Alzheimer's Disease Process Research Articles

Deciphering the Interacting Mechanisms of Circadian Disruption and Alzheimer's Disease.

Alzheimer's disease (AD) is one of the crucial causative factors for progressive dementia. Neuropathologically, AD is characterized by the extracellular accumulation of amyloid beta plaques and intracellular neurofibrillary tangles in cortical and limbic regions of the human brain. The circadian system is one of the many affected physiological processes in AD, the dysfunction of which may reflect in the irregularity of the sleep/wake cycle. The interplay of circadian and sleep disturbances inducing AD progression is bidirectional. Sleep-associated pathological alterations are frequently evident in AD. Understanding the interrelation between circadian disruption and AD may allow for earlier identification of AD pathogenesis as well as better suited approaches and potential therapies to combat dementia. In this article, we examine the existing literature related to the molecular mechanisms of the circadian clock and interacting mechanisms of circadian disruption and AD pathogenesis.

The Main Alkaloids in Uncaria rhynchophylla and Their Anti-Alzheimer's Disease Mechanism Determined by a Network Pharmacology Approach.

Alzheimer’s disease (AD) is a growing concern in modern society, and effective drugs for its treatment are lacking. Uncaria rhynchophylla (UR) and its main alkaloids have been studied to treat neurodegenerative diseases such as AD. This study aimed to uncover the key components and mechanism of the anti-AD effect of UR alkaloids through a network pharmacology approach. The analysis identified 10 alkaloids from UR based on HPLC that corresponded to 90 anti-AD targets. A potential alkaloid target-AD target network indicated that corynoxine, corynantheine, isorhynchophylline, dihydrocorynatheine, and isocorynoxeine are likely to become key components for AD treatment. KEGG pathway enrichment analysis revealed the Alzheimers disease (hsa05010) was the pathway most significantly enriched in alkaloids against AD. Further analysis revealed that 28 out of 90 targets were significantly correlated with Aβ and tau pathology. These targets were validated using a Gene Expression Omnibus (GEO) dataset. Molecular docking studies were carried out to verify the binding of corynoxine and corynantheine to core targets related to Aβ and tau pathology. In addition, the cholinergic synapse (hsa04725) and dopaminergic synapse (hsa04728) pathways were significantly enriched. Our findings indicate that UR alkaloids directly exert an AD treatment effect by acting on multiple pathological processes in AD.

Role of insulin receptor substance-1 modulating PI3K/Akt insulin signaling pathway in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease, also regarded as "type 3 diabetes" for the last few years because of the brain insulin resistance (IR) and dysregulation of insulin signaling in the brain, which can further promote pathological progression of AD. IRS-1/PI3K/Akt insulin signaling pathway disorder and its downstream cascade reaction are responsible for cognitive decline in the brain. In recent years, a growing number of studies has documented that dysregulation of insulin signaling is a key feature of AD and has crucial correlations with serine/tyrosine (Ser/Tyr) phosphorylation of insulin receptor substance-1(IRS-1). Phosphorylation of this protein has been identified as an important molecule involved in the process of amyloid-β (Aβ) deposition into senile plaques (SPs) and tau hyperphosphorylation into neurofibrillary tangles (NFTs). In this paper, we review the links between IRS-1 and the PI3K/Akt insulin signaling pathway, and highlight phosphorylated IRS-1 which negatively regulated by downstream effector of Akt such as mTOR, S6K, and JNK, among others in AD. Furthermore, anti-diabetic drugs including metformin, thiazolidinediones, and glucagon-like peptide-1 (GLP-1) analogue could modulate IRS-1 phosphorylation, brain IR, PI3K/Akt insulin signaling pathway, and other pathologic processes of AD. The above suggest that anti-diabetic drugs may be promising strategies for AD disease-modifying treatments.

Structure Prediction of the Transmembrane Region of Alpha- and Beta- Secretases using Replica-Exchange Molecular Dynamics Simulations, and the Interaction between Amyloid Precursor Protein and Them

Alzheimer’s disease (AD) is known as one of dementia, and the number of patients has been increasing around the world. Amyloid Precursor Protein (APP) is one of the key membrane proteins in the pathogenesis of AD according to the amyloid hypothesis. in the early stage of Alzheimer’s disease, APP is cleaved by beta- and gamma-secretases in the lipid raft environments, and amyloid-beta peptides are produced. The amyloid-beta peptides are aggregated with each other and the senile plaques are produced. in a normal situation, the APP is usually cleaved by alpha-secretase in non-raft environments. This process is not related to the process of AD. Thus, the interactions among APP, alpha- and beta- secretases are very important in the progressing of the disease. However, the tertiary structure of the transmembrane domain of alpha- and beta- secretases have not been solved experimentally. Therefore, currently it is difficult to understand the interaction among APP, alpha- and beta- secretases in the biological membrane.To understand the interaction among APP, alpha- and beta- secretases, we performed the structure prediction of the transmembrane domain of alpha- and beta- secretases using the Replica-exchange molecular dynamics simulations (REMD). The structure of the transmembrane domain of alpha-secretase has one long transmembrane helix with the bending outside of the membrane, and that of beta-secretase has two domains with a bend at the proline in the membrane. We also carried out the Coarse-Grained molecular dynamics simulations of the transmembrane domain of alpha/beta- secretase and the transmembrane domain of APP complex system in the biological membrane environments. in the hetero-dimerization of beta-secretase and APP, sphingolipids and cholesterols support the interaction between secretases and APP.

Research Advantages in Marine Microbial Acetylcholinesterase Inhibitors Against Alzheimer’s Disease: An Overview

Public health is significantly threatened by neurodegenerative disorders, especially Alzheimer's disease (AD). A significant cause of dementia is Alzheimer's disease (AD), accounting for up to 75 percent of all cases of dementia. Degeneration of neurons and synapses, primarily characterized by cholinergic dysfunction, are the pathophysiological processes defined for AD progression. This function makes inhibitors of acetylcholinesterase (AChEi) the main class of drugs commonly used to treat the dementia process of AD. The symptomatic progress of Alzheimer's disease (AD) remains a highly viable target since the cholinergic deficiency is a clear and early finding in AD. More and more marine compounds have been isolated from marine animals for the medicinal treatment of neurological conditions, including Alzheimer's disease (AD). Significant producers of AChEIs are fungi and bacteria. Alkaloids, terpenoids, phenylpropanoids, and steroids are the active components in fermentation products. In this review, we provide an overview of the different marine microbe-derived AChEIs and their producing strains.

Microglial Hyperreactivity Evolved to Immunosuppression in the Hippocampus of a Mouse Model of Accelerated Aging and Alzheimer's Disease Traits.

Neuroinflammation is a risk factor for Alzheimer’s disease (AD). We sought to study the glial derangement in AD using diverse experimental models and human brain tissue. Besides classical pro-inflammatory cytokines, we analyzed chitinase 3 like 1 (CHI3L1 or YKL40) and triggering receptor expressed on myeloid cells 2 (TREM2) that are increasingly being associated with astrogliosis and microgliosis in AD, respectively. The SAMP8 mouse model of accelerated aging and AD traits showed elevated pro-inflammatory cytokines and activated microglia phenotype. Furthermore, 6-month-old SAMP8 showed an exacerbated inflammatory response to peripheral lipopolysaccharide in the hippocampus and null responsiveness at the advanced age (for this strain) of 12 months. Gene expression of TREM2 was increased in the hippocampus of transgenic 5XFAD mice and in the cingulate cortex of autosomal dominant AD patients, and to a lesser extent in aged SAMP8 mice and sporadic early-onset AD patients. However, gene expression of CHI3L1 was increased in mice but not in human AD brain samples. The results support the relevance of microglia activation in the pathways leading to neurodegeneration and suggest diverse neuroinflammatory responses according to the AD process. Therefore, the SAMP8 mouse model with marked alterations in the dynamics of microglia activation and senescence may provide a complementary approach to transgenic mouse models for the study of the neuroinflammatory mechanisms underlying AD risk and progression.

The proteome of granulovacuolar degeneration and neurofibrillary tangles in Alzheimer\u2019s disease

Granulovacuolar degeneration (GVD) is a common feature in Alzheimer’s disease (AD). The occurrence of GVD is closely associated with that of neurofibrillary tangles (NFTs) and GVD is even considered to be a pre-NFT stage in the disease process of AD. Currently, the composition of GVD bodies, the mechanisms associated with GVD and how GVD exactly relates to NFTs is not well understood. By combining immunohistochemistry (IHC) and laser microdissection (LMD) we isolated neurons with GVD and those bearing tangles separately from human post-mortem AD hippocampus (n = 12) using their typical markers casein kinase (CK)1δ and phosphorylated tau (AT8). Control neurons were isolated from cognitively healthy cases (n = 12). 3000 neurons per sample were used for proteome analysis by label free LC–MS/MS. In total 2596 proteins were quantified across samples and a significant change in abundance of 115 proteins in GVD and 197 in tangle bearing neurons was observed compared to control neurons. With IHC the presence of PPIA, TOMM34, HSP70, CHMP1A, TPPP and VXN was confirmed in GVD containing neurons. We found multiple proteins localizing specifically to the GVD bodies, with VXN and TOMM34 being the most prominent new protein markers for GVD bodies. In general, protein groups related to protein folding, proteasomal function, the endolysosomal pathway, microtubule and cytoskeletal related function, RNA processing and glycolysis were found to be changed in GVD neurons. In addition to these protein groups, tangle bearing neurons show a decrease in ribosomal proteins, as well as in various proteins related to protein folding. This study, for the first time, provides a comprehensive human based quantitative assessment of protein abundances in GVD and tangle bearing neurons. In line with previous functional data showing that tau pathology induces GVD, our data support the model that GVD is part of a pre-NFT stage representing a phase in which proteostasis and cellular homeostasis is disrupted. Elucidating the molecular mechanisms and cellular processes affected in GVD and its relation to the presence of tau pathology is highly relevant for the identification of new drug targets for therapy.

Enzyme inhibitors as controllers of neurodegenerative diseases: An update of in vitro effects of medicinal plants

Considering the increase of the elderly population in recent years, the growing prevalence of age-related neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), has become one of the leading healthcare problems. Currently, available therapies for AD and PD are still limited, while medicinal plants used in traditional medicine for millennia can inhibit enzymes involved in the neurodegeneration processes in AD (acetylcholinesterase, AChE, and butyrylcholinesterase, BChE) and PD (tyrosinase, TYR), hence their inhibiting effects are continuously being investigated especially in the past decade. This study was aimed to review data on medicinal plants as potential cholinesterases and TYR inhibitors reported from January 2018 until May 2021. The literature search was performed using several online bibliographical databases (Scopus, Web of Science, Science Direct, Google Scholar, PubMed, and ResearchGate) and two websites. Data analysis showed that the highest number of representatives belongs to Lamiaceae family (up to 20 %), followed by Asteraceae. Almost half of the tested samples were prepared from whole plant/aerial plant parts followed by leaves. The most frequently tested preparations were methanolic extracts (about 25 % of the samples examined). Additionally, synergistic interactions between different herbs and/or isolated compounds were considered as a promising strategy for further research. The presented data showed that medicinal plants preparations represent an unlimited source for research of new and more effective AD and PD treatments. This review will provide a useful starting point for further research on this topic.

Interaction between Aβ and Tau in the Pathogenesis of Alzheimer's Disease.

Extracellular neuritic plaques composed of amyloid‑β (Aβ) protein and intracellular neurofibrillary tangles containing phosphorylated tau protein are the two hallmark proteins of Alzheimer's disease (AD), and the separate neurotoxicity of these proteins in AD has been extensively studied. However, interventions that target Aβ or tau individually have not yielded substantial breakthroughs. The interest in the interactions between Aβ and tau in AD is increasing, but related drug investigations are in their infancy. This review discusses how Aβ accelerates tau phosphorylation and the possible mechanisms and pathways by which tau mediates Aβ toxicity. This review also describes the possible synergistic effects between Aβ and tau on microglial cells and astrocytes. Studies suggest that the coexistence of Aβ plaques and phosphorylated tau is related to the mechanism by which Aβ facilitates the propagation of tau aggregation in neuritic plaques. The interactions between Aβ and tau mediate cognitive dysfunction in patients with AD. In summary, this review summarizes recent data on the interplay between Aβ and tau to promote a better understanding of the roles of these proteins in the pathological process of AD and provide new insights into interventions against AD.

MicroRNA-146a switches microglial phenotypes to resist the pathological processes and cognitive degradation of Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and currently has no effective treatment. Mainstream research on the mechanisms and therapeutic targets of AD is focused on the two most important hallmarks, Aβ and Tau, but the results from clinical studies are not encouraging. Abnormal microglial polarization is a clear typical pathological feature in the progression of AD. Microglia can be neuroprotective by degrading and removing Aβ and Tau. However, under AD conditions, microglia transform into a pro-inflammatory phenotype that decreases the phagocytic activity of microglia, damages neurons and promotes the pathology of AD. We previously reported that a miR-146a polymorphism is associated with sporadic AD risk, and the nasal administration of miR-146a mimics reduced cognitive impairment and the main pathological features of AD. However, it is not clear by what mechanism miR-146a resists the pathological process of AD. In this study, we discovered that microglia-specific miR-146a overexpression reduced cognitive deficits in learning and memory, attenuated neuroinflammation, reduced Aβ levels, ameliorated plaque-associated neuritic pathology, and prevented neuronal loss in APP/PS1 transgenic mice. In addition, we found that miR-146a switched the microglial phenotype, reduced pro-inflammatory cytokines and enhanced phagocytic function to protect neurons in vitro and in vivo. Moreover, transcriptional analysis confirmed that miR-146a opposed the pathological process of AD mainly through neuroinflammation-related pathways. In summary, our results provide sufficient evidence for the mechanism by which miR-146a opposes AD and strengthen the conclusion that miR-146a is a promising target for AD and other microglia-related diseases.

Alzheimer's, Parkinson's Disease and Amyotrophic Lateral Sclerosis Gene Expression Patterns Divergence Reveals Different Grade of RNA Metabolism Involvement.

Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterized by a progressive degeneration of the central or peripheral nervous systems. A central role of the RNA metabolism has emerged in these diseases, concerning mRNAs processing and non-coding RNAs biogenesis. We aimed to identify possible common grounds or differences in the dysregulated pathways of AD, PD, and ALS. To do so, we performed RNA-seq analysis to investigate the deregulation of both coding and long non-coding RNAs (lncRNAs) in ALS, AD, and PD patients and controls (CTRL) in peripheral blood mononuclear cells (PBMCs). A total of 293 differentially expressed (DE) lncRNAs and 87 mRNAs were found in ALS patients. In AD patients a total of 23 DE genes emerged, 19 protein coding genes and four lncRNAs. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses, we found common affected pathways and biological processes in ALS and AD. In PD patients only five genes were found to be DE. Our data brought to light the importance of lncRNAs and mRNAs regulation in three principal neurodegenerative disorders, offering starting points for new investigations on deregulated pathogenic mechanisms.

Repositioning of Immunomodulators: A Ray of Hope for Alzheimer's Disease?

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder characterized by cognitive decline and by the presence of amyloid β plaques and neurofibrillary tangles in the brain. Despite recent advances in understanding its pathophysiological mechanisms, to date, there are no disease-modifying therapeutic options, to slow or halt the evolution of neurodegenerative processes in AD. Current pharmacological treatments only transiently mitigate the severity of symptoms, with modest or null overall improvement. Emerging evidence supports the concept that AD is affected by the impaired ability of the immune system to restrain the brain’s pathology. Deep understanding of the relationship between the nervous and the immune system may provide a novel arena to develop effective and safe drugs for AD treatment. Considering the crucial role of inflammatory/immune pathways in AD, here we discuss the current status of the immuno-oncological, immunomodulatory and anti-TNF-α drugs which are being used in preclinical studies or in ongoing clinical trials by means of the drug-repositioning approach.

Network‐level relationships between cortical neurodegeneration and FDG‐PET hypometabolism across clinical and A/T/N subgroups in AD

AbstractBackgroundConverging evidence suggests that Alzheimer’s disease (AD) affects multiple large‐scale brain networks. Determining the relationship between network‐level alterations in neuroimaging‐derived metrics of brain structure and function and whether concordance between metrics varies by clinical presentation or pathological status can increase our understanding of the disease process in AD. To this aim, we evaluated the relationship between cortical thinning (neurodegeneration) and cortical glucose hypometabolism within distributed brain networks in individuals across clinical (AD, MCI who later progress to AD, MCI who remain stable, and normal controls) and CSF‐defined A/T/N subgroups.MethodT1‐MPRAGE and FDG‐PET scans were downloaded from the Alzheimer’s Disease Neuroimaging Initiative website (cohorts ADNI‐1&2 at baseline only). Regional W‐score maps were computed for each patient and each imaging modality, to adjust for the effect of normal aging. Using a well‐validated atlas from the Human Connectome Project/Glasser et al. (2016) and the corresponding cortical network solution by Ji et al. (2019), network‐level Pearson correlations were computed between cortical thickness and FDG metabolism, for each participant, reflecting individual consistency in the degree of atrophy and hypometabolism at each network. Multivariate analysis of variance models assessing the effects of clinic diagnostic category and, separately, A/T/N status, on correlations while accounting for age, education and APOE‐4 status were examined.ResultsAmong clinical diagnostic groups, atrophy‐hypometabolism correlations showed significant differences in 11 of 12 networks (Table 1), with correlations increasing by disease severity specifically within networks known to be affected by AD (e.g., frontoparietal, default mode, ventral multimodal; Figures 1 and 2). Among A/T/N subgroups, significant differences in correlation scores were found only within select networks including frontoparietal and default mode networks (Table 2; Figure 3).ConclusionWith increased disease severity, cortical atrophy is increasingly related to cortical FDG hypometabolism across brain networks. In the A/T/N framework, our findings suggest that both amyloid and tau increase this structure‐function relationship. However, considerable heterogeneity was present among all A/T/N subgroups, warranting further exploration. Multimodal neuroimaging analyses can unravel the structure‐function relationships that contribute to clinical outcomes and diagnostic uncertainty in AD.

Oral immunization with soybean storage protein containing amyloid β4‐10 prevents spatial learning decline

AbstractBackgroundAmyloid‐β protein (Aβ) plays a central role in the pathogenesis of Alzheimer’s disease (AD). Because AD pathologies begin two decades before the onset of dementia, prevention of Aβ amyloidosis has been proposed as a mean to block the pathological cascade. We generated a transgenic plant‐based vaccine, a soybean storage protein containing Aβ4‐10, named Aβ+, for oral Aβ immunization.MethodOne mg of Aβ+ or control protein (Aβ‐) with 10 mg cholera toxin subunit B was orally administered via a catheter to TgCRND8 mice once a week from 9 weeks. Extended Morris water maze tests for 10 consecutive days were examined every 4 weeks. Mice were analyzed at 23 weeks (Aβ+ n = 9, Aβ– n = 11), 43 weeks (Aβ+ n = 7, Aβ– n = 6), and 59 weeks (Aβ+ n = 6, Aβ– n = 7).ResultAβ+ immunization raised both anti‐Aβ antibodies and cellular immune responses. Plasma from Aβ+ treated mice showed staining of Aβ oligomers. Spatial learning decline was prevented in the Aβ+ immunized group from 21 weeks. In Tris‐buffered saline (TBS), sodium dodecyl sulfate (SDS), and formic acid (FA) serial extractions, all sets of Aβ species from Aβ monomer, low to high molecular weight Aβ oligomers, and Aβ smears had different solubility in TgCRND8 brains. Aβ oligomers decreased in TBS fractions, corresponding to an increase in high molecular weight Aβ oligomers in SDS extracts and Aβ smears in FA fraction of the Aβ+ treated group. There was significant inhibition of histological Aβ burden, especially in diffuse plaques, and suppression of microglial inflammation. Processing of amyloid‐β protein precursor was not different between Aβ+ and Aβ‐ groups. No evidence of amyloid‐related inflammatory angiopathy was observed.ConclusionAβ+ oral immunization could be a promising, cheap, and long‐term safe disease‐modifying therapy to prevent the pathological process in AD.

Increased functional connectivity of anterior insula to anterior cingulate cortex in amnestic mild cognitive impairment: A longitudinal resting‐state fMRI study

AbstractBackgroundThe insula has been reported as a crucial role in Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI). However, the mechanism and functional connectivity (FC) changes of insula in follow‐up remain unclear. Exploring specific insula network interaction can contribute to a better understanding of integration and segregation patterns of aMCI.MethodTwenty aMCI and twenty healthy controls (HC) participants were recruited and underwent resting‐state functional magnetic resonance imaging (rs‐fMRI) and neuropsychological assessment at baseline and 15 months afterward. Rs‐fMRI data were preprocessed using SPM 12 and CONN software. FC of two insular subregions in each hemisphere were defined as anterior insula connectivity (AIC) and posterior insula connectivity (PIC). Using data driven clustering technique, the insular lobe was subdivided based on whole brain functional connectivity. Two‐way analysis of covariance was used with covariates of gender, age, education, follow‐up interval, volume of gray matter and global correlation (GCOR).ResultWithin group FC maps of HC and aMCI exhibited similar patterns both at baseline and follow‐up. For the left anterior insula, significant connectivity with bilateral anterior cingulate gyrus (ACC), paracingulate gyrus, putamen, frontal orbital cortex, inferior frontal gyrus, and temporal pole were identified. The right anterior insula was positively associated with bilateral insula, ACC, central opercular cortex, frontal orbital cortex, and right junction region of temporal, frontal and parietal lobe. The posterior zone of the insula (both the right and the left) exhibited significant connectivity with the bilateral Insular, ACC, central opercular cortex, precentral gyrus, postcentral gyrus, supramarginal gyrus, parietal operculum cortex, as well as the junction region of temporal, frontal and parietal lobe. For interactive main effects, the right AIC showed significantly increased FC with the left ACC, while the left PIC showed decreased FC with the right precuneous, in aMCI as compared to HC.ConclusionInsula rsFC changes could be potential biomarkers of aMCI and reveal some definite neuropathological mechanism due to pathologic processes in AD. We considered the rsFC increase of AIC with ACC as compensatory and decrease of the PIC with the precuneus as deterioration of follow‐up due to the course of disease.

Hypersynchronization, a common feature along the AD process

AbstractBackgroundIn the last decade there are more and more literature indicating that subjects at different stages of Alzheimer´s Disease (AD) continuum, have a disrupted organization of their anatomo‐functional networks. Neurophysiological findings with MEG have indicated an increased brain synchrony between different brain regions across different stages of the disease. In this talk we will concentrate on these neurophysiological findings in humans comparing magnetoencephalography (MEG) findings with clinical and current biomarkersMethodIn a series of studies using magnetoencephalography, we have recorded resting state activity in patients with Mild Cognitive Impairment (MCI), Subjective Cognitive Decline (SCD) and in healthy subjects at preclinical stage or at risk for developing dementia. We used functional connectivity in the source space to assess how the brain oscillatory activity synchronize across brain regions. MEG findings will be compared with clinical stages, amyloid‐PET, cerebrospinal fluid (p‐tau), or brain atrophy.ResultMCI patients and SCD participants showed an increased functional connectivity values in anterior regions of the brain in the alpha band. This was in combination with a posterior hyposynchronization which was slightly higher in MCI patients compared to SCD. MCI patients who did convert to dementia showed hypersynchronization between anterior cingulate cortex and posterior regions in the alpha band. A second MEG scan on MCI converters (when they were at the dementia stage) showed a decrease in brain synchrony in a similar region, indicating that hypersynchrony accelerate the process of network dysfunction (the “X Model”). These profiles of brain synchrony were evaluated in comparison with biomarkers. MCI patients with elevated p‐tau in the CSF showed again increased synchronization between anterior cingulate and the medial temporal lobe. Healthy subjects (no memory complaints, no brain atrophy, no hypometabolism) with a positive amyloid PET showed as well increased brain synchrony. Finally, young relatives of AD patients showed increased phase synchrony in similar brain regions than that found in MCI patients in the alpha band.ConclusionAll these findings together indicate that hypersynchronization of the brain networks could be an excellent non‐invasive biomarker for tracking the disease and evaluate interventions.

The Atlas of Retinal Imaging in Alzheimer’s Study (ARIAS): Study design and objectives

AbstractBackgroundThe development of widely accessible, minimally invasive, cost‐effective Alzheimer’s disease (AD) biomarkers is a global public health imperative. There is a definite need for a multi‐stage neurodiagnostic screening system that is sensitive and specific to identify high risk individuals prior to cognitive decline. There is rapidly growing evidence that retinal biomarkers have the potential to serve as diagnostic or prognostic AD biomarkers. However, some results have been discordant due to variations in methodology, equipment, and study populations. Moreover, longitudinal data is sparse, and there is lack of insight as to which retinal biomarkers are relevant for each disease stage. Finally, the field needs to understand how structural, functional/metabolic, and angiographic retinal biomarkers interact in the AD process, and whether or not these interactions reflect cerebral pathophysiology. We propose a multi‐site longitudinal, prospective, observational study evaluating the natural history of retinal imaging biomarkers associated with AD disease risk, disease burden, and disease progression. The study objective is to create a ‘gold standard’ reference database of structural anatomic and functional imaging of the retina, in order to enable the identification and development of both sensitive and reliable markers of disease risk and/or disease progression.MethodParticipants (N=330 aged 55‐80; 50 CN– low AD risk, 200 CN – high AD risk, 50 MCI, and 30 mild AD) will be examined 4 times over 5 years. Exams will include neuropsychological testing, blood draw, APOE E4 genotyping, medical/functional assessment, gait assessment, and sleep analysis for 14 days post‐visit. Retinal OCT and OCT‐A will be completed on the Heidelberg SPECTRALIS II. Pupillometry and contrast sensitivity measures will be collected at each visit.ResultWe aim to use these data to develop a multivariate screening tool with sufficient sensitivity and specificity for identifying and tracking AD severity, including the preclinical stage of the disease.ConclusionLongitudinal study of structural, functional, metabolic, and angiographic retinal AD biomarkers in a large cohort could provide the foundation for the development of early stage screening biomarkers that can be applied by point‐of‐care clinicians. Our reference database will be open access, so that researchers worldwide can use these data to develop retinal AD biomarkers.

Novel MRI techniques identifying vascular leak and paravascular flow reduction in early Alzheimer disease

AbstractBackgroundWith beta amyloid and tau antibody treatment trial failures, avenues directed to other aspects of the disease pathophysiology are being explored to treat in the preclinical or early clinical state. Clear evidence of blood brain barrier (BBB) breakdown occurring early in the AD process has recently been established. Likewise, the glymphatic system regulating water and solute inflow and outflow in parallel with the vascular system is affected causing delayed clearance of fluid waste. Its dysfunction as a component of AD along with BBB leak are reasonable candidates to explore for future treatments.MethodWe will review the known physiology and anatomy of the BBB system, its relationship to the glymphatic system and the microglial surveillance system. Ideally, human medication trials require a non or minimally invasive method of quantifying both improvements in BBB integrity and glymphatic fluid clearance correlated with clinical outcomes.ResultDysfunction of this tripart system occurring in Alzheimer disease (AD) will be reviewed along with existing MRI tools for identifying altered flow dynamics useful for monitoring improved functionality with future treatments.ConclusionHigh resolution dynamic contrast enhanced MRI imaging demonstrating BBB leak and the recently reported non‐invasive 3D PASL MRI pilot study demonstrating significant delay in glymphatic clearance in AD subjects appear to be the best candidates.

Clinical and biomarker trajectories in sporadic Alzheimer's disease: A longitudinal study

AbstractBackgroundIt has been documented that β‐amyloid (Aβ) deposition, tau pathology and neuronal degeneration precedes clinical symptoms in autosomal dominant Alzheimer's disease (AD). Since the divergence on pathogenesis between sporadic and familial AD limits the extension of these findings to sporadic AD, where and magnitude of pathologic processes in sporadic AD are of significant importance to clinical management.MethodIn this longitudinal study, we analyzed data from 982 ADNI participants with abnormal amyloid accumulations who underwent cerebrospinal fluid (CSF) test, brain imaging and cognitive assessments. We compared the levels of clinical outcomes and biomarkers at baseline and the rates of change in follow‐up between different stages of AD. The slope of the regression model over years was applied to estimate rates of change for Aβ deposition, tau alteration, hypometabolism, brain atrophy, and cognitive decline.ResultIn total 167 healthy controls, 133 patients with preclinical AD, 451 patients with MCI due to AD, and 231 patients with dementia due to AD were studied. The levels of clinical and biomarkers at baseline and their change rates at follow‐up significantly differed among the four groups. In terms of average years, Aβ deposition was observed over a range of 45·6 years for CSF Aβ, and 31·1 years with amyloid imaging, although Aβ markers began to be abnormal at 27·8 years for CSF Aβ and 26·3 years for neuroimaging. When Aβ markers exceeded the threshold, CSF tau and other non‐ Aβ markers started to change, and patients were estimated to take 29·1 years (CSF tau),12·7 years (memory), 12·2 years (hippocampus atrophy), 10·1years (hypometabolism) to transition from clinically normal to dementia. Finally, CSF p‐tau significantly increased as dementia onset approached.ConclusionOur results reveal the trajectory of biomarkers in sporadic Alzheimer's disease is led by Aβ accumulation, followed by CSF tau change, memory deficits, brain atrophy, hypometabolism, cognitive decline, and lastly CSF p‐tau increase.

Assessment of brain iron accumulation in Alzheimer's disease with quantitative susceptibility mapping

AbstractBackgroundEmerging evidence suggests that regional iron accumulation is involved in the early pathology of Alzheimer’s Disease (AD), which can be evaluated using quantitative susceptibility mapping (QSM). Therefore, the purpose of this study was to evaluate QSM as an early imaging biomarker in AD by comparing regional iron accumulation using QSM in patients with AD, mild cognitive impairment (MCI) and cognitively unimpaired (CU) subjects.MethodThirty‐seven patients with AD, twenty patients with MCI, and forty‐three CU subjects were recruited. All subjects received MRI QSM scans. All QSM images were reconstructed using NMEDI method. Using one‐way analysis of variance (ANOVA) test, the difference in regional iron accumulation between the three groups was studied in the regions of interest (ROI) including bilateral caudate nucleus and putamen. Pairwise multiple comparison was implemented using the least significant difference (LSD) method. For whole brain analysis, we applied a voxel‐based analysis using ANOVA followed by a post hoc analysis. A significant level of family‐wise error (FWE) corrected p < 0.05 with a cluster size of 30 voxels was applied to locate brain regions with significant differences among three groups. We used paired sample t test within 6‐month follow‐up data to see if there is any difference.ResultBased on ROI analysis, average susceptibility of the bilateral caudate and left putamen was significantly different among groups (p<0.001, respectively). Maximal susceptibility of the left caudate was significantly different among groups (p<0.001). For the whole brain analysis, significant difference in iron accumulation among AD, MCI and CU was found in parahippocampus, caudate, putamen, insula, cingulate gyrus, cuneus, precuneus, angular gyrus, thalamus, fusiform, lingual gyrus, corpus callosum, cortex and subcortical white matter, some cerebellum structures and so on. No significant difference was detected with the follow‐up data in each group.ConclusionThis study described brain iron accumulation patterns using QSM during AD progression. This may reveal secondary neuronal changes due to pathologic processes (e.g. oxidative stress) in AD. In addition, this study is the first to observe QSM changes in certain cerebellar regions. Further study is needed to confirm this finding.