Abstract Alzheimer Research Articles

Shared and differing functional connectivity abnormalities of the default mode network in mild cognitive impairment and Alzheimer’s disease

Abstract Alzheimer’s disease (AD) and mild cognitive impairment (MCI) both show abnormal resting-state functional connectivity (rsFC) of default mode network (DMN), but it is unclear to what extent these abnormalities are shared. Therefore, we performed a comprehensive meta-analysis, including 31 MCI studies and 20 AD studies. MCI patients, compared to controls, showed decreased within-DMN rsFC in bilateral medial prefrontal cortex/anterior cingulate cortex (mPFC/ACC), precuneus/posterior cingulate cortex (PCC), right temporal lobes, and left angular gyrus and increased rsFC between DMN and left inferior temporal gyrus. AD patients, compared to controls, showed decreased rsFC within DMN in bilateral mPFC/ACC and precuneus/PCC and between DMN and left inferior occipital gyrus and increased rsFC between DMN and right dorsolateral prefrontal cortex. Conjunction analysis showed shared decreased rsFC in mPFC/ACC and precuneus/PCC. Compared to MCI, AD had decreased rsFC in left precuneus/PCC and between DMN and left inferior occipital gyrus and increased rsFC in right temporal lobes. MCI and AD share a decreased within-DMN rsFC likely underpinning episodic memory deficits and neuropsychiatric symptoms, but differ in DMN rsFC alterations likely related to impairments in other cognitive domains such as language, vision, and execution. This may throw light on neuropathological mechanisms in these two stages of dementia.

LONGITUDINAL CHANGES IN PROTEOMIC BIOMARKERS IN ALZHEIMER’S DISEASE AND CARDIOVASCULAR DISEASE

Abstract Alzheimer’s disease (AD) and cardiovascular diseases (CVDs) commonly co-occur in older adults. This correlation prompts an investigation into the potential shared risk factors linking AD and CVDs, and the potential direct causative role of cardiovascular risk factors in AD. The cohort comprised 566 older adults including 111 individuals with AD, 58 without AD, 383 with mild cognitive impairment (MCI), 410 with CVD and 156 without CVD from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The multivariable linear mixed model (LMM) was used to investigate the associations of AD and CVD on longitudinal changes of 146 proteomic biomarkers (measured at baseline and 12-month follow-up), while adjusted for age, gender, education, racial groups, and APOE-ε4 alleles. The LMM showed that AD and CVD were associated with longitudinal changes in 48 and 46 proteomic biomarkers, respectively (p< 0.05). Interestingly, both AD and CVD were associated with longitudinal changes in 14 proteomic biomarkers (A1Micro, ApoH, B2M, BNP, Complement C3, Cystatin C, KIM1, NGAL, PPP, TIM1, THP, TFF3, TM, and VEGF). Furthermore, the single biggest risk gene for sporadic AD, APOE-ε4 was associated with 22 proteomic biomarkers. Moreover, MCI and CVD were associated with 13 proteomic biomarkers (A1Micro, ApoD, AXL, BNP, Calcitonin, CD40, C-peptide, pM, PPP, THP, TNFR2, TTR, and VEGF), while MCI, CVD and APOE-ε4 were associated with four proteomic biomarkers (A1Micro, Calcitonin, THP, and TNFR2). This study provides valuable insights into the shared and distinct pathophysiological mechanisms at play, offering a stepping-stone towards a deeper comprehension of the interrelationship between AD and CVDs.

DIFFERENCES IN COGNITIVE DECLINE DUE TO ALZHEIMER’S DISEASE, NEURODEGENERATIVE DISORDERS, AND TRAUMA

Abstract Alzheimer’s disease (AD) is a form of progressive dementia associated with significant personal, social, and economic burdens, making targeted interventions aimed at mitigating the effects of this condition on cognitive decline highly desirable. However, AD is but one of a range Neurodegenerative Disorders (ND) classified as dementias of aging. Furthermore, neither AD/ ND nor cognitive decline itself are monolithic: each individual disorder degrades specific aspects of cognition at differing rates. Isolating the most vulnerable facet of good cognitive health associated with each condition can lead the way to more personalized health interventions and an overall reduction of the burdens posed by AD /ND. In this paper we assess how the presence of AD and/or other ND degrade immediate (IR) and delayed (DR) recall over an extended period of time vs. the effect of non-degenerative brain trauma and AD/ND-free aging. Using Medicare-linked data from the Health and Retirement Study we found that, when compared to AD/ND-free aging, the onset of AD accelerates the decrease of IR by an overage of 0.30-0.37 points bi-annually, with similar effects on DR. Vascular dementia was associated with a 0.24-point loss of IR, but only for individuals with initially low recall capacity (≤5); those with high initial recall capacity (6+) did not experience loss of IR but lost 1.01 points of DR bi-annually. For comparison, traumatic brain injury was associated with 0.12-0.23 points decline in IR and 0.15 in DR bi-annually.

A MECHANISM OF ACTION OF HUMAN-ORIGIN PROBIOTIC COCKTAIL IN ATTENUATING ALZHEIMER’S DISEASE PATHOLOGY

Abstract Alzheimer’s disease (AD) is a detrimental public health problem affecting millions of older adults in the USA alone, with no or limited treatment options. Emerging evidence indicates the pivotal role of gut microbiota in AD pathology, but mechanisms remain largely unknown. Also, microbiome modulators like probiotics are proven beneficial in preventing AD with little understanding of their mechanisms. Therefore, we investigated how a microbiota metabolite-short-chain free fatty acid receptor-2 (FFAR2) signaling in the intestine affects AD pathology in brain using intestinal FFAR2 knock-out APP/PS-1 mice; as well as determined if a human-origin-probiotic cocktail exhibits its actions via FFAR2 signaling. We measured changes in the microbiome, permeability in gut and blood-brain barriers (BBB), neuroinflammation, AD pathology, and cognitive behaviors. Results showed, the mice lacking FFAR2 in their intestine exacerbated AD pathology by developing abnormal changes in gut microbiome and intestinal permeability, which in turn promotes permeability in BBB and neuroinflammation. It’s also promoting microglia activation linked with increased Aβ accumulation and cognitive decline. It’s interesting to note that probiotic cocktail feeding reversed these abnormalities in AD mouse models. Further, this probiotic cocktail showed its mechanism in both FFAR2-dependent and independent manner. Overall, our findings indicate that the microbiome sensing mechanism FFAR2 signaling participates in regulating the gut-brain in AD pathology, and a human-origin probiotic cocktail improves the abnormal changes in the microbiome-intestinal & BBB permeability-neuroinflammation axis to ameliorate AD pathology. Thus, FFAR2 agonism and probiotic therapy can be viable options to prevent/ delay the risk of AD progression in older adults.

DIGITAL CLOCK DRAWING PERFORMANCE ASSOCIATIONS WITH ALZHEIMER’S DISEASE GENETIC RISK SCORE AND APOE IN OLDER ADULTS

Abstract Alzheimer’s disease (AD) is the leading cause of dementia in older adults, but most people are not diagnosed until clinical signs and symptoms are present. Non-invasive and cost-effective digital biomarkers for AD have the potential to improve early detection. We examined the validity of DCTclockTM (a digitized clock drawing task) as an AD susceptibility biomarker. We used two primary independent variables, Apolipoprotein E (APOE) ɛ4 allele carrier status and polygenic risk score (PRS). We examined APOE and PRS associations with DCTclockTM composite scores as dependent measures. We used existing data from the Framingham Heart Study (FHS), a community-based study with the largest dataset of digital clock drawing data to date. The sample consisted of 2,398 older adults ages 60-94 with DCTclockTM data (mean age of 72.3, 55% female and 92% White). PRS was calculated using 38 variants identified in a recent large genome-wide association study (GWAS) and meta-analysis of late-onset AD (LOAD). Results showed that DCTclockTM performance decreased with advancing age, lower education, and the presence of one or more copies of APOE ε4. Lower DCTclockTM Total Score as well as lower composite scores for Information Processing Speed and Drawing Efficiency were significantly associated with higher PRS levels and more copies of APOE ε4. Associations displayed similar effect sizes in men and women. This is the first study to demonstrate significant differences in clock drawing performance on the basis of APOE status or PRS.

P. GINGIVALIS–LPS-INDUCED NLRP3 INFLAMMASOME ACTIVATION DRIVES AD PATHOLOGIES

Abstract Alzheimer’s disease (AD) is the leading cause of dementia among older adults. AD is characterized by amyloid-β deposition, abnormal hyperphosphorylation of tau leading to the formation of neurofibrillary tangles, and neuroinflammation. Porphyromonas gingivalis, the keystone-pathogen of periodontitis, is being increasingly linked with AD and Alzheimer’s disease-related dementias (ADRD). Poor oral health is common in older populations, and literature suggests that oral health correlates with prevalence of ADRD. NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated IL-1β is significantly involved in periodontal diseases. However, the exact mechanism by which NLRP3 inflammasome is regulated in response to pathogenic bacteria remains unclear. We hypothesized that P. gingivalis-LPS may be responsible for the neuroinflammation via TLR4 activation and its downstream caspase-1, caspase-3 or caspase-4/5/11 dependent cell signaling. Our results suggest that P. gingivalis accelerated the induction of NLRP3. Furthermore, NLRP3/Caspase-1/Caspase-4/5/11 dependent IL-1β production may contribute to the dysregulated neuroinflammatory response in AD pathogenesis.

HEALTH COACHING IMPROVES EVERYDAY COGNITION AMONG INDIVIDUALS AT RISK FOR ALZHEIMER’S DISEASE

Abstract Alzheimer’s disease (AD) is the 7th leading cause of death and 6th most burdensome disease among US older adults. With pharmacological treatments for AD being predominantly ill-effective, alternative, non-pharmacological prevention and treatment strategies warrant exploration. Personal health coaching provides individualized strategies designed to improve physical, social, and emotional health leading to positive behavior changes that may improve cognitive ability. The purpose of the present investigation was to examine the effects of a Health Coaching (HC) intervention on cognitive outcomes. Adults (n=182) over 45 years of age were randomly assigned to HC or control arm of a 12-month intervention. Participants (age = 61.9 + 8.4 years) had their cognition (ECog-12) tested at baseline, 16, and 52 weeks. Participants assigned to the HC intervention met with a health coach once per month to establish healthful goals and implementation strategies improving the health and well-being of the participants. The control group received bi-weekly emails including similar information presented during the health coaching sessions. Results revealed a main effect for time for improved ECog-12 scores (p=.04) with a 3.2% improvement in ECog-12 after 52 weeks. Upon further analysis, HC had a significant improvement in cognitive performance after both 16 and 52 weeks, while the control group remained unchanged. Improvement in self-reported cognition was 4.0% (p=.03) and 5.5% (p=.01) in the HC group after 16 and 52 weeks, respectively. These results suggest HC is an effective non-pharmacological prevention strategy for cognitive decline among a group of adults at-risk for developing AD.

Markov model combined with MR diffusion tensor imaging for predicting the onset of Alzheimer's disease.

Alzheimer's disease (AD) affects cognition, behavior, and memory of brain. It causes 60-80% of dementia cases. Cross-sectional imaging investigations of AD show that magnetic resonance (MR) with diffusion tensor image (DTI)-detected lesion locations in AD patients are heterogeneous and distributed across the imaging area. This study suggested that Markov model (MM) combined with MR-DTI (MM + MR-DTI) was offered as a method for predicting the onset of AD. In 120 subjects (normal controls [NCs], amnestic mild cognitive impairment [aMCI] patients, and AD patients) from a discovery dataset and 122 subjects (NCs, aMCI, and AD) from a replicated dataset, we used them to evaluate the white matter (WM) integrity and abnormalities. We did this by using automated fiber quantification, which allowed us to identify 20 central WM tracts. Point-wise alterations in WM tracts were shown using discovery and replication datasets. The statistical analysis revealed a substantial correlation between microstructural WM alterations and output in the patient groups and cognitive performance, suggesting that this may be a potential biomarker for AD. The MR-based classifier demonstrated the following performance levels for the basis classifiers, with DTI achieving the lowest performance. The following outcomes were seen in MM + MR-DTI using multimodal techniques when combining two modalities. Finally, a combination of every imaging method produced results with an accuracy of 98%, a specificity of 97%, and a sensitivity of 99%. In summary, DTI performs better when paired with structural MR, despite its relatively weak performance when used alone. These findings support the idea that WM modifications play a significant role in AD.

Azilsartan ameliorates aluminium chloride induced Alzheimer’s disease like pathology

Abstract Alzheimer’s disease (AD) is a neurodegenerative disease manifested with accumulation of neurotoxic proteins like beta-amyloid (Aβ) and hyperphosphorylated tau. Administration of angiotensin receptor blockers (ARBs) such as Telmisartan has demonstrated to generate significant memory improvement in AD. Azilsartan is an ARB with better bioavailability than Telmisartan. Hence, the present work evaluates the efficacy of Azilsartan against aluminium chloride (AlCl3) induced AD. In the work, albino rats were divided into five groups (n=6). Group I served as control and received saline (10 ml/kg). Group-II was treated with AlCl3 (100 mg/kg) for 42 days; Group-III and IV received Azilsartan (5 mg/kg) and Telmisartan (10 mg/kg) with AlCl3 daily for 42 days. Y-maze, elevated plus maze and radial arm maze were used to evaluate memory functions. This was followed by biochemical and histological studies, along-with determination of Aβ content and anti-oxidant status. AlCl3 was found to significantly (p <0.05) reduce cognition and increased concentration of Aβ in a hippocampus with elevated lipid peroxidation levels. It also significantly (p<0.05) decreased superoxide dismutase and increased malondialdehyde content. However, brain histology showed presence of neurofibrillary tangles, neuronal dead cells, and pyknotic cells compared to normal group. Still, Azilsartan and Telmisartan significantly (p<0.05) reversed cognitive dysfunction, improved antioxidant status and decreased Aβ production. Thus we conclude that Azilsartan protects AlCl3 induced AD-like pathology but, to a degree less than Telmisartan.

The elusive role of herpesviruses in Alzheimer's disease: current evidence and future directions.

Alzheimer's disease (AD) is the most common cause of dementia. While pathologic hallmarks, such as extracellular beta-amyloid plaques, are well-characterized in affected individuals, the pathogenesis that causes plaque formation and eventual cognitive decline is not well understood. A recent resurgence of the decades-old "infectious hypothesis" has garnered increased attention on the potential role that microbes may play in AD. In this theory, it is thought that pathogens such as viruses may act as seeds for beta-amyloid aggregation, ultimately leading to plaques. Interest in the infectious hypothesis has also spurred further investigation into additional characteristics of viral infection that may play a role in AD progression, such as neuroinflammation, latency, and viral DNA integration. While a flurry of research in this area has been recently published, with herpesviruses being of particular interest, the role of pathogens in AD remains controversial. In this review, the insights gained thus far into the possible role of herpesviruses in AD are summarized. The challenges and potential future directions of herpesvirus research in AD and dementia are also discussed.

Nanoparticles for the potential treatment of Alzheimer’s disease: A physiopathological approach

Abstract Alzheimer’s disease (AD) is a multifactorial neurodegenerative central system disease with a high prevalence among the elderly and is the most common form of dementia. Oxidative stress is crucial on AD pathogenesis and leads to deposition of neurofibrillary tangles and Aβ plaques; therefore, the use of natural antioxidants or ROS scavengers could help avoid the formation of these aggregates. Similarly, Aβ-degrading/anti-aggregating molecules could help arrest AD progression. Otherwise, traditional anti-Alzheimer drugs such as acetylcholinesterase inhibitors help improve memory and attention deficits. Nevertheless, all these drugs are extensively metabolized, have low plasma concentration, and cannot cross the blood–brain barrier freely. This review discusses different strategies for nanocarrier conjugation of these drugs for brain targeting and delivery, and new approaches on AD treatment according to the most accepted hypotheses of AD pathogenesis. Although none of the existent compounds or drugs can completely arrest the disease’s progression, nanocarrier development of anti-Alzheimer drugs could help delaying the initial or late stages of neurodegeneration. The discovery of new and more complex nanosystems with multiple approaches in AD treatment is needed and will be the next step in AD treatment in the near future.

Continued food allergen consumption exacerbates beta-amyloid accumulation in allergen-sensitized App NL-G-Fmice

Abstract Alzheimer’s disease (AD) is the most common neurodegenerative disease, with β-amyloid (Aβ) plaque deposition being one of the hallmark pathologies. However, the etiology of AD remains elusive. While chronic inflammation from recurrent infections or injury seems to contribute to AD development, it is unclear whether atopic diseases, such as allergies, are associated with AD. We previously reported that continuous consumption of a whey protein (WP)-containing diet led to lasting neuroinflammation in C57BL/6J mice that were sensitized but tolerant to a bovine milk allergen, β-lactoglobulin (BLG; Bos d 5). Thus, we hypothesized that the persisting neuroinflammation due to repeated allergen consumption would exacerbate AD pathology over time in genetically predisposed, allergen-tolerant individuals. To address this hypothesis, we sensitized 1-month-old male and female transgenic App NL-G-Fknock-in mice to BLG and subsequently fed them either a whey-free control or a WP diet for 6 months. Despite their lack of overt allergic reactions, BLG-sensitized mice showed elevated plasma levels of BLG-specific IgE and IgG1. Leukocyte infiltration was observed in the hippocampus of sensitized mice, and WP-fed sham mice to a lesser extent. In contrast, mast cell accumulation was apparent in the dura of sensitized mice regardless of the diet. Importantly, Aβ plaque load and Aβ peptide levels were greater in the hippocampus of BLG-sensitized mice on the WP diet compared to the respective sham group. These results indicated that continuous allergen consumption exacerbated AD-like pathology in BLG-sensitized App NL-G-Fmice, suggesting that chronic food allergen exposure may promote the progression of AD in susceptible individuals. Supported by the National Institute of Health/National Institute on Aging (NIH/NIA) under grant number R21AG070412

Characterization of the transcriptome and TCR of brain and cerebrospinal fluid infiltrated CD8 +T cells in an Alzheimer’s disease mouse model

Abstract Alzheimer’s disease (AD) is a common form of dementia characterized by the accumulation of protein aggregates in the brain of older adults. It has been observed that CD8 +T cells, particularly CD8 +TEMRA cells, infiltrate the brain and cerebrospinal fluid (CSF) of AD patients. However, the precise role of these cells in the development and progression of AD is not well understood. In this study, we used single-cell RNA sequencing (scRNAseq) and single-cell T cell receptor sequencing (scTCRseq) to examine the CD8 +T cells in the brain and CSF of a mouse model of AD (5xFAD) and its wild-type (WT) littermate controls. The AD mice (age 40–70 weeks) used in our experiments have developed memory deficits. Our analysis revealed a significant increase in the number of CD8 +T cells in the brain and CSF of AD mice compared to WT controls (n=4, p<0.05). Furthermore, these cells displayed a distinct transcriptome profile characterized by increased expression of inflammatory pathways, compared to WT mice. Through TCR sequence analysis, we also observed significant clonal expansion of CD8 +T cells in AD mice compared to WT mice. These findings provide a starting point for further investigation into the role of infiltrating CD8 +T cells in the pathogenesis of AD in this mouse model.

Inhibitory, But Not Excitatory Synapses Are Reduced in the Hippocampus of the Six-Month-Old Alzheimer’s Disease Model Mouse

Abstract Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and the most common cause of elderly dementia. One of the main features of AD diseased brain are amyloid plaques, pathological depositions made of β-amyloid peptide, derived from β- amyloid precursor protein (APP). To assess how AD pathology affects synapses in the hippocampus, brain region to be one of the earliest with obvious pathological changes, we examined APPPS1 mice, transgeneticaly expressing human APP mutation (“Swedish mutation”) and human presenilin-1 mutation under the neuron-specific promoter, which develop AD symptoms early in life. We analyzed inhibitory and excitatory synapses using immunoflourescent staining and laser scanning confocal microscopy. In APPPS1 mice, inhibitory synaptic terminals labeled with vesicular inhibitory transmitter transporter (VGAT) were reduced in CA1 and CA3 regions of the hippocampus in APPPS1 mice compared to controls. This was true for both parvalbumin-positive and parvalbumin-negative terminals. On the other hand, excitatory synapses, coming from either hippocampal or entorhinal projections were similar between the genotypes. We conclude that first changes in the hippocampus caused by amyloid pathology affect inhibitory, but not excitatory synapses.

Impaired episodic-like memory in a mouse model of Alzheimer's disease is associated with hyperactivity in prefrontal-hippocampal regions.

Alzheimer's disease (AD) is a degenerative brain disorder with a long prodromal period. An APPNL-G-F knock-in mouse model is a preclinical model to study incipient pathologies during the early stages of AD. Despite behavioral tests revealing broad cognitive deficits in APPNL-G-F mice, detecting these impairments at the early disease phase has been challenging. In a cognitively demanding task that assessed episodic-like memory, 3-month-old wild-type mice could incidentally form and retrieve 'what-where-when' episodic associations of their past encounters. However, 3-month-old APPNL-G-F mice, corresponding to an early disease stage without prominent amyloid plaque pathology, displayed impairment in recalling 'what-where' information of past episodes. Episodic-like memory is also sensitive to the effect of age. Eight-month-old wild-type mice failed to retrieve conjunctive 'what-where-when' memories. This deficit was also observed in 8-month-old APPNL-G-F mice. c-Fos expression revealed that impaired memory retrieval in APPNL-G-F mice was accompanied by abnormal neuronal hyperactivity in the medial prefrontal cortex and CA1 dorsal hippocampus. These observations can be used for risk stratification during preclinical AD to detect and delay the progression into dementia.

FUNGAL INFECTIONS, USE OF ANTIFUNGAL AGENTS, AND THE RISK OF ALZHEIMER’S DISEASE

Abstract Alzheimer’s Disease (AD) is a complex neurodegenerative disorder leading to progressive cognitive decline and death. Accumulating evidence suggests that common adult infections, such as recurrent fungal infections, may play a major role in AD development. In this study we used administrative claims data, 1991-2017, from a 5% sample of U.S. Medicare beneficiaries age 65+ to study the potential relationship between fungal infections, use of antifungal drugs and AD onset. In unweighted analysis using the Cox model, we found that after accounting for demographic and health-related differences, the presence of fungal infections, independent of treatment increased the risk of AD [Hazard Ratio(HR):1.98; 95% Confidence Interval(CI):1.89-1.92]. The strength of the effect did not change when the population was restricted to Medicare beneficiaries with Medicare Part D (prescription drug) coverage in 2006+ (HR:1.99; CI:1.97-2.01). We then split the latter group into yearly split-episode data and calculated the medication possession ratios (MPR) of three major groups of antifungal agents: imidazole, triazole and polyenes and re-estimated our models. Although the effect associated with fungal infection did not change, higher MPRs of imidazole (HR:0.61; CI:0.48-0.76) and especially triazole (HR:0.37; CI:0.24-0.58) were found to be protective. In contrast, higher MPRs of polyenes were associated with increased risk (HR:1.32; CI:1.08-1.63). In summary, fungal infections were found to be strongly associated with AD risk with the effect being strongly modified by use of common antifungal treatments. More research is required to better define the biological mechanisms engendering these associations.

A MOLECULAR LENS FOCUSED ON UNDERSTANDING ALZHEIMER'S DISEASE HEALTH DISPARITIES

Abstract Alzheimer’s disease (AD), the most common cause of dementia in older adults, disproportionally affects African Americans (AA) with an incidence rate as much as three times higher, compared to other racial/ethnic groups. Multiple factors contribute to this racial disparity however, an in-depth understanding of the biological or genetic contributions does not exist. Compelling evidence indicate that genetic variants of the lipid transport protein, ABCA7, is more strongly associated with AD in African Americans. To understand how ABCA7 contributes to AD on the molecular level, we used a combination of structural and cell biology techniques. Our results suggest that the ABCA7 variant (T319A) reported to confer risk in AA, may contribute to AD by reducing the levels of phosphoinositol bisphosphate (PIP2), a phospholipid reported to be decreased in the AD brain. These results provide a framework for targeting mechanisms that increase PIP2 levels as an effective strategy mitigating AD disparities.

INTEGRATIVE MULTI-OMICS ANALYSIS REVEALS THE CRITICAL ROLE OF PBXIP1 GENE IN AGING-RELATED ALZHEIMER'S DISEASE

Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder, and its strongest risk factor is aging. A few studies have explored the relationship between aging and AD, while the underlying mechanism remains unclear. We assembled data cross multi-omics (i.e., epigenetics, transcriptomics, and proteomics, based on frozen tissues from the dorsolateral prefrontal cortex) and neuropathological and clinical traits from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP). Aging was assessed using six epigenetic clocks (including Horvath clock, Hannum clock, Levine clock, Horvathskin clock, Lin clock, and Cortical clock) that capture mortality risk in literature. After accounting for age, we first identified a gene module (including 263 genes) that was related to most epigenetic clocks (e.g., P=3.61×10−5 for Levine clock) and three neuropathological traits of AD (i.e., β-amyloid, Tau tangles, and tangle density). Interestingly, among 20 key genes with top intramodular connectivity of the module, PBXIP1 was the only one that was significantly associated with all three neuropathological traits of AD at the protein level after Bonferroni correction. Furthermore, PBXIP1 was associated with clinical diagnosis of AD in both ROSMAP and two independent datasets. The results suggest the critical role of PBXIP1 in aging-related AD and support the potential and feasibility of using multi-omics data to investigate mechanisms of complex diseases. However, more validations in different populations and experiments in vitro and in vivo are required in the future.

Modelling Alzheimer's disease using human brain organoids: current progress and challenges

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by gradual memory loss and declining cognitive and executive functions. AD is the most common cause of dementia, affecting more than 50 million people worldwide, and is a major health concern in society. Despite decades of research, the cause of AD is not well understood and there is no effective curative treatment so far. Therefore, there is an urgent need to increase understanding of AD pathophysiology in the hope of developing a much-needed cure. Dissecting the cellular and molecular mechanisms of AD pathogenesis has been challenging as the most commonly used model systems such as transgenic animals and two-dimensional neuronal culture do not fully recapitulate the pathological hallmarks of AD. The recent advent of three-dimensional human brain organoids confers unique opportunities to study AD in a humanised model system by encapsulating many aspects of AD pathology. In the present review, we summarise the studies of AD using human brain organoids that recapitulate the major pathological components of AD including amyloid-β and tau aggregation, neuroinflammation, mitochondrial dysfunction, oxidative stress and synaptic and circuitry dysregulation. Additionally, the current challenges and future directions of the brain organoids modelling system are discussed.

FAD-deficient P187S mutation of NAD(P)H:quinone oxidoreductase 1 (NQO1*2) binds and accelerates β-amyloid aggregation.

Alzheimer's disease (AD) is one of the most prominent neurodegenerative diseases. Results from animal and cellular models suggest that FAD-deficient forms of NAD(P)H quinone oxidoreductase 1 (NQO1) may accelerate the aggregation of Alzheimer's amyloid-β peptide (Aβ1-42). Here, we examined in vitro whether NQO1 and its FAD-deficient P187S mutation (NQO1*2) directly interact with Aβ1-42 and modify its rate of aggregation. When monitored using the fluorescence of either noncovalent thioflavin T (ThT) or HiLyte Fluor 647 (HF647) dye covalently attached to the Aβ1-42 peptide, the aggregation kinetics of Aβ1-42 were markedly more rapid in the presence of NQO1*2 than the wild-type (WT) NQO1. Experiments using apo-NQO1 indicate that this increase is linked to the inability of NQO1*2 to bind to FAD. Furthermore, dicoumarol, an NQO1 inhibitor that binds near the FAD-binding site and stabilizes NQO1*2, markedly decreased the aggregation kinetics of Aβ1-42. Imaging flow cytometry confirmed in-vitro coaggregation of NQO1 isoforms and Aβ1-42. Aβ1-42 alone forms rod-shaped fibril structures while in the presence of NQO1 isoforms, Aβ1-42 is incorporated in the middle of larger globular protein aggregates surrounded by NQO1 molecules. Isothermal titration calorimetry (ITC) analysis indicates that Aβ1-42 interacts with NQO1 isoforms with a specific stoichiometry through a hydrophobic interaction with positive enthalpy and entropy changes. These data define the kinetics, mechanism, and shape of coaggregates of Aβ1-42 and NQO1 isoforms and the potential relevance of FAD-deficient forms of NQO1 for amyloid aggregation diseases.