25 results for “Alzheimer's & dementia : the journal of the Alzheimer's Association”. Showing 25 of 39,449.
ABCA7 and the altered lipidostasis hypothesis of Alzheimer's disease.
We propose the altered lipidostasis hypothesis of Alzheimer's disease (AD). It holds that vulnerable neurons of the entorhinal region generate a neurodegenerative lipid during normal function, adenosine triphosphate-binding cassette transporter subfamily A member 7 (ABCA7) protects from AD pathogenesis by removing it out of the cell, generation of the lipid increases with age, and the minimal amount of ABCA7 needed to dispose of the rising volumes of the lipid also increases with age. A survey of ABCA7 protein levels in the hippocampus or parietal cortex of 123 individuals with or without AD neuropathology showed that individuals with low ABCA7 developed AD neuropathology at a younger age, those with intermediate ABCA7 developed it later, and individuals who developed it very late had high ABCA7, the same as the youngest controls. ABC transporters closely similar to ABCA7 protect cells by removing toxic lipids. ABCA7 may have analogous functions. The hypothesis predicts lipidosis and membrane protein dysfunction in neurons with low ABCA7. Further work will identify the neurodegenerative lipid and determine approaches to exploit ABCA7 for therapeutic purposes.
ABCA7 deletion lowers age at onset of Alzheimer's disease and interacts with APOE ε4 synergistically in African-ancestry populations.
INTRODUCTION: Apolipoprotein E (APOE) and ABCA7 genes are among the strongest heritable risk factors for Alzheimer's disease (AD) in African-ancestry (AA) populations. APOE 𝜀4 affects both risk and age at onset (AAO), with lower risk in AA populations. This study evaluates the independent and interactive effects of the AA-specific ABCA7 frameshift deletion and APOE 𝜀4 allele on AAO. METHODS: We analyzed 3510 AA individuals, including AD cases and controls. Cox regression models assessed the effects of ABCA7 deletion, APOE genotypes, and their interactive influence on AAO. RESULTS: APOE ε3/ε4 carriers with the ABCA7 deletion had a significantly shorter survival compared to ε3/ε4 carriers without the deletion. No significant differences were found between deletion carriers and non-carriers with APOE ε3/ε3 or ε4/ε4 genotypes. DISCUSSION: Our study showed that the ABCA7 deletion lowered the AAO of AD in APOE ε3/ε4 carriers from AA populations. These findings suggest that the AA-specific ABCA7 deletion and the APOE ε4 allele have synergistic effects on AAO. HIGHLIGHTS: AA-specific ABCA7 deletion lowers AAO of AD in APOE ε3/ε4 carriers from AA populations. Findings suggest an interaction between ABCA7 deletion and APOE ε4 on AAO. APOE ε4 has a strong, dose-dependent effect on AAO of AD in AA individuals. ABCA7 deletion impact on AAO of AD is stronger in females with APOE ε3/ε4.
A blood-based multi-pathway biomarker assay for early detection and staging of Alzheimer's disease across ethnic groups.
INTRODUCTION: Existing blood-based biomarkers for Alzheimer's disease (AD) mainly focus on its pathological features. However, studies on blood-based biomarkers associated with other biological processes for a comprehensive evaluation of AD status are limited. METHODS: We developed a blood-based, multiplex biomarker assay for AD that measures the levels of 21 proteins involved in multiple biological pathways. We evaluated the assay's performance for classifying AD and indicating AD-related endophenotypes in three independent cohorts from Chinese or European-descent populations. RESULTS: The 21-protein assay accurately classified AD (area under the receiver operating characteristic curve [AUC] = 0.9407 to 0.9867) and mild cognitive impairment (MCI; AUC = 0.8434 to 0.8945) while also indicating brain amyloid pathology. Moreover, the assay simultaneously evaluated the changes of five biological processes in individuals and revealed the ethnic-specific dysregulations of biological processes upon AD progression. DISCUSSION: This study demonstrated the utility of a blood-based, multi-pathway biomarker assay for early screening and staging of AD, providing insights for patient stratification and precision medicine. HIGHLIGHTS: The authors developed a blood-based biomarker assay for Alzheimer's disease. The 21-protein assay classifies AD/MCI and indicates brain amyloid pathology. The 21-protein assay can simultaneously assess activities of five biological processes. Ethnic-specific dysregulations of biological processes in AD were revealed.
ADO: a disease ontology representing the domain knowledge specific to Alzheimer's disease.
Biomedical ontologies offer the capability to structure and represent domain-specific knowledge semantically. Disease-specific ontologies can facilitate knowledge exchange across multiple disciplines, and ontology-driven mining approaches can generate great value for modeling disease mechanisms. However, in the case of neurodegenerative diseases such as Alzheimer's disease, there is a lack of formal representation of the relevant knowledge domain. Alzheimer's disease ontology (ADO) is constructed in accordance to the ontology building life cycle. The Protégé OWL editor was used as a tool for building ADO in Ontology Web Language format. ADO was developed with the purpose of containing information relevant to four main biological views-preclinical, clinical, etiological, and molecular/cellular mechanisms-and was enriched by adding synonyms and references. Validation of the lexicalized ontology by means of named entity recognition-based methods showed a satisfactory performance (F score = 72%). In addition to structural and functional evaluation, a clinical expert in the field performed a manual evaluation and curation of ADO. Through integration of ADO into an information retrieval environment, we show that the ontology supports semantic search in scientific text. The usefulness of ADO is authenticated by dedicated use case scenarios. Development of ADO as an open ADO is a first attempt to organize information related to Alzheimer's disease in a formalized, structured manner. We demonstrate that ADO is able to capture both established and scattered knowledge existing in scientific text.
Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference.
INTRODUCTION: The apolipoprotein E gene (APOE) is an established central player in the pathogenesis of Alzheimer's disease (AD), with distinct apoE isoforms exerting diverse effects. apoE influences not only amyloid-beta and tau pathologies but also lipid and energy metabolism, neuroinflammation, cerebral vascular health, and sex-dependent disease manifestations. Furthermore, ancestral background may significantly impact the link between APOE and AD, underscoring the need for more inclusive research. METHODS: In 2023, the Alzheimer's Association convened multidisciplinary researchers at the "AAIC Advancements: APOE" conference to discuss various topics, including apoE isoforms and their roles in AD pathogenesis, progress in apoE-targeted therapeutic strategies, updates on disease models and interventions that modulate apoE expression and function. RESULTS: This manuscript presents highlights from the conference and provides an overview of opportunities for further research in the field. DISCUSSION: Understanding apoE's multifaceted roles in AD pathogenesis will help develop targeted interventions for AD and advance the field of AD precision medicine. HIGHLIGHTS: APOE is a central player in the pathogenesis of Alzheimer's disease. APOE exerts a numerous effects throughout the brain on amyloid-beta, tau, and other pathways. The AAIC Advancements: APOE conference encouraged discussions and collaborations on understanding the role of APOE.
A genetic and proteomic comparison of key AD biomarkers across tissues.
INTRODUCTION: Plasma has been proposed as an alternative to cerebrospinal fluid (CSF) for measuring Alzheimer's disease (AD) biomarkers, but no studies have analyzed in detail which biofluid is more informative for genetics studies of AD. METHOD: Eleven proteins associated with AD (α-synuclein, apolipoprotein E [apoE], CLU, GFAP, GRN, NfL, NRGN, SNAP-25, TREM2, VILIP-1, YKL-40) were assessed in plasma (n = 2317) and CSF (n = 3107). Both plasma and CSF genome-wide association study (GWAS) analyses were performed for each protein, followed by functional annotation. Additional characterization for each biomarker included calculation of correlations and predictive power. RESULTS: Eighteen plasma protein quantitative train loci (pQTLs) associated with 10 proteins and 16 CSF pQTLs associated with 9 proteins were identified. Plasma and CSF shared some genetic loci, but protein levels between tissues correlated weakly. CSF protein levels better associated with AD compared to plasma. DISCUSSION: The present results indicate that CSF is more informative than plasma for genetic studies in AD. HIGHLIGHTS: The identification of novel protein quantitative trait loci (pQTLs) in both plasma and cerebrospinal fluid (CSF). Plasma and CSF levels of neurodegeneration-related proteins correlated weakly. CSF is more informative than plasma for genetic studies of Alzheimer's disease (AD). Neurofilament light (NfL), triggering receptor expressed on myeloid cells 2 (TREM2), and chitinase-3-like protein 1 (YKL-40) tend to show relatively strong inter-tissue associations. A novel signal in the apolipoprotein E (APOE) region was identified, which is an eQTL for APOC1.
A genome-wide association meta-analysis of all-cause and vascular dementia.
INTRODUCTION: Dementia is a multifactorial disease with Alzheimer's disease (AD) and vascular dementia (VaD) pathologies making the largest contributions. Yet, most genome-wide association studies (GWAS) focus on AD. METHODS: We conducted a GWAS of all-cause dementia (ACD) and examined the genetic overlap with VaD. Our dataset includes 800,597 individuals, with 46,902 and 8702 cases of ACD and VaD, respectively. Known AD loci for ACD and VaD were replicated. Bioinformatic analyses prioritized genes that are likely functionally relevant and shared with closely related traits and risk factors. RESULTS: For ACD, novel loci identified were associated with energy transport (SEMA4D), neuronal excitability (ANO3), amyloid deposition in the brain (RBFOX1), and magnetic resonance imaging markers of small vessel disease (SVD; HBEGF). Novel VaD loci were associated with hypertension, diabetes, and neuron maintenance (SPRY2, FOXA2, AJAP1, and PSMA3). DISCUSSION: Our study identified genetic risks underlying ACD, demonstrating overlap with neurodegenerative processes, vascular risk factors, and cerebral SVD. HIGHLIGHTS: We conducted the largest genome-wide association study of all-cause dementia (ACD) and vascular dementia (VaD). Known genetic variants associated with AD were replicated for ACD and VaD. Functional analyses identified novel loci for ACD and VaD. Genetic risks of ACD overlapped with neurodegeneration, vascular risk factors, and cerebral small vessel disease.
Aggregate effects of vascular risk factors on cerebrovascular changes in autopsy-confirmed Alzheimer's disease.
We examined the relationships of antemortem vascular risk factors to postmortem cerebrovascular and Alzheimer's disease (AD) pathologies. Eighty-four AD patients underwent an assessment of vascular risk (blood pressure, cholesterol, smoking, cardiovascular disease, diabetes, atrial fibrillation, transient ischemic attack [TIA], or stroke) and later underwent brain autopsy. Given our aim to examine mild cerebrovascular changes (CVCs), individuals were excluded if autopsy revealed large stroke. The most common forms of CVC were circle of Willis atherosclerosis followed by arteriosclerosis, lacunes, and microinfarcts. Excluding the history of TIA/clinical stroke, individual vascular risk factors were not associated with CVC. However, the presence of multiple vascular risk factors was associated with CVC. Furthermore, the presence of CVC was associated with lower Braak and Braak stage. These findings highlight the importance of aggregate risk in the vascular contribution to dementia. Interventions designed to maintain cerebrovascular health may represent important opportunities for preventing or delaying dementia, even when AD is the dominant pathology.
A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment.
INTRODUCTION: Unlike for glucose, uptake of the brain's main alternative fuel, ketones, remains normal in mild cognitive impairment (MCI). Ketogenic medium chain triglycerides (kMCTs) could improve cognition in MCI by providing the brain with more fuel. METHODS: Fifty-two subjects with MCI were blindly randomized to 30 g/day of kMCT or matching placebo. Brain ketone and glucose metabolism (quantified by positron emission tomography; primary outcome) and cognitive performance (secondary outcome) were assessed at baseline and 6 months later. RESULTS: Brain ketone metabolism increased by 230% for subjects on the kMCT (P < .001) whereas brain glucose uptake remained unchanged. Measures of episodic memory, language, executive function, and processing speed improved on the kMCT versus baseline. Increased brain ketone uptake was positively related to several cognitive measures. Seventy-five percent of participants completed the intervention. DISCUSSION: A dose of 30 g/day of kMCT taken for 6 months bypasses a significant part of the brain glucose deficit and improves several cognitive outcomes in MCI.
Alzheimer's Association clinical practice guideline for the Diagnostic Evaluation, Testing, Counseling, and Disclosure of Suspected Alzheimer's Disease and Related Disorders (DETeCD-ADRD): Executive summary of recommendations for primary care.
US clinical practice guidelines for the diagnostic evaluation of cognitive impairment due to Alzheimer's disease (AD) or AD and related dementias (ADRD) are decades old and aimed at specialists. This evidence-based guideline was developed to empower all-including primary care-clinicians to implement a structured approach for evaluating a patient with symptoms that may represent clinical AD/ADRD. Through a modified-Delphi approach and guideline-development process (7374 publications were reviewed; 133 met inclusion criteria) an expert workgroup developed recommendations as steps in a patient-centered evaluation process. This summary focuses on recommendations, appropriate for any practice setting, forming core elements of a high-quality, evidence-supported evaluation process aimed at characterizing, diagnosing, and disclosing the patient's cognitive functional status, cognitive-behavioral syndrome, and likely underlying brain disease so that optimal care plans to maximize patient/care partner dyad quality of life can be developed; a companion article summarizes specialist recommendations. If clinicians use this guideline and health-care systems provide adequate resources, outcomes should improve in most patients in most practice settings. Highlights US clinical practice guidelines for the diagnostic evaluation of cognitive impairment due to Alzheimer's disease (AD) or AD and related dementias (ADRD) are decades old and aimed at specialists. This evidence-based guideline was developed to empower all-including primary care-clinicians to implement a structured approach for evaluating a patient with symptoms that may represent clinical AD/ADRD. This summary focuses on recommendations, appropriate for any practice setting, forming core elements of a high-quality, evidence-supported evaluation process aimed at characterizing, diagnosing, and disclosing the patient's cognitive functional status, cognitive-behavioral syndrome, and likely underlying brain disease so that optimal care plans to maximize patient/care partner dyad quality of life can be developed; a companion article summarizes specialist recommendations. If clinicians use this guideline and health-care systems provide adequate resources, outcomes should improve in most patients in most practice settings.
Alzheimer's Association Clinical Practice Guideline on the use of blood-based biomarkers in the diagnostic workup of suspected Alzheimer's disease within specialized care settings.
A panel of clinicians, subject-matter experts, and guideline methodologists convened by the Alzheimer's Association conducted a systematic review and formulated evidence-based recommendations for using blood-based biomarkers (BBMs) in the diagnostic workup of suspected Alzheimer's disease (AD) within specialized care settings. The scope focuses on individuals with objective cognitive impairment, including those with mild cognitive impairment (MCI) or dementia, who are undergoing evaluation by providers trained and experienced in memory disorders, where AD is the suspected underlying etiology. The panel conducted a systematic review to assess the diagnostic accuracy of BBMs in detecting AD pathology. The BBMs of interest included plasma phosphorylated-tau (p-tau) and amyloid-beta (Aβ) tests measuring the following analytes: p-tau217, ratio of p-tau217 to non-p-tau217 ×100 (%p-tau17), p-tau181, p-tau231, and ratio of Aβ42 to Aβ40. The reference standard tests included cerebrospinal fluid (CSF) AD biomarkers, amyloid positron emission tomography (PET), or neuropathology. The panel applied the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of the evidence and the GRADE evidence-to-decision (EtD) Framework to develop its recommendations. The key recommendations in this Clinical Practice Guideline (CPG) are: (1) BBM tests with ≥90% sensitivity and ≥75% specificity can be used as a triaging test and (2) BBM tests with ≥90% sensitivity and specificity can serve as a substitute for amyloid PET imaging or CSF AD biomarker testing in patients with cognitive impairment presenting to specialized care for memory disorders. The panel cautions users of this guideline that there is significant variability in diagnostic test accuracy and many commercially available BBM tests do not meet these thresholds, especially using a single cutoff. Additionally, these tests do not serve as a substitute for comprehensive clinical evaluation by a healthcare professional and should be used only as part of a full diagnostic workup of patients with cognitive impairment presenting to specialized care settings, and with careful consideration of pretest probability of AD pathology. This CPG provides performance-based, brand-agnostic recommendations for the use of BBMs in the diagnostic workup of suspected AD within specialized care settings. By linking recommendations to a systematic review and associated living updates, and using a robust and transparent methodology, the guideline ensures scientific rigor, adaptability, and sustained relevance as evidence evolves. Clinicians are encouraged to stay informed about emerging paradigms-such as biomarker combinations or ratios and multi-threshold testing-that may further refine the diagnostic accuracy of BBMs as the field evolves.
Alzheimer's disease and its co-pathologies: Implications for hippocampal degeneration, cognitive decline, and the role of APOE ε4.
INTRODUCTION: In neurodegenerative dementias, the co-occurrence and interaction of amyloid β peptide (Aβ), tau pathology, and other pathological lesions confound their individual contributions to neurodegeneration and their modulation by risk factors. METHODS: We analyzed 480 post mortem human brains (ages 50-99) using regression and structural equation models to assess the relationships among Aβ, tau, limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), α-synuclein, other age-related lesions, and apolipoprotein E (APOE) ε4, as well as their effects on CA1 neuronal density, brain weight, and cognitive status. RESULTS: Aβ, tau, LATE-NC, and amygdala-predominant α-synuclein pathology were mutually interdependent. Tau was the strongest predictor of global neurodegeneration, while LATE-NC primarily, but not exclusively, affected hippocampal neuron loss. Small vessel disease correlated with both LATE-NC and α-synuclein, while APOE ε4 was mainly associated with extracellular parenchymal and capillary Aβ pathology. DISCUSSION: Although Alzheimer's disease pathology plays a central role in brain degeneration, coexisting pathologies can both exacerbate and independently contribute to it. These factors should be considered in patient stratification. HIGHLIGHTS: In aging individuals, amyloid β peptide (Aβ), tau pathology, limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), and amygdala-predominant α-synuclein pathology were interrelated but contributed independently to neurodegeneration. LATE-NC was the strongest driver of CA1 neuronal loss, while tau burden was the strongest predictor of global brain degeneration. Apolipoprotein E ε4 was associated with both extracellular and capillary Aβ deposits, but not with tau burden. Temporal lobe small vessel disease was associated with both LATE-NC and amygdala-predominant α-synuclein pathology. Neural network models can reliably identify hippocampal pyramidal neurons on hematoxylin-stained histological slides.
Alzheimer's disease as an innate autoimmune disease (AD2): A new molecular paradigm.
A new model of Alzheimer's disease (AD) is presented: Alzheimer's disease as an autoimmune disease (AD2). In response to pathogen-/damage-associated molecular pattern-stimulating events (e.g., infection, trauma, ischemia, pollution), amyloid beta (Aβ) is released as an early responder cytokine triggering an innate immunity cascade in which Aβ exhibits immunomodulatory/antimicrobial duality. However, Aβ's antimicrobial properties result in a misdirected attack upon "self" neurons, arising from the electrophysiological similarities between neurons and bacteria in terms of transmembrane potential gradients and anionic charges on outer membrane macromolecules. The subsequent breakdown products of necrotic neurons elicit further release of Aβ leading to a chronic, self-perpetuating cycle. In AD2, amino acid (trp, arg) metabolism is a central control player in modulating AD autoimmunity. AD2 includes Aβ as an important molecular player, but rejects the "amyloid hypothesis," recognizing Aβ as a physiologically oligomerizing cytokine and part of a larger immunopathic conceptualization of AD.
Alzheimer's disease-associated PLCG2 variants alter microglial state and function in human induced pluripotent stem cell-derived microglia-like cells.
Variants of phospholipase C gamma 2 (PLCG2), a key microglial immune signaling protein, are genetically linked to Alzheimer's disease (AD) risk. Understanding how PLCG2 variants alter microglial function is critical for identifying mechanisms that drive neurodegeneration or resiliency in AD. Induced pluripotent stem cell (iPSC) -derived microglia carrying the protective PLCG2P522R or risk-conferring PLCG2M28L variants, or loss of PLCG2, were generated to ascertain the impact on microglial transcriptome and function. Protective PLCG2P522R microglia showed significant transcriptomic similarity to isogenic controls. In contrast, risk-conferring PLCG2M28L microglia shared similarities with PLCG2KO microglia, with functionally reduced TREM2 expression, blunted inflammatory responses, and increased proliferation and cell death. Uniquely, PLCG2P522R microglia showed elevated cytokine secretion after lipopolysaccharide (LPS) stimulation and were protected from apoptosis. These findings demonstrate that PLCG2 variants drive distinct microglia transcriptomes that influence microglial functional responses that could contribute to AD risk and protection. Targeting PLCG2-mediated signaling may represent a powerful therapeutic strategy to modulate neuroinflammation. The impact of Alzheimer's disease protective- and risk-associated variants of phospholipase C gamma 2 (PLCG2) on the transcriptome and function of induced pluripotent stem cell (iPSC) -derived microglia was investigated. PLCG2 risk variant microglia exhibited a basal transcriptional profile similar to PLCG2-deficient microglia but significantly different from isotype control and the transcriptionally similar PLCG2 protective variant microglia. PLCG2 risk variant and PLCG2-deficient microglia show decreased levels of triggering receptor expressed on myeloid cells 2 (TREM2). The differential transcriptional pathways of protective and risk-associated PLCG2 variant microglia functionally affect proliferation, apoptosis, and immune response. Protective PLCG2 microglia show resilience to apoptosis and increased cytokine/chemokine secretion upon exposure to lipopolysaccharide (LPS).
Amyloid and tau-PET in early-onset AD: Baseline data from the Longitudinal Early-onset Alzheimer's Disease Study (LEADS).
We aimed to describe baseline amyloid-beta (Aβ) and tau-positron emission tomograrphy (PET) from Longitudinal Early-onset Alzheimer's Disease Study (LEADS), a prospective multi-site observational study of sporadic early-onset Alzheimer's disease (EOAD). We analyzed baseline [18F]Florbetaben (Aβ) and [18F]Flortaucipir (tau)-PET from cognitively impaired participants with a clinical diagnosis of mild cognitive impairment (MCI) or AD dementia aged < 65 years. Florbetaben scans were used to distinguish cognitively impaired participants with EOAD (Aβ+) from EOnonAD (Aβ-) based on the combination of visual read by expert reader and image quantification. 243/321 (75.7%) of participants were assigned to the EOAD group based on amyloid-PET; 231 (95.1%) of them were tau-PET positive (A+T+). Tau-PET signal was elevated across cortical regions with a parietal-predominant pattern, and higher burden was observed in younger and female EOAD participants. LEADS data emphasizes the importance of biomarkers to enhance diagnostic accuracy in EOAD. The advanced tau-PET binding at baseline might have implications for therapeutic strategies in patients with EOAD. 72% of patients with clinical EOAD were positive on both amyloid- and tau-PET. Amyloid-positive patients with EOAD had high tau-PET signal across cortical regions. In EOAD, tau-PET mediated the relationship between amyloid-PET and MMSE. Among EOAD patients, younger onset and female sex were associated with higher tau-PET.
Amyloid-beta misfolding and GFAP predict risk of clinical Alzheimer's disease diagnosis within 17 years.
Blood-based biomarkers for Alzheimer's disease (AD) are urgently needed. Here, four plasma biomarkers were measured at baseline in a community-based cohort followed over 17 years, and the association with clinical AD risk was determined. Amyloid beta (Aβ) misfolding status as a structure-based biomarker as well as phosphorylated tau 181 (P-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) concentration levels were determined at baseline in heparin plasma from 68 participants who were diagnosed with AD and 240 controls without dementia diagnosis throughout follow-up. Aβ misfolding exhibited high disease prediction accuracy of AD diagnosis within 17 years. Among the concentration markers, GFAP showed the best performance, followed by NfL and P-tau181. The combination of Aβ misfolding and GFAP increased the accuracy. Aβ misfolding and GFAP showed a strong ability to predict clinical AD risk and may be important early AD risk markers. Aβ misfolding illustrated its potential as a prescreening tool for AD risk stratification in older adults.
An accurate fully automated panel of plasma biomarkers for Alzheimer's disease.
There is a great need for fully automated plasma assays that can measure amyloid beta (Aβ) pathology and predict future Alzheimer's disease (AD) dementia. Two cohorts (n = 920) were examined: Panel A+ (n = 32 cognitively unimpaired [CU], n = 106 mild cognitive impairment [MCI], and n = 89 AD) and BioFINDER-1 (n = 461 CU, n = 232 MCI). Plasma Aβ42/Aβ40, phosphorylated tau (p-tau)181, two p-tau217 variants, ApoE4 protein, neurofilament light, and GFAP were measured using Elecsys prototype immunoassays. The best biomarker for discriminating Aβ-positive versus Aβ-negative participants was Aβ42/Aβ40 (are under the curve [AUC] 0.83-0.87). Combining Aβ42/Aβ40, p-tau181, and ApoE4 improved the AUCs significantly (0.90 to 0.93; P< 0.01). Adding additional biomarkers had marginal effects (ΔAUC ≤0.01). In BioFINDER, p-tau181, p-tau217, and ApoE4 predicted AD dementia within 6 years in CU (AUC 0.88) and p-tau181, p-tau217, and Aβ42/Aβ40 in MCI (AUC 0.87). The high accuracies for Aβ pathology and future AD dementia using fully automated instruments are promising for implementing plasma biomarkers in clinical trials and clinical routine.
APOE and immunity: Research highlights.
At the Alzheimer's Association's APOE and Immunity virtual conference, held in October 2021, leading neuroscience experts shared recent research advances on and inspiring insights into the various roles that both the apolipoprotein E gene (APOE) and facets of immunity play in neurodegenerative diseases, including Alzheimer's disease and other dementias. The meeting brought together more than 1200 registered attendees from 62 different countries, representing the realms of academia and industry. During the 4-day meeting, presenters illuminated aspects of the cross-talk between APOE and immunity, with a focus on the roles of microglia, triggering receptor expressed on myeloid cells 2 (TREM2), and components of inflammation (e.g., tumor necrosis factor α [TNFα]). This manuscript emphasizes the importance of diversity in current and future research and presents an integrated view of innate immune functions in Alzheimer's disease as well as related promising directions in drug development.
APOE Christchurch-mimetic therapeutic antibody reduces APOE-mediated toxicity and tau phosphorylation.
INTRODUCTION: We discovered that the APOE3 Christchurch (APOE3Ch) variant may provide resistance to Alzheimer's disease (AD). This resistance may be due to reduced pathological interactions between ApoE3Ch and heparan sulfate proteoglycans (HSPGs). METHODS: We developed and characterized the binding, structure, and preclinical efficacy of novel antibodies targeting human ApoE-HSPG interactions. RESULTS: We found that one of these antibodies, called 7C11, preferentially bound ApoE4, a major risk factor for sporadic AD, and disrupts heparin-ApoE4 interactions. We also determined the crystal structure of a Fab fragment of 7C11 and used computer modeling to predict how it would bind to ApoE. When we tested 7C11 in mouse models, we found that it reduced recombinant ApoE-induced tau pathology in the retina of MAPT*P301S mice and curbed pTau S396 phosphorylation in brains of systemically treated APOE4 knock-in mice. Targeting ApoE-HSPG interactions using 7C11 antibody may be a promising approach to developing new therapies for AD.
APOE ε4-associated downregulation of the IL-7/IL-7R pathway in effector memory T cells: Implications for Alzheimer's disease.
INTRODUCTION: The apolipoprotein E (APOE) ε4 allele exerts a significant influence on peripheral inflammation and neuroinflammation, yet the underlying mechanisms remain elusive. METHODS: The present study enrolled 54 patients diagnosed with late-onset Alzheimer's disease (AD; including 28 APOE ε4 carriers and 26 non-carriers). Plasma inflammatory cytokine concentration was assessed, alongside bulk RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) analysis of peripheral blood mononuclear cells (PBMCs). RESULTS: Plasma tumor necrosis factor α, interferon γ, and interleukin (IL)-33 levels increased in the APOE ε4 carriers but IL-7 expression notably decreased. A negative correlation was observed between plasma IL-7 level and the hippocampal atrophy degree. Additionally, the expression of IL-7R and CD28 also decreased in PBMCs of APOE ε4 carriers. ScRNA-seq data results indicated that the changes were mainly related to the CD4+ Tem (effector memory) and CD8+ Tem T cells. DISCUSSION: These findings shed light on the role of the downregulated IL-7/IL-7R pathway associated with the APOE ε4 allele in modulating neuroinflammation and hippocampal atrophy. HIGHLIGHTS: The apolipoprotein E (APOE) ε4 allele decreases plasma interleukin (IL)-7 and aggravates hippocampal atrophy in Alzheimer's disease. Plasma IL-7 level is negatively associated with the degree of hippocampal atrophy. The expression of IL-7R signaling decreased in peripheral blood mononuclear cells of APOE ε4 carriers Dysregulation of the IL-7/IL-7R signal pathways enriches T cells.
Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs.
INTRODUCTION: Alzheimer apolipoprotein E (APOE) ɛ4/ɛ4 carriers have earlier disease onset and more protein aggregates than patients with other APOE genotypes. Autophagy opposes aggregation, and important autophagy genes are coordinately regulated by transcription factor EB (TFEB) binding to "coordinated lysosomal expression and regulation" (CLEAR) DNA motifs. METHODS: Autophagic gene expression was assessed in brains of controls and Alzheimer's disease (AD) patients parsed by APOE genotype and in a glioblastoma cell line expressing either apoE3 or apoE4. Computational modeling assessed interactions between apoE and mutated apoE with CLEAR or modified DNA. RESULTS: Three TFEB-regulated mRNA transcripts-SQSTM, MAP1LC3B, and LAMP2-were lower in AD ɛ4/ɛ4 than in AD ɛ3/ɛ3 brains. Computational modeling predicted avid specific binding of apoE4 to CLEAR motifs. ApoE was found in cellular nuclei, and in vitro binding assays suggest competition between apoE4 and TFEB at CLEAR sites. CONCLUSION: ApoE4-CLEAR interactions may account for suppressed autophagy in APOE ɛ4/ɛ4 carriers and, in this way, contribute to earlier AD onset.
Arteriolar degeneration and stiffness in cerebral amyloid angiopathy are linked to Aβ deposition and lysyl oxidase.
INTRODUCTION: The morphological and molecular changes associated with the degeneration of arterioles in cerebral amyloid angiopathy (CAA) are incompletely understood. METHODS: Post mortem brains from 26 patients with CAA or neurological controls were analyzed using light-sheet microscopy, and morphological features of microvascular degeneration were quantified using surface volume rendering. Vascular stiffness was analyzed using atomic force microscopy. RESULT: Vascular smooth muscle cells (VSMCs) volume was reduced by ≈ 55% in CAA. This loss of VSMC volume correlated with increased arteriolar diameter, variability in diameter, and the volume of amyloid beta (Aβ) deposition in the vessel. Vessels with CAA were > 300% stiffer than controls. The volume of extracellular matrix cross-linking enzyme lysyl oxidase (LOX) correlated closely with vascular degenerative features. DISCUSSION: Our findings provide valuable insights into the connections among LOX, Aβ deposition, and vascular stiffness in CAA. Restoration of physiologic extracellular matrix properties in penetrating arteries may yield a novel therapeutic strategy for CAA. HIGHLIGHTS: We conducted 3D microscopy on human brains with cerebral amyloid angiopathy. We quantified features of vascular degeneration, β-amyloid, and lysyl oxidase in CAA Vascular degeneration correlated with Aβ, loss of VSMCs , and increased LOX. Arterioles with CAA were stiffer than controls in data from atomic force microscopy. Vascular extracellular matrix properties may be a therapeutic target for CAA.
Assessment of brain-derived extracellular vesicle enrichment for blood biomarker analysis in age-related neurodegenerative diseases: An international overview.
Brain-derived extracellular vesicles (BEVs) in blood allows for minimally-invasive investigations of central nervous system (CNS) -specific markers of age-related neurodegenerative diseases (NDDs). Polymer-based EV- and immunoprecipitation (IP)-based BEV-enrichment protocols from blood have gained popularity. We systematically investigated protocol consistency across studies, and determined CNS-specificity of proteins associated with these protocols. NDD articles investigating BEVs in blood using polymer-based and/or IP-based BEV enrichment protocols were systematically identified, and protocols compared. Proteins used for BEV-enrichment and/or post-enrichment were assessed for CNS- and brain-cell-type-specificity, extracellular domains (ECD+), and presence in EV-databases. A total of 82.1% of studies used polymer-based (ExoQuick) EV-enrichment, and 92.3% used L1CAM for IP-based BEV-enrichment. Centrifugation times differed across studies. A total of 26.8% of 82 proteins systematically identified were CNS-specific: 50% ECD+, 77.3% were listed in EV-databases. We identified protocol steps requiring standardization, and recommend additional CNS-specific proteins that can be used for BEV-enrichment or as BEV-biomarkers. Across NDDs, we identified protocols commonly used for EV/BEV enrichment from blood. We identified protocol steps showing variability that require harmonization. We assessed CNS-specificity of proteins used for BEV-enrichment or found in BEV cargo. CNS-specific EV proteins with ECD+ or without were identified. We recommend evaluation of blood-BEV enrichment using these additional ECD+ proteins.
Association and interaction of blood homocysteine and p-tau217 levels with temporal cortical thinning and cognitive impairment in Alzheimer's disease.
INTRODUCTION: The relationships between blood homocysteine (Hcy), amyloid beta (Aβ), tau pathology, and their combined effects on cortical thinning and cognitive impairment in Alzheimer's disease (AD) remain poorly understood. METHODS: Participants were stratified into Aβ+ and Aβ- groups by positron emission tomography. Blood levels of Hcy, AD biomarkers (phosphorylated tau-217 [p-tau217], p-tau181, and Aβ), cortical thickness (via magnetic resonance imaging), and cognitive performance were assessed. RESULTS: Aβ+ individuals exhibited increased blood Hcy and p-tau217 levels, which negatively correlated with temporal cortical thickness and cognitive function. A significant interaction between Hcy and p-tau217 was observed in Aβ+ participants, with high Hcy exacerbating the detrimental effects of p-tau217 on temporal cortical thinning and cognitive deficits. In Aβ- individuals, Hcy levels were independently associated with tau pathology. DISCUSSION: Increased Hcy and p-tau217 levels synergistically contribute to cortical thinning and cognitive impairment, highlighting that Hcy may be a modifiable risk factor for AD progression. Highlights Increased blood levels of homocysteine (Hcy) and phosphorylated tau-217 (p-tau217) are independently and interactively associated with temporal cortical thinning and cognitive deficits. Hcy may predominantly affect tau pathology compared to amyloid aggregation, with its impact on neurodegeneration depending on coexisting pathologies. Hcy may serve as a supplementary indicator rather than as an independent predictor in Alzheimer's disease. Hcy may serve as a modifiable risk factor, whereas p-tau217 as a superior diagnostic biomarker and potential therapeutic target.
Association of common and rare variants with Alzheimer's disease in more than 13,000 diverse individuals with whole-genome sequencing from the Alzheimer's Disease Sequencing Project.
INTRODUCTION: Alzheimer's disease (AD) is a common disorder of the elderly that is both highly heritable and genetically heterogeneous. METHODS: We investigated the association of AD with both common variants and aggregates of rare coding and non-coding variants in 13,371 individuals of diverse ancestry with whole genome sequencing (WGS) data. RESULTS: Pooled-population analyses of all individuals identified genetic variants at apolipoprotein E (APOE) and BIN1 associated with AD (p < 5 × 10-8). Subgroup-specific analyses identified a haplotype on chromosome 14 including PSEN1 associated with AD in Hispanics, further supported by aggregate testing of rare coding and non-coding variants in the region. Common variants in LINC00320 were observed associated with AD in Black individuals (p = 1.9 × 10-9). Finally, we observed rare non-coding variants in the promoter of TOMM40 distinct of APOE in pooled-population analyses (p = 7.2 × 10-8). DISCUSSION: We observed that complementary pooled-population and subgroup-specific analyses offered unique insights into the genetic architecture of AD. HIGHLIGHTS: We determine the association of genetic variants with Alzheimer's disease (AD) using 13,371 individuals of diverse ancestry with whole genome sequencing (WGS) data. We identified genetic variants at apolipoprotein E (APOE), BIN1, PSEN1, and LINC00320 associated with AD. We observed rare non-coding variants in the promoter of TOMM40 distinct of APOE.