated in AD through its multifaceted roles in various cellular processes. Firstly, in response to hypoxia, HIF-1α promotes the expression of genes involved in angiogenesis, which is crucial for maintaining cerebral blood flow and oxygen delivery to the brain. However, in the context of AD, dysregulated HIF-1α activation may exacerbate cerebral hypoperfusion, contributing to neuronal damage. Moreover, HIF-1α is implicated in the regulation of Aβ metabolism. It can influence the production and clearance of Aβ peptides, potentially modulating their accumulation and toxicity in the brain. Additionally, HIF-1α activation has been linked to neuroinflammation, a key feature of AD pathology. It can promote the expression of pro-inflammatory cytokines and exacerbate neuronal damage. Furthermore, HIF-1α may play a role in synaptic plasticity and neuronal survival, which are impaired in AD. Dysregulated HIF-1α signaling could disrupt these processes, contributing to cognitive decline and neurodegeneration. Overall, the involvement of HIF-1α in various aspects of AD pathophysiology highlights its potential as a therapeutic target. Modulating HIF-1α activity could offer novel strategies for mitigating neurodegeneration and preserving cognitive function in AD patients. However, further research is needed to elucidate the precise mechanisms underlying HIF-1α dysregulation in AD and to develop targeted interventions.

Association of modifiable risk factors with progression to dementia in relation to amyloid and tau pathology

BackgroundDementia preventive interventions targeting multiple modifiable risk factors are a promising approach. However, the impact of modifiable risk factors in the presence of beta-amyloid or phosphorylated-tau (p-tau) pathology is unclear.MethodsThe objective of the study was to examine the role of modifiable risk factors (vascular factors, depression, and smoking) in the progression to mild cognitive impairment (MCI) or dementia among 434 cognitively unimpaired (CU) and 611 individuals with MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Vascular risk factors were summarized with the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) score, dichotomized into higher versus lower risk. Depression and smoking (yes/no) were categorised according to medical history or current symptoms. Analyses were stratified by beta-amyloid negative (A-) and positive (A +), p-tau negative (T-) and positive (T +), or beta-amyloid and p-tau negative (A-T-) and positive (A + T +) biomarker status. Cox proportional hazard models were adjusted for age, sex, education, baseline MMSE score, baseline hippocampal volume and ApoE4 carrier status.ResultsHigher CAIDE score was associated with increased risk of progression to all-cause dementia in most MCI subgroups: adjusted hazard ratios (aHR) [95% CI] were 3.1 [1.43; 6.53] in the A- subgroup, 1.7 [1.20–2.27] in T + , 2.6 [1.06–6.59] in A-T-, and 1.6 [1.15–2.22] in the A + T + subgroup. Smoking (yes/no) was associated with increased dementia aHR in the A + MCI subgroup: 1.6 [1.07–2.34]. Depression increased dementia aHR in the T + MCI subgroup: 1.5 [1.06–2.02]. No significant associations were found in the CU biomarker subgroups.ConclusionAddressing modifiable risk factors carries an important potential for reducing the risk of dementia even after the onset of Alzheimer's pathology. Knowledge of biomarker status can further optimize prevention strategies.

Coffee and Alzheimer's Disease: Reviewing the Neuroprotective Effects of Bioactive Compounds

Alzheimer's disease (AD) is a common neurodegenerative disorder primarily managed with symptomatic treatments. Coffee, a popular beverage, contains bioactive compounds like caffeine, chlorogenic acid, quercetin, trigonelline, caffeic acid, and kaempferol, which may offer neuroprotective benefits. These compounds could potentially address AD-related pathologies such as amyloid-beta accumulation, tau hyperphosphorylation, oxidative stress, and inflammation. This review explores the neuroprotective potential of coffee's bioactive components in AD. Aim of the Study This study aims to review research on the neuroprotective effects of coffee and its bioactive compounds in Alzheimer's disease. It seeks to understand how these compounds may mitigate AD-related pathologies and their potential in preventive and therapeutic applications. The study also identifies knowledge gaps and suggests future research directions. Material and Methods We reviewed literature from PubMed, Google Scholar and other scientific sources using keywords: Alzheimer's disease, coffee, neuroprotective, caffeine, chlorogenic acid, quercetin, trigonelline, caffeic acid, and kaempferol. Conclusions Emerging evidence indicates that coffee's bioactive compounds may offer neuroprotective benefits against Alzheimer's disease. Compounds such as caffeine, chlorogenic acid, quercetin, trigonelline, caffeic acid, and kaempferol show potential in mitigating key AD pathologies. However, the current evidence is preliminary, and more research is needed to fully understand their cognitive benefits and mechanisms. Investigating these properties is particularly relevant given the aging global population and the age-related nature of AD.

Exploring the Dynamic Changes of Brain Lipids, Lipid Rafts, and Lipid Droplets in Aging and Alzheimer’s Disease

Aging induces complex changes in the lipid profiles across different areas of the brain. These changes can affect the function of brain cells and may contribute to neurodegenerative diseases such as Alzheimer’s disease. Research shows that while the overall lipid profile in the human brain remains quite steady throughout adulthood, specific changes occur with age, especially after the age of 50. These changes include a slow decline in total lipid content and shifts in the composition of fatty acids, particularly in glycerophospholipids and cholesterol levels, which can vary depending on the brain region. Lipid rafts play a crucial role in maintaining membrane integrity and facilitating cellular signaling. In the context of Alzheimer’s disease, changes in the composition of lipid rafts have been associated with the development of the disease. For example, alterations in lipid raft composition can lead to increased accumulation of amyloid β (Aβ) peptides, contributing to neurotoxic effects. Lipid droplets store neutral lipids and are key for cellular energy metabolism. As organisms age, the dynamics of lipid droplets in the brain change, with evidence suggesting a decline in metabolic activity over time. This reduced activity may lead to an imbalance in lipid synthesis and mobilization, contributing to neurodegenerative processes. In model organisms like Drosophila, studies have shown that lipid metabolism in the brain can be influenced by diet and insulin signaling pathways, crucial for maintaining metabolic balance. The interplay between lipid metabolism, oxidative stress, and inflammation is critical in the context of aging and Alzheimer’s disease. Lipid peroxidation, a consequence of oxidative stress, can lead to the formation of reactive aldehydes that further damage neurons. Inflammatory processes can also disrupt lipid metabolism, contributing to the pathology of AD. Consequently, the accumulation of oxidized lipids can affect lipid raft integrity, influencing signaling pathways involved in neuronal survival and function.

Increased expression of the proapoptotic presenilin associated protein is involved in neuronal tangle formation in human brain

Presenilin-associated protein (PSAP) is a mitochondrial proapoptotic protein as established in cell biology studies. It remains unknown whether it involves in neurodegenerative diseases. Here, we explored PASP expression in adult and aged human brains and its alteration relative to Alzheimer-disease (AD)-type neuropathology. In pathology-free brains, light PASP immunoreactivity (IR) occurred among largely principal neurons in the cerebrum and subcortical structures. In the brains with AD pathology, enhanced PSAP IR occurred in neuronal and neuritic profiles with a tangle-like appearance, with PSAP and pTau protein levels elevated in neocortical lysates relative to control. Neuronal/neuritic profiles with enhanced PSAP IR partially colocalized with pTau, but invariably with Amylo-Glo labelled tangles. The neuronal somata with enhanced PASP IR also showed diminished IR for casein kinase 1 delta (Ck1δ), a marker of granulovacuolar degeneration; and diminished IR for sortilin, which is normally expressed in membrane and intracellular protein sorting/trafficking organelles. In old 3xTg-AD mice with β-amyloid and pTau pathologies developed in the brain, PSAP IR in the cerebral sections exhibited no difference relative to wildtype mice. These findings indicate that PSAP upregulation is involved in the course of tangle formation especially in the human brain during aging and in AD pathogenesis.

Molecular mechanisms underlying amyloid beta peptide mediated upregulation of vascular cell adhesion molecule-1 in Alzheimer's disease.

Amyloid beta (Aβ) deposition and neurofibrillary tangles are widely considered as the primary pathological hallmarks of familial and sporadic forms of Alzheimer's disease (AD). However, cerebrovascular inflammation, which is prevalent in 70% of AD patients is emerging as another core feature of AD pathology. In addition, activation of inflammatory signaling pathways have been observed in AD patients; specifically, cerebrovascular inflammation was found to be augmented in Alzheimer's patients. Our studies have demonstrated that the inflammation signaling pathway is upregulated in AD patient brains. Moreover, vascular cell adhesion molecule-1 (VCAM-1), a cerebrovascular inflammatory marker expressed on the blood-brain barrier (BBB) endothelium, was observed to be upregulated in APP,PS1 mice (a mouse model that overexpresses Ab42), as detected by dynamic SPEC/CT imaging. While there is a strong association between Aβ42 exposure and an increase in VCAM-1 expression, the mechanisms underlying the influence of Aβ42 on VCAM-1 expression remain understudied. Therefore, we investigated the hypothesis that Ab42 exposure increases VCAM-1 expression in human cerebral microvascular endothelial cell (hCMEC/D3) monolayers. In addition, reverse phase protein array assays (RPPA) and immunocytochemistry demonstrated that Ab42 increases VCAM-1 expression through the Src/p38/MEK signaling pathway specifically within the blood-brain barrier (BBB) endothelium. In summary, these results demonstrate that Ab42 augments cerebrovascular inflammation by elevating VCAM-1 expression via Src/MEK/p38 pathway. Hence, targeting VCAM-1 at the BBB as a diagnostic and therapeutic marker may hold potential for detecting and mitigating cerebrovascular inflammation in Alzheimer's disease. Significance Statement While considered a core pathological feature of Alzheimer's disease, molecular pathways leading to cerebrovascular inflammation remain partially understood. Moreover, clinical diagnostic methods for detecting cerebrovascular inflammation are underdeveloped. In this study, we demonstrated VCAM-1 detection using radio-iodinated VCAM-1 antibody and SPECT/CT imaging. The study demonstrated that the exposure to Aβ42 increases VCAM-1 expression on the BBB endothelium via Src/p38/MEK pathway. These findings are expected to aid in the development of diagnostic and therapeutic approaches for addressing cerebrovascular inflammation in AD.

Delineating three distinct spatiotemporal patterns of brain atrophy in Parkinson's disease.

The clinical manifestation of Parkinson's disease exhibits significant heterogeneity in the prevalence of non-motor symptoms and the rate of progression of motor symptoms, suggesting that Parkinson's disease can be classified into distinct subtypes. In this study, we aimed to explore this heterogeneity by identifying a set of subtypes with distinct patterns of spatiotemporal trajectories of neurodegeneration. We applied Subtype and Stage Inference (SuStaIn), an unsupervised machine learning algorithm that combined disease progression modelling with clustering methods, to cortical and subcortical neurodegeneration visible on 3 T structural MRI of a large cross-sectional sample of 504 patients and 279 healthy controls. Serial longitudinal data were available for a subset of 178 patients at the 2-year follow-up and for 140 patients at the 4-year follow-up. In a subset of 210 patients, concomitant Alzheimer's disease pathology was assessed by evaluating amyloid-β concentrations in the CSF or via the amyloid-specific radiotracer 18F-flutemetamol with PET. The SuStaIn analysis revealed three distinct subtypes, each characterized by unique patterns of spatiotemporal evolution of brain atrophy: neocortical, limbic and brainstem. In the neocortical subtype, a reduction in brain volume occurred in the frontal and parietal cortices in the earliest disease stage and progressed across the entire neocortex during the early stage, although with relative sparing of the striatum, pallidum, accumbens area and brainstem. The limbic subtype represented comparative regional vulnerability, which was characterized by early volume loss in the amygdala, accumbens area, striatum and temporal cortex, subsequently spreading to the parietal and frontal cortices across disease stage. The brainstem subtype showed gradual rostral progression from the brainstem extending to the amygdala and hippocampus, followed by the temporal and other cortices. Longitudinal MRI data confirmed that 77.8% of participants at the 2-year follow-up and 84.0% at the 4-year follow-up were assigned to subtypes consistent with estimates from the cross-sectional data. This three-subtype model aligned with empirically proposed subtypes based on age at onset, because the neocortical subtype demonstrated characteristics similar to those found in the old-onset phenotype, including older onset and cognitive decline symptoms (P < 0.05). Moreover, the subtypes correspond to the three categories of the neuropathological consensus criteria for symptomatic patients with Lewy pathology, proposing neocortex-, limbic- and brainstem-predominant patterns as different subgroups of α-synuclein distributions. Among the subtypes, the prevalence of biomarker evidence of amyloid-β pathology was comparable. Upon validation, the subtype model might be applied to individual cases, potentially serving as a biomarker to track disease progression and predict temporal evolution.

Deciphering the role of lipid metabolism-related genes in Alzheimer’s disease: a machine learning approach integrating Traditional Chinese Medicine

BackgroundAlzheimer’s disease (AD) represents a progressive neurodegenerative disorder characterized by the accumulation of misfolded amyloid beta protein, leading to the formation of amyloid plaques and the aggregation of tau protein into neurofibrillary tangles within the cerebral cortex. The role of carbohydrates, particularly apolipoprotein E (ApoE), is pivotal in AD pathogenesis due to its involvement in lipid and cholesterol metabolism, and its status as a genetic predisposition factor for the disease. Despite its significance, the mechanistic contributions of Lipid Metabolism-related Genes (LMGs) to AD remain inadequately elucidated. This research endeavor seeks to bridge this gap by pinpointing biomarkers indicative of early-stage AD, with an emphasis on those linked to immune cell infiltration. To this end, advanced machine-learning algorithms and data derived from the Gene Expression Omnibus (GEO) database have been employed to facilitate the identification of these biomarkers.MethodsDifferentially expressed genes (DEGs) were identified by comparing gene expression profiles between healthy individuals and Alzheimer’s disease (AD) patients, using data from two Gene Expression Omnibus (GEO) datasets: GSE5281 and GSE138260. Functional enrichment analysis was conducted to elucidate the biological relevance of the DEGs. To ensure the reliability of the results, samples were randomly divided into training and validation sets. The analysis focused on lipid metabolism-related DEGs (LMDEGs) to explore potential biomarkers for AD. Machine learning algorithms, including Support Vector Machine-Recursive Feature Elimination (SVM-RFE) and the Least Absolute Shrinkage and Selection Operator (LASSO) regression model, were applied to identify a key gene biomarker. Additionally, immune cell infiltration and its relationship with the gene biomarker were assessed using the CIBERSORT algorithm. The Integrated Traditional Chinese Medicine (ITCM) database was also referenced to identify Chinese medicines related to lipid metabolism and their possible connection to AD. This comprehensive strategy aims to integrate modern computational methods with traditional medicine to deepen our understanding of AD and its underlying mechanisms.ResultsThe study identified 137 genes from a pool of 751 lipid metabolism-related genes (LMGs) significantly associated with autophagy and immune response mechanisms. Through the application of LASSO and SVM-RFE machine-learning techniques, four genes—choline acetyl transferase (CHAT), member RAS oncogene family (RAB4A), acyl-CoA binding domain-containing protein 6 (ACBD6), and alpha-galactosidase A (GLA)—emerged as potential biomarkers for Alzheimer’s disease (AD). These genes demonstrated strong therapeutic potential due to their involvement in critical biological pathways. Notably, nine Chinese medicine compounds were identified to target these marker genes, offering a novel treatment approach for AD. Further, ceRNA network analysis revealed complex regulatory interactions involving these genes, underscoring their importance in AD pathology. CIBERSORT analysis highlighted a potential link between changes in the immune microenvironment and CHAT expression levels in AD patients, providing new insights into the immunological dimensions of the disease.ConclusionThe discovery of these gene markers offers substantial promise for the diagnosis and understanding of Alzheimer’s disease (AD). However, further investigation is necessary to validate their clinical utility. This study illuminates the role of Lipid Metabolism-related Genes (LMGs) in AD pathogenesis, offering potential targets for therapeutic intervention. It enhances our grasp of AD’s complex mechanisms and paves the way for future research aimed at refining diagnostic and treatment strategies.

Enrichment for clinical trials of early AD: Combining genetic risk factors and plasma p-tau as screening instruments.

Identifying low-cost, minimally-invasive screening instruments for Alzheimer's disease (AD) trial enrichment will improve the efficiency of AD trials. A total of 685 cognitively normal (CN) individuals and individuals with mild cognitive impairment (MCI) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were grouped according to cutoffs of genetic risk factor (G) polygenic hazard score (PHS) and tau pathology (T) plasma phosphorylated tau-181 (p-tau181) into four groups: G+T+, G-T-, G+T-, and G-T+. We assessed the associations between group level and longitudinal cognitive decline and AD conversion. Power analyses compared the estimated sample size required to detect differences in cognitive decline. The G+T+ group was associated with faster cognitive decline and higher AD risk. Clinical trials enrolling G+T+ participants would benefit from significantly reduced sample sizes compared with similar trials using only single makers as an inclusion criterion. The combination of two low-cost, minimally-invasive measures-genetics and plasma biomarkers-would be a promising screening procedure for clinical trial enrollment. Participants with unimpaired or mildly impaired cognition were grouped based on cutoffs on genetic risk factors (G: polygenic hazardous score [PHS]) and Alzheimer's pathology (T: baseline plasma phosphorylated tau-181 [p-tau181]). Participants with high PHSs and plasma p-tau181 levels (G+T+) were at risk of faster cognitive decline and AD progression. The combination of PHS and plasma p-tau181 could enhance clinical trial enrichment more effectively than using single biomarkers.

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

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. 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. We characterized adaptive, AD-associated gene, and AD-associated protein responses. SH-SY5Y cells and iPSC neurons responded to mtDNA transcript translation inhibition by increasing mtDNA copy number and transcription. Nuclear-expressed respiratory chain mRNA and protein levels also changed. There were AD-consistent concordant and model-specific changes in amyloid precursor protein, beta amyloid, apolipoprotein E, tau, and α-synuclein biology. Primary mitochondrial dysfunction induces compensatory organelle responses, changes nuclear gene expression, and alters the biology of AD-associated genes and proteins in ways that may recapitulate brain aging and AD molecular phenomena. In AD, mitochondrial dysfunction could represent a disease cause or consequence. We inhibited mitochondrial translation in human neuronal cells and neurons. Mitochondrial and nuclear gene expression shifted in adaptive-consistent patterns. APP, Aβ, APOE, tau, and α-synuclein biology changed in AD-consistent patterns. Mitochondrial stress creates an environment that promotes AD pathology.

Unraveling the interplay of kinesin-1, tau, and microtubules in neurodegeneration associated with Alzheimer’s disease

Alzheimer’s disease (AD) is marked by the gradual and age-related deterioration of nerve cells in the central nervous system. The histopathological features observed in the brain affected by AD are the aberrant buildup of extracellular and intracellular amyloid-β and the formation of neurofibrillary tangles consisting of hyperphosphorylated tau protein. Axonal transport is a fundamental process for cargo movement along axons and relies on molecular motors like kinesins and dyneins. Kinesin’s responsibility for transporting crucial cargo within neurons implicates its dysfunction in the impaired axonal transport observed in AD. Impaired axonal transport and dysfunction of molecular motor proteins, along with dysregulated signaling pathways, contribute significantly to synaptic impairment and cognitive decline in AD. Dysregulation in tau, a microtubule-associated protein, emerges as a central player, destabilizing microtubules and disrupting the transport of kinesin-1. Kinesin-1 superfamily members, including kinesin family members 5A, 5B, and 5C, and the kinesin light chain, are intricately linked to AD pathology. However, inconsistencies in the abundance of kinesin family members in AD patients underline the necessity for further exploration into the mechanistic impact of these motor proteins on neurodegeneration and axonal transport disruptions across a spectrum of neurological conditions. This review underscores the significance of kinesin-1’s anterograde transport in AD. It emphasizes the need for investigations into the underlying mechanisms of the impact of motor protein across various neurological conditions. Despite current limitations in scientific literature, our study advocates for targeting kinesin and autophagy dysfunctions as promising avenues for novel therapeutic interventions and diagnostics in AD.

Cognitive status and demographics modify the association between subjective cognition and amyloid.

This study examined the effect of cognitive status, education, and sex on the association between subjective cognitive decline (SCD) and Alzheimer's disease (AD) biomarkers in non-demented older adults. Vanderbilt Memory and Aging Project participants (n = 129), dementia or stroke free, completed fasting lumbar puncture, SCD assessment, and cognitive assessment. Cerebrospinal fluid (CSF) biomarkers for AD were analyzed. Linear regression models related SCD to CSF AD biomarkers and follow-up models assessed interactions of SCD × cognitive status, sex, reading level, and education on AD biomarkers. In main effect models, higher SCD was associated with more amyloidosis (p-values <0.004). SCD was not associated with tau, p-tau, or neurofilament light (NFL) levels (p-values >0.38). SCD score interacted with cognitive status (p < 0.02), sex (p = 0.03), and education (p-values <0.005) on amyloidosis. In stratified models, higher SCD was associated with more amyloid in cognitively unimpaired (p-values <0.003), men (p = 0.0003), and higher education. No SCD score × reading-level interaction was found (p-values >0.51) though SCD related to amyloid markers in the higher reading-level group (p-values <0.004). Higher SCD was associated with greater cerebral amyloid accumulation, one of the earliest pathological AD changes. SCD appears most useful in detecting early AD-related brain changes prior to objective cognitive impairment, in men, and those with higher quantity and quality of education and highlight the importance of considering these factors.