Alzheimer's Disease Pathophysiology Research Articles

Altered synaptic plasticity at hippocampal CA1-CA3 synapses in Alzheimer's disease: integration of amyloid precursor protein intracellular domain and amyloid beta effects into computational models.

Alzheimer's disease (AD) is a progressive memory loss and cognitive dysfunction brain disorder brought on by the dysfunctional amyloid precursor protein (APP) processing and clearance of APP peptides. Increased APP levels lead to the production of AD-related peptides including the amyloid APP intracellular domain (AICD) and amyloid beta (Aβ), and consequently modify the intrinsic excitability of the hippocampal CA1 pyramidal neurons, synaptic protein activity, and impair synaptic plasticity at hippocampal CA1-CA3 synapses. The goal of the present study is to build computational models that incorporate the effect of AD-related peptides on CA1 pyramidal neuron and hippocampal synaptic plasticity under the AD conditions and investigate the potential pharmacological treatments that could normalize hippocampal synaptic plasticity and learning in AD. We employ a phenomenological N-methyl-D-aspartate (NMDA) receptor-based voltage-dependent synaptic plasticity model that includes the separate receptor contributions on long-term potentiation (LTP) and long-term depression (LTD) and embed it into the a detailed compartmental model of CA1 pyramidal neuron. Modeling results show that partial blockade of Glu2NB-NMDAR-gated channel restores intrinsic excitability of a CA1 pyramidal neuron and rescues LTP in AICD and Aβ conditions. The model provides insight into the complex interactions in AD pathophysiology and suggests the conditions under which the synchronous activation of a cluster of synaptic inputs targeting the dendritic tree of CA1 pyramidal neuron leads to restored synaptic plasticity.

A conformationally-locked p-hydroxybenzylidene imidazolinone derivative for detecting Aβ42 aggregation

Alzheimer’s disease (AD) is a common type of neurodegenerative disease, which can only be symptomatically relieved but does not yet have a cure. Among the different Aβ species, amyloid-β 42 (Aβ42) aggregates are proposed to be more neurotoxic than that of Aβ40, and oligomeric Aβ42 is thought to play a harmful role in the pathophysiology of AD. Therefore, the detection of Aβ42 aggregation is very meaningful in the AD field. We herein report a conformationally-locked p- hydroxybenzylidene imidazolinone derivative, BDI, which exhibits selectivity and specificity towards Aβ42 aggregation and remarkable fluorescent enhancement with a large Stokes shift (more than 100 nm). In the fluorescent co-localization study, BDI can sensitively detect a large population of Aβ42 aggregation over that of Aβ40 in the brain tissues of AD transgenic mouse models. Therefore, this new probe could provide a useful tool for the rapid detection of important Aβ species in AD.

Pathways linking microbiota-gut-brain axis with neuroinflammatory mechanisms in Alzheimer's pathophysiology.

Disturbances in the local and peripheral immune systems are closely linked to a wide range of diseases. In the context of neurodegenerative disorders such as Alzheimer's disease (AD), inflammation plays a crucial role, often appearing as a common manifestation despite the variability in the occurrence of other pathophysiological hallmarks. Thus, combating neuroinflammation holds promise in treating complex pathophysiological diseases like AD. Growing evidence suggests the gut microbiome's crucial role in shaping the pathogenesis of AD by influencing inflammatory mediators. Gut dysbiosis can potentially activate neuroinflammatory pathways through bidirectional signaling of the gut-brain axis; however, the precise mechanisms of this complex interweaved network remain largely unclear. In these milieus, this review attempts to summarize the contributing role of gut microbiome-mediated neuroinflammatory signals in AD pathophysiology, while also pondering potential mechanisms through which commensal and pathogenic gut microbes affect neuroinflammation. While certain taxa such as Roseburia and Escherichia have been strongly correlated with AD, other clades such as Bacteroides and Faecalibacterium exhibit variations at the species and strain levels. In order to disentangle the inflammatory aspects of neurodegeneration attributed to the gut microbiome, it is imperative that future mechanistic studies investigate the species/strain-level dependency of commensals, opportunistic, and pathogenic gut microbes that consistently show correlations with AD patients across multiple associative studies.

Health System Change for Alzheimer's Disease-Modifying Therapies in Canada: Beginning the Discussion.

Alzheimer's disease (AD) is a neurodegenerative disorder that accounts for 60%-70% of patients with dementia, and it is estimated that over one million Canadians will be living with dementia by 2030. Disease-modifying therapies (DMTs) targeting the underlying pathophysiology of AD are currently in development. Several models have demonstrated that the potential arrival of Alzheimer's DMTs will most likely overwhelm the already-constrained Canadian healthcare system. Canada does not have a strategy to address the extensive requirements of using DMTs, including providing an early diagnosis of AD, confirming DMT eligibility via amyloid biomarkers, and conducting ongoing treatment monitoring. Thus, a multidisciplinary group of experts involved in AD care in Canada gathered to review (1) the current barriers to diagnosis and management of AD; (2) how existing clinic models, including those used in multiple sclerosis (MS), could be applied to address key barriers in AD; and (3) how to design and implement optimal care pathways in the future. The actions outlined in this review will help clinicians and healthcare systems improve readiness to integrate the use of disease-modifying therapies in Alzheimer's disease, if such therapies are approved in Canada.

Comorbidities Incorporated to Improve Prediction for Prevalent Mild Cognitive Impairment and Alzheimer's Disease in the HABS-HD Study.

Blood biomarkers have the potential to transform Alzheimer's disease (AD) diagnosis and monitoring, yet their integration with common medical comorbidities remains insufficiently explored. This study aims to enhance blood biomarkers' sensitivity, specificity, and predictive performance by incorporating comorbidities. We assess this integration's efficacy in diagnostic classification using machine learning, hypothesizing that it can identify a confident set of predictive features. We analyzed data from 1,705 participants in the Health and Aging Brain Study-Health Disparities, including 116 AD patients, 261 with mild cognitive impairment, and 1,328 cognitively normal controls. Blood samples were assayed using electrochemiluminescence and single molecule array technology, alongside comorbidity data gathered through clinical interviews and medical records. We visually explored blood biomarker and comorbidity characteristics, developed a Feature Importance and SVM-based Leave-One-Out Recursive Feature Elimination (FI-SVM-RFE-LOO) method to optimize feature selection, and compared four models: Biomarker Only, Comorbidity Only, Biomarker and Comorbidity, and Feature-Selected Biomarker and Comorbidity. The combination model incorporating 17 blood biomarkers and 12 comorbidity variables outperformed single-modal models, with NPV12 at 92.78%, AUC at 67.59%, and Sensitivity at 65.70%. Feature selection led to 22 chosen features, resulting in the highest performance, with NPV12 at 93.76%, AUC at 69.22%, and Sensitivity at 70.69%. Additionally, interpretative machine learning highlighted factors contributing to improved prediction performance. In conclusion, combining feature-selected biomarkers and comorbidities enhances prediction performance, while feature selection optimizes their integration. These findings hold promise for understanding AD pathophysiology and advancing preventive treatments.

Improvement of Key Molecular Events Linked to Alzheimer's Disease Pathology Using Postbiotics.

In the past 50 years, life expectancy has increased by more than 20 years. One consequence of this increase in longevity is the rise of age-related diseases such as dementia. Alzheimer's disease (AD) is the most common form of dementia, accounting for 60-70% of cases. AD pathogenesis is not restricted to the neuronal compartment but includes strong interactions with other brain cells, particularly microglia triggering the release of inflammatory mediators, which contribute to disease progression and severity. There is growing evidence revealing the diverse clinical benefits of postbiotics in many prevalent conditions, including neurodegenerative diseases. Here, we tested the ability of bacterial conditioned media (BCM) derived from selected lactic acid bacteria (LAB) strains to regulate core mechanisms relevant to AD pathophysiology in the microglia cell line BV-2. Levilactobacillus brevis CRL 2013, chosen for its efficient production of the neurotransmitter GABA, and Lactobacillus delbrueckii subsp. lactis CRL 581, known for its anti-inflammatory properties, were selected alongside Enterococcus mundtii CRL 35, a LAB strain that can significantly modulate cytokine production. BCM from all 3 strains displayed antioxidant capabilities, reducing oxidative stress triggered by beta-amyloid oligomers (oAβ1-42). Additionally, BCM effectively mitigated the expression of inflammatory cytokines, namely, TNF-α, IL-1β, and IL-6 triggered by oAβ1-42. Furthermore, our study identified that BCM from CRL 581 inhibit the activity of acetylcholinesterase (AChE), a crucial enzyme in AD progression, in both human erythrocytes and mouse brain tissues. Notably, the inhibitory effect was mediated by low-molecular-weight components of the BCM. L. delbrueckii subsp. lactis CRL 581 emerged as a favorable candidate for production of postbiotics with potential benefits for AD therapy since it demonstrated potent antioxidant activity, reduction of cytokine expression, and partial AChE inhibition. On the other hand, E. mundtii CRL 35 showed that the antioxidant activity failed to inhibit AChE and caused induction of iNOS expression, rendering it unsuitable as a potential therapeutic for AD. This study unveils the potential benefits of LAB-derived postbiotics for the development of new avenues for therapeutic interventions for AD.

Possible role of gut derived metabolites in communication between systemic inflammation and CNS in delirium development.

AbstractBackgroundDementia and delirium are strongly correlated. Patients with dementia are more prone to develop delirium, while delirium can lead to accelerated cognitive decline. Biomarkers present in the CSF have been considered to belong to the pathophysiological pathways between systemic inflammation, neuroinflammation, gut microbiota and consequently, contribute to the etiology of both the cognition impairments, ie. delirium and dementia. Despite multiple studies on inflammatory biomarkers in CSF, the link with systemic inflammation has still not been deciphered. Multiple studies have indicated that inflammatory pathways in patients with cognitive decline are mediated by gut microbiota.MethodIn this narrative review we screened PubMed for studies, where neuroinflammatory biomarkers detected in CSF were investigated in relation to delirium. We will explain the link to microbiome by comparing these delirium studies to microbiome studies in dementia. These studies were published in English till January 2023.ResultWe found that in patients with Alzheimer’s disease (AD) and delirium altered levels of at least 70 different neuroinflammatory biomarkers in CSF were found. Also altered microbiome has been identified in AD and its correlation with the CNS inflammation was shown. Interestingly, in case of AD, a recent study demonstrated that a microbial‐derived metabolite, trimethylamine N‐oxide (TMAO), reaches the CNS and that its elevated levels are present in AD patients.In case of delirium, we found two studies indicating contribution of disbalanced gut microbiota in acute CNS inflammation in human. It has been shown that preoperative status of gut microbiota can allow prediction of postoperative delirium in patients with gastric cancer. Interestingly, there was already one case described where fecal microbiota transplantation ameliorated patient’s infection and delirium. No studies on microbiome‐derived metabolites, which could constitute a possible link with the acute inflammation of CNS in delirium, have been found.ConclusionThere is irrefutable evidence that altered levels of neuroinflammatory biomarkers in CSF are associated with pathology of both AD and delirium. Implication of the microbiome, and microbial‐derived metabolite TMAO in inflammatory processes and in pathophysiology of AD has already been found. This has encouraged us to investigate the role of TMAO in the acute CNS inflammatory condition, i.e. delirium.

Amyloid‐beta immunotherapy induces novel methylomic changes in Alzheimer’s disease brain

AbstractBackgroundPost‐mortem neuropathological examinations following the first active immunotherapy strategy (AN‐1792, Elan Pharmaceuticals, 2000) for Alzheimer’s disease (AD) have evidenced amyloid‐β (Aβ) plaque clearance and increased microglial phagocytic activity in immunised individuals. This study characterises the epigenetic profiles of individuals who underwent Aβ immunotherapy with the aim of discovering novel therapeutic targets and biomarkers.MethodDNA was isolated from post‐mortem prefrontal cortex tissue of 16 immunised AD cases who received varying doses (ug) and number of doses during the trial period, including placebos. DNA methylation was quantified using methylation arrays and the raw intensity values processed and normalised for subsequent statistical analysis to identify differentially methylated positions (DMPs) across the genome associated with Aβ immunotherapy. Additional analyses included regions of enrichment analysis for identification of differentially methylated regions (DMRs) and weighted gene co‐expression network analysis to identify gene clusters with highly correlated methylation levels.ResultAfter correcting for known (age, sex, cell type composition) and unknown variables, a DMP located within Chromosome 19 Open Reading Frame 12 (C19Orf12) at the genome‐wide significance level (P < 9.00E−08) was associated with Aβ immunisation. 10 DMRs were further associated with immunisation, with three regions consisting of ≥ 3 CpG sites and having a Sidak‐corrected P < 0.05. These regions were located within the CRISP2 (chr6; 49681178:49681391 [8 probes], Sidak‐corrected P = 8.29E‐05), CTTNA1 (chr5; 138210906:138211184 [8 probes], Sidak‐corrected P = 5.96E‐06), and RNF39 (chr6; 30038859:30039025 [12 probes], Sidak‐Corrected P = 2.60E‐05) genes.ConclusionIndicating better inflammatory markers can help inform of effective preventative care strategies for elders. This study provides evidence for altered epigenetic processes in the pathophysiology of AD and identifies novel processes specific to Aβ immunotherapy. The next step for this project includes analysing RNA sequencing data, to determine if observed methylomic changes correlate with gene expression, and genotyping array data.

Blood‐derived extracellular vesicles phosphoproteome as a resource of biomarker candidates for Alzheimer’s disease

AbstractBackgroundProtein phosphorylation plays a crucial role in cell communication, signaling and by extension is relevant to Alzheimer´s disease (AD) pathogenesis. Extracellular vesicles (EVs) are recognized as important mediators in intercellular communication and can be isolated from peripheral biofluids, where the content reflects the cellular origin. EVs’ role in AD pathophysiology and their value as biomarker resources is being unraveled. However, little is known regarding EVs’ phosphoproteome in AD and it has still to be determined if blood‐derived EVs are suitable for phosphoproteome profiling. Hence, this work aimed to characterize plasma‐derived EVs (pdEVs) and plasma supernatant EVs free (plasma‐depleted EVs) phosphoproteomes, to potential unravel disease mechanisms and/or new biomarker candidates for AD.MethodA pool of human plasma was used for pdEVs isolation using a precipitation‐based methodology. Both pdEVs and plasma‐depleted EVs samples were analyzed using an antibody‐based phosphospecific microarray. Characterization of the phosphoproteomes obtained was achieved by Gene Ontology enrichment analysis and the most relevant Reactome pathways associated, using ClueGo and CluePedia plugins from Cytoscape v3.9.1. In addition, protein‐protein interaction network of the pdEVs phosphoproteome was retrieved from STRING database and analyzed using Cytoscape “Network Analyzer”, employing the betweenness centrality option to highlight central nodes. Further, the pdEVs phosphoproteome (corresponding gene names) was overlapped with a list of genes associated with AD, collated from DisGenet database.ResultsMore than 70 proteins were enriched ≥40% in bdEVs when compared to plasma‐depleted. Top biological processes were mainly related to cell proliferation/division, apoptosis and phosphorylation. Reactome pathways analysis revealed terms associated to toll like receptor cascade and MAPK signaling. In the network constructed for the pdEVs enriched proteins, PTEN appeared as a central node. Additionally, overlap with AD gene list from DisGenet revealed that 60% of the pdEVs phosphoproteome is AD‐related. Among these, several kinases already described in senile plaques and/or neurofibrillary tangles were identified.ConclusionIn sum, bdEVs phosphoproteome is enriched in AD‐related targets, exhibiting potential as a biomarker candidate resource for AD diagnosis.This work was funded by the Alzheimer’s Association under Grant 2019‐AARG‐644347, supported by iBiMED‐UIDB/04501/2020,iBiMED‐UIDB/04501/2020,ADPro‐SAICT‐45‐2021‐02 and TSM individual PhD grant SFRH/BD/145979/2019. Health Ethics Committee ARS Centro(No.012804‐04.04.2012) and CNPD(No.369/2012).

Sex and genotype dependent differences in amyloid beta levels and lipid metabolism in type 2 diabetic APPxhQC transgenic mice

AbstractBackgroundAccumulation of amyloid beta (Aβ) and tau proteins have for decades been thought to be central in the pathogenesis of Alzheimer’s disease (AD). More recently, a plethora of evidence emerged that links metabolic dysfunctions such as obesity, type 2 diabetes (T2D), and dyslipidemia with the pathophysiology of AD. In this study, we investigated the effects of streptozocin and high fat diet (HFD) induced T2D on lipid and amyloid beta metabolism in APPxhQC transgenic mice and their wild‐type littermates.MethodAPPxhQC mice were generated by crossbreeding APPSL with hQC mice. As controls wild‐type littermates were used. APPSL mice express human APP751 with the Swedish and the London mutation on a C57Bl/6RccHsd background. hQC mice express human glutaminyl cyclase (QC) enzyme on B6CBAF1/J background. Plasma lipids (triglycerides and cholesterol) and liver function enzymes (aspartate aminotransferase and alanine transaminase, ALT and ALT, respectively) were determined by ELISA. Brain concentrations of soluble and insoluble Aβ 1‐38, 1‐40 and 1‐42 peptides were determined using an immunosorbent assay (Mesoscale discovery immunosorbent assay) while pGlu Aβ1‐42 was measured by ELISA. Hepatic mRNA expression levels of genes involved in cholesterol efflux and lipid metabolism were determined by quantitative real time polymerase chain reaction (qRT‐PCR).ResultT2D induced increased concentrations of plasma cholesterol as well as AST and ALT levels. The magnitudes, however, were dependent on sex and genotype and were statistically significant in female wild‐type mice, while a similar pattern was observed in APPxhQC transgenes. These increased plasma concentrations were accompanied by a down‐regulation of hepatic gene expression levels of LRP1, ABCA1, PPARα, PBC1β, and NEP that were statistically significant in female wild‐type mice, while a similarly pattern was observed in APPxhQC transgenic mice. More interestingly, T2D provoked a progressive shift of brain Aβ 1‐38 and 1‐40 from soluble to insoluble forms in male APPxhQC mice and a significant increase of pyroglutamate modified Aβ 1‐42 in female mice.ConclusionT2D in APPxhQC mice provokes a shift from soluble to large insoluble polymers of Aβ in the brain, corroborates the deteriorating role of T2D in the progression of AD

Lower serum vitamin D aggravates hippocampal neurodegeneration related with amyloid pathology

AbstractBackgroundPrevious studies reported the associations between vitamin D deficiency and increased risk of Alzheimer’s disease (AD) dementia in older adults, but little is known how vitamin D is involved in the pathophysiology of AD. Thus, we aimed to examine the association and interaction of serum vitamin D level with in vivo AD pathologies including beta‐amyloid (Aβ) and neurodegeneration in nondemented older adults.MethodNondemented older adults consisting of cognitively normal and mild cognitive impairment groups were recruited from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease, an ongoing prospective cohort that began in 2014. All participants underwent comprehensive clinical assessments, measurement of serum 25(OH)D, and multimodal brain imaging including Pittsburgh compound‐B (PiB) positron emission tomography and magnetic resonance imaging at baseline. Global PiB retention was measured for Aβ biomarker, and hippocampal volume adjusted for intracranial volume (HVa) was used for neurodegeneration biomarker. Age, sex, apolipoprotein E (APOE) e4 positivity was controlled as covariates in all analyses.ResultA total 428 participants (mean age [SD]: 70.54 [7.97], female [N, %]: 182 [43%]) were included for analysis. Serum 25(OH)D levels were directly associated neither Aβ deposition nor HVa. However, serum 25(OH)D level had significant moderation effect on the association between Aβ and hippocampal neurodegeneration, in that lower serum 25(OH)D level significantly exacerbate the negative association between global Aβ retention and HVa (β = 34.612, p = 0.008) (Figure).ConclusionThe present findings suggest that lower serum vitamin D level may increase AD dementia risk by aggravating Aβ‐related neurodegeneration.

Plasma protein profiling reveals novel specific biomarkers reflecting the multifactorial nature of Alzheimer´s disease continuum

AbstractBackgroundPlasma‐based biomarkers able to depict the molecular diversity associated to Alzheimer´s disease (AD) are needed to better track disease progression and for developing biological therapies targeting different pathomechanisms. Here we aimed to identify plasma protein changes covering different biological pathways along the AD continuum and specific for this neurodegenerative disease.MethodProximity extension‐based multiplex immunoassays were used to analyse 1572 proteins in 1003 plasma samples collected from 6 international centres (JPND bPRIDE consortium), including 330 cognitively unimpaired (CU) controls (CTRL) with negative amyloidosis biomarkers, 164 CU subjects with positive amyloidosis biomarkers (preAD), 129 MCI due to AD (MCI‐AD), 137 AD at dementia stage (AD‐dem), 171 Dementia with Lewy Bodies (DLB) and 170 Frontotemporal dementia (FTD) patients (see Table 1). Data were analysed using nested linear models adjusted for multiple testing and penalized regressions.ResultWe detected >200 proteins differentially regulated along the AD continuum compared to CTRL (q<0.05). More than 300 of the proteins differentially regulated at AD‐dem were also changed between AD‐dem and FTD/DLB (e.g., CALCOCO1, MAP3K5, BIN2, GFAP). Enrichment in pathways related to autophagy, ubiquitination, mitotic cell cycle and protein kinase activity was detected along the AD continuum. GFAP showed the strongest performance to discriminate any AD stage from CTRL (AUCs 0.68‐0.82) as well as AD from FTD (0.75 AUC). SUSD1 showed the strongest performance to discriminate AD from DLB (AUC 0.77). Most promising biomarker candidates are shown in Figure 1. We identified panels (17‐21 proteins) discriminating MCI‐AD or AD‐dem from controls and AD‐dem from FTD or DLB with AUCs>0.80. Proteins within these panels are associated to different biological functions (e.g., phagocytosis, myelination, endolysosomal system, calcium signalling, energy metabolism). All the proteins that discriminated both MCI‐AD and AD‐dem from CTRL (Figure 1, e.g., GFAP, MAP3K5, CALCOCO1, TNFSF10) showed an incremental increase/decrease from preclinical to dementia AD stages.ConclusionThis unprecedent large proteome study unveils novel plasma protein changes along the full AD continuum associated to processes involved in AD pathophysiology. We identified plasma protein panels depicting the biological diversity of this neurodegenerative disease. Customized multiplex assays will be developed for these panels for widespread validation in clinical settings and trials.

Race, inflammation, and amyloid deposition in Black/African American and Non‐Hispanic White older adults

AbstractBackgroundBlack/African American (AA) older adults are twice as likely as Non‐Hispanic White (NHW) older adults to be diagnosed with Alzheimer’s Disease (AD) and related dementias. Inflammation and brain beta‐amyloid (Ab) may play a differential role in AD pathophysiology in AA and NHW older adults. We hypothesized that there would be racialized group differences in inflammation, amyloid deposition, and everyday discrimination.MethodOne hundred and ninety‐eight participants (Table 1) were recruited in Pittsburgh, PA and the surrounding areas as a part of the Human Connectome Project. Blood‐based biomarkers of inflammatory markers interleukin 6 (IL6) and tumor necrosis factor alpha (TNFa) were examined. Brain Ab was quantified using Pittsburgh Compound‐B (PiB) Positron Emission Tomography (PET) imaging standardized uptake value ratio (SUVr). Experiences of discrimination were measured on a subset of 66 participants (mean age = 62.62±9.37 years, 46.97% AA) using the Everyday Discrimination Scale (EDS). Analysis of covariance, controlling for age, were conducted to examine the racialized group differences for TNFa, IL6, Ab SUVr. Independent samples t‐tests were conducted to compare EDS by racialized group.ResultParticipants. AA participants were on average 6.58 years younger than NHW participants and more likely to have a clinical diagnosis of impaired without complaints, mild cognitive impairment (MCI), or AD (all p’s<.05) (Table 1). Additionally, in the subset of participants with EDS data, AA participants experienced higher total discrimination than NHW participants (p<.05).Inflammation. NHW participants had higher TNFa inflammation levels than AA participants (p = .029). No differences by racialized group were observed for IL6.PiB‐PET. The frequency of amyloid positivity was higher in NHW than AA participants (p = <.001). Global Ab SUVr was higher in NHW than AA participants (p<.05).ConclusionThe results from this study provide evidence of higher peripheral blood inflammation and PiB PET binding in NHW than AA participants, but higher likelihood of clinical diagnoses and more experiences of discrimination in the AA than in NHW participants. Future investigation of these racialized differences as they relate to age and other determinants of health are needed.

Alzheimer’s disease plasma markers and depressive symptoms: an IPD meta‐analysis

AbstractBackgroundDepression has been associated with an increased risk of Alzheimer’s disease (AD), but the biological mechanisms are still not fully understood. Plasma biomarkers, such as amyloid‐beta, tau, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL), have been associated with AD pathophysiology. However, the relationship with depression is unclear. Assessing these biomarkers in the blood allows for the opportunity to assess if AD pathology is related to depressive symptoms on a large‐scale. We hypothesized if depression is part of the AD process, then these markers will be associated with depressive symptoms.MethodA two‐stage IPD meta‐analysis was performed based on eight cohorts of individuals without dementia as part of the Netherlands Consortium of Dementia Cohorts (NCDC). We examined the cross‐sectional association between each plasma marker for AD (amyloid‐beta42/40 ratio, p‐tau181, NfL, and GFAP) with depressive symptoms (the GDS‐15, PHQ‐9, CES‐D, and SF‐36). Plasma markers were assessed using Single Molecular Array (Simoa; Quanterix) assays. Both plasma markers and depressive symptoms were standardized. We estimated the effect per plasma marker with depressive symptoms using linear regressions, correcting for age, sex, education, and APOE e4 allele presence, in each cohort. The effect estimates were entered into a random‐effects meta‐analysis. We also performed subgroup analyses assessing sex differences and between those with and without an APOE e4 allele.ResultThis study involved 7210 participants with an age range of 38 to 102 years. Based on clinical cut‐offs per questionnaire, high depressive symptomology ranged from one to 22% per cohort. None of the plasma markers were associated with depressive symptoms in the meta‐analysis. However, subgroup analyses found an association with NfL and depressive symptoms in women (beta 0.07; 95% CI: 0.03‐0.10, p < 0.001) and in those with an APOE e4 allele (beta 0.11; 95% CI: 0.05‐0.17, p = 0.001).ConclusionAD pathology did not show an overall relationship with depressive symptoms. However, in women and in those with a genetic risk for AD, NfL showed an association. As NfL is a marker of overall neurodegeneration, this pathology in plasma may be specific to depressive symptoms in certain subgroups.

Impairment of the locus coeruleus‐transentorhinal cortex pathway in persons at risk of Alzheimer’s disease

AbstractBackgroundRecent studies reported microstructural alterations in the locus coeruleus ‐ transentorhinal cortex (LC‐TEC) pathway in patients with Alzheimer’s disease (AD) but data in subjects at risk of AD (i.e., cognitively intact APOEe4 carriers) are missing. In this study, we apply in‐vivo diffusion weighted images (DWI) to study the effect of APOEe4 on the LC‐TEC pathway in cognitively unimpaired subjects.MethodForty‐five participants (14 APOEe4 carriers: age = 68±7 years, 45% females, MMSE score = 29±0.9; 31 non‐carriers: age = 68±6 years, 57% females, MMSE score = 30±0.6) underwent multimodal 3T MRI and multidomain neuropsychological exams. DWI were corrected for distortions with topup and eddy tools (part of FMRIB’s Software Library – FSL). Microstructural measures as fractional anisotropy (FA), mean (MD), axial (AxD), and radial (RD) diffusivities maps were estimated using the FMRIB’s Diffusion Toolbox (part of FSL) after the exclusion of cerebrospinal fluid voxels. Microstructural integrity of LC‐TEC was assessed using a thresholded probabilistic atlas non‐linearly warped on native maps with FNIRT (part of FSL). A Bonferroni multivariate generalized linear model, corrected for age and sex, was conducted to compare the diffusivity indexes between APOEe4 carriers and non‐carriers. Association with memory functioning (immediate and delayed recall) was also tested using Spearman’s rank correlations test.ResultAPOEe4 carriers and non‐carriers were comparable for cognitive performance (p>.246). Compared to non‐carriers, APOEe4 carriers showed lower FA (p = 0.048) and higher RD (p = 0.036) in the left LC‐TEC. In APOEe4 carriers, left RD negatively correlated with both immediate (rho = ‐0.808, p<0.001) and delayed (rho = ‐0.673, p = 0.025) memory recall.ConclusionMicrostructural alterations of the LC‐TEC pathway are detectable in subjects at‐risk for AD and correlate with lower memory performance. These preliminary results support the view that LC‐TEC impairment may play a role in AD pathophysiology since its early stages.

Baseline Amyloid and Tau Deposition Predict Distinct Patterns of Longitudinal White Matter Degeneration: A Diffusion MRI Investigation

AbstractBackgroundNeuritic plaques with fibrillar beta‐amyloid (Aβ) peptides and tau‐protein neurofibrillary tangles are hallmark features of Alzheimer’s disease (AD) pathology. While concomitant differences in white matter (WM) integrity were found in association with Aβ deposition or tau pathology, a unique effect of each pathology on WM integrity remains unknown. In this study, we examined the unique effects of AD pathologies on WM integrity both cross‐sectionally and longitudinally.MethodA total of 334 participants (188 cognitively normal (CN), 114 mild cognitive impairment, and 32 AD) was selected from the ADNI database, based on the availability of two timepoints of diffusion MRI (dMRI) data, and baseline amyloid and tau PET data. The dMRI data were processed using FSL’s TBSS pipeline to quantify the degree of fractional anisotropy (FA) and annualized FA change maps were created to measure voxel‐wise WM change over time. Baseline global amyloid SUVR values were converted to a centiloid scale. Baseline tau SUVRs were evaluated by Braak staging (I‐entorhinal, II‐hippocampal, III/IV‐limbic, V/VI‐neocortex). The associations between AD pathologies and cross‐sectional and longitudinal WM integrity were assessed by FSL’s randomise and cluster‐level correction, controlling for age and sex.ResultCross‐sectionally, baseline tau burden in Braak stages I, III/IV, and V/VI related to lower WM integrity, independent of Aβ, while there was no association between baseline Aβ and WM integrity, independent of tau. Longitudinally, limbic and neocortical tau at baseline uniquely predicted WM integrity loss across widespread regions, including left superior longitudinal fasciculus and the body and splenium of corpus callosum. Moreover, baseline Aβ burden significantly related to WM integrity loss across widespread regions, only when entorhinal and hippocampal tau was controlled for. Similar, but weaker, patterns of the associations between baseline AD pathology and longitudinal WM integrity loss were also found only within CN group.ConclusionThese findings suggest distinctive associations between AD pathology and WM degeneration such that Aß exerts widespread deleterious effects on WM integrity primarily early in AD pathophysiology, whereas, once spreading to the neocortex, tau burden drives WM neurodegeneration. The distinctive downstream pathways associated with each AD pathology may underlie differential cognitive profiles across the disease stages.

Impairment of the locus coeruleus‐transentorhinal cortex pathway in persons at risk of Alzheimer’s disease.

AbstractBackgroundRecent studies reported microstructural alterations in the locus coeruleus ‐ transentorhinal cortex (LC‐TEC) pathway in patients with Alzheimer’s disease (AD) but data in subjects at risk of AD (i.e., cognitively intact APOEε4 carriers) are missing. In this study, we apply in‐vivo diffusion weighted images (DWI) to study the effect of APOEε4 on the LC‐TEC pathway in cognitively unimpaired subjects.MethodForty‐five participants (14 APOEε4 carriers: age = 68±7 years, 45% females, MMSE score = 29±0.9; 31 non‐carriers: age = 68±6 years, 57% females, MMSE score = 30±0.6) underwent multimodal 3T MRI and multidomain neuropsychological exams. DWI were corrected for distortions with topup and eddy tools (part of FMRIB’s Software Library – FSL). Microstructural measures as fractional anisotropy (FA), mean (MD), axial (AxD), and radial (RD) diffusivities maps were estimated using the FMRIB’s Diffusion Toolbox (part of FSL) after the exclusion of cerebrospinal fluid voxels. Microstructural integrity of LC‐TEC was assessed using a thresholded probabilistic atlas non‐linearly warped on native maps with FNIRT (part of FSL). A Bonferroni multivariate generalized linear model, corrected for age and sex, was conducted to compare the diffusivity indexes between APOEε4 carriers and non‐carriers. Association with memory functioning (immediate and delayed recall) was also tested using Spearman’s rank correlations test.ResultAPOEε4 carriers and non‐carriers were comparable for cognitive performance (p>.246). Compared to non‐carriers, APOEε4 carriers showed lower FA (p = 0.048) and higher RD (p = 0.036) in the left LC‐TEC. In APOEε4 carriers, left RD negatively correlated with both immediate (rho = ‐0.808, p<0.001) and delayed (rho = ‐0.673, p = 0.025) memory recall.ConclusionMicrostructural alterations of the LC‐TEC pathway are detectable in subjects at‐risk for AD and correlate with lower memory performance. These preliminary results support the view that LC‐TEC impairment may play a role in AD pathophysiology since its early stages.

Impact of sex and ApoE4 on the longitudinal association of plasma ptau‐181 and NFL with cognitive decline in non‐demented older adults

AbstractBackgroundAPOE4 is a strong genetic risk factor for Alzheimer’s disease (AD). Sex‐dependent differences has been shown in AD pathophysiology and clinical course. Here, we aim to assess the association between longitudinal changes in ptau‐181 and neurofilament light protein (NfL) and concurrent changes in cognitive measures in non‐demented individuals and to evaluate if this association is impacted by sex and ApoE4 status.MethodParticipants (N = 738) were non‐demented (cognitively unimpaired or mild cognitive impairment) older adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI, N = 738) with up to 4ys of longitudinal data. Linear Mixed Effects (LME) models were used to study the effect of ptau‐181 and NFL on cognition as measured by the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS‐cog11; Range 0‐70) and Clinical Dementia Rating, sum of boxes (CDR‐SB). Sex by time and APOE4 by time interactions were assessed in the models for the entire sample. Analyses was repeated after separately stratifying sample by sex and APOE4.ResultAt baseline, both ADAS‐11 and CDRSB values correlated with plasma p‐Tau181 and NfL measures (Table 1). The longitudinal change in plasma p‐Tau181 correlated only with baseline CDR‐SB while that of NfL correlated with baseline ADAS‐11. The APOE4*time interaction, but not sex‐time interaction, were significant in LME models of both p‐Tau181 and NFL (Table 2). When stratified by sex, in females longitudinal increase in p‐Tau181 was associated with cognitive decline measured by both ADAS‐11 and CDR‐SB. In males, longitudinal increase in p‐Tau181 was associated with increase in ADAS‐11 scores and NfL was associated with cognitive decline on both outcomes. When stratified by APOE4 status, longitudinal changes in plasma biomarkers were only associated with cognitive decline in the APOE4+ subsample.ConclusionPlasma NfL and pTau increase during early AD and can be used to monitor disease progression. The relationship between increase in plasma ptau‐181 and NFL levels and worsening of cognition is affected by APOE4 status.

Sulfanegen, a 3‐mercaptopyruvate sulfurtransferase substrate, as a therapeutic option for Alzheimer’s disease

AbstractBackgroundThe oxidative stress evident in the Alzheimer’s disease (AD) brain leads to compromised 3‐mercaptopyruvate sulfurtransferase (3MST) function, one of the endogenous hydrogen sulfide (H2S) producing enzymes.1,2 Impaired 3MST function is expected to contribute toward potentiation of oxidative stress by depleting cellular glutathione (GSH) stores, and exacerbation of AD pathology by enhancing Aβ aggregation resulting in neurodegeneration. Preclinical studies with H2S donors such as NaSH have been promising,3,4 however further clinical translation efforts are thwarted due to their poor chemical stability, bioavailability, and dose‐limiting toxicities. We have developed a stable, bioavailable prodrug of 3MST substrate 3‐mercaptopyruvate, named sulfanegen, which can supplement the enzymatic reaction releasing H2S.2 Thus provision of sulfanegen could prove beneficial in mitigating AD‐related neurodegenerative consequences.MethodAged, symptomatic cohorts APP/PS1 mice (7 and 12 month old) were treated with saline (N = 8) or sulfanegen (75 mg/kg, i.p., N = 8) for 12 weeks. Cognitive behavioral assessments (T‐maze) were conducted 10‐11 weeks after treatment initiation. Equal numbers of both sexes of mice were used as much as possible. The harvested brain tissues were analyzed biochemically for cortical/hippocampal Aβ1‐42 burden, oxidative stress and inflammatory markers (protein carbonyls, lipid peroxidation, glutathione assay, TNF‐α and IL6. Quantitative stereological analysis of Aβ pathology, neuroinflammation and progressive neurodegeneration were also conducted.ResultTreatment of symptomatic Alzheimer’s mice with sulfanegen prevented cognitive impairment resulting from AD pathology (Figure 1).2 This was corroborated by reduced brain amyloid load as well as the reversal of oxidative stress and neuroinflammation. Neuropathological analysis also displayed modest, but significant effect of sulfanegen on Aβ levels, reactive astrogliosis and microglial reactivity. More importantly, sulfanegen caused attenuation of progressive degeneration of noradrenergic system in the LC. Additionally, administration of sulfanegen supplemented brain 3MP levels, resulting in restoration of brain 3MST function.ConclusionCollectively, our results show that the provision of a 3MST substrate, sulfanegen, exhibits neuroprotective effects, along with restoration of cognitive function in an AD mouse model. This study suggests an important role of 3MST in AD pathophysiology and potential therapeutic utility of sulfanegen as a disease‐modifying treatment.

Predicting cognitive dysfunction and regional hubs using Braak staging amyloid-beta biomarkers and machine learning

Mild cognitive impairment (MCI) is a transitional stage between normal aging and early Alzheimer’s disease (AD). The presence of extracellular amyloid-beta (Aβ) in Braak regions suggests a connection with cognitive dysfunction in MCI/AD. Investigating the multivariate predictive relationships between regional Aβ biomarkers and cognitive function can aid in the early detection and prevention of AD. We introduced machine learning approaches to estimate cognitive dysfunction from regional Aβ biomarkers and identify the Aβ-related dominant brain regions involved with cognitive impairment. We employed Aβ biomarkers and cognitive measurements from the same individuals to train support vector regression (SVR) and artificial neural network (ANN) models and predict cognitive performance solely based on Aβ biomarkers on the test set. To identify Aβ-related dominant brain regions involved in cognitive prediction, we built the local interpretable model-agnostic explanations (LIME) model. We found elevated Aβ in MCI compared to controls and a stronger correlation between Aβ and cognition, particularly in Braak stages III–IV and V–VII (p < 0.05) biomarkers. Both SVR and ANN, especially ANN, showed strong predictive relationships between regional Aβ biomarkers and cognitive impairment (p < 0.05). LIME integrated with ANN showed that the parahippocampal gyrus, inferior temporal gyrus, and hippocampus were the most decisive Braak regions for predicting cognitive decline. Consistent with previous findings, this new approach suggests relationships between Aβ biomarkers and cognitive impairment. The proposed analytical framework can estimate cognitive impairment from Braak staging Aβ biomarkers and delineate the dominant brain regions collectively involved in AD pathophysiology.