Browsing by Subject "Alzheimer's disease (AD)"
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Item 15 Years of Longitudinal Genetic, Clinical, Cognitive, Imaging, and Biochemical Measures in DIAN(medRxiv, 2024-08-09) Daniels, Alisha J.; McDade, Eric; Llibre-Guerra, Jorge J.; Xiong, Chengjie; Perrin, Richard J.; Ibanez, Laura; Supnet-Bell, Charlene; Cruchaga, Carlos; Goate, Alison; Renton, Alan E.; Benzinger, Tammie L. S.; Gordon, Brian A.; Hassenstab, Jason; Karch, Celeste; Popp, Brent; Levey, Allan; Morris, John; Buckles, Virginia; Allegri, Ricardo F.; Chrem, Patricio; Berman, Sarah B.; Chhatwal, Jasmeer P.; Farlow, Martin R.; Fox, Nick C.; Day, Gregory S.; Ikeuchi, Takeshi; Jucker, Mathias; Lee, Jae-Hong; Levin, Johannes; Lopera, Francisco; Takada, Leonel; Sosa, Ana Luisa; Martins, Ralph; Mori, Hiroshi; Noble, James M.; Salloway, Stephen; Huey, Edward; Rosa-Neto, Pedro; Sánchez-Valle, Raquel; Schofield, Peter R.; Roh, Jee Hoon; Bateman, Randall J.; Dominantly Inherited Alzheimer Network; Neurology, School of MedicineThis manuscript describes and summarizes the Dominantly Inherited Alzheimer Network Observational Study (DIAN Obs), highlighting the wealth of longitudinal data, samples, and results from this human cohort study of brain aging and a rare monogenic form of Alzheimer's disease (AD). DIAN Obs is an international collaborative longitudinal study initiated in 2008 with support from the National Institute on Aging (NIA), designed to obtain comprehensive and uniform data on brain biology and function in individuals at risk for autosomal dominant AD (ADAD). ADAD gene mutations in the amyloid protein precursor (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2) genes are deterministic causes of ADAD, with virtually full penetrance, and a predictable age at symptomatic onset. Data and specimens collected are derived from full clinical assessments, including neurologic and physical examinations, extensive cognitive batteries, structural and functional neuro-imaging, amyloid and tau pathological measures using positron emission tomography (PET), flurordeoxyglucose (FDG) PET, cerebrospinal fluid and blood collection (plasma, serum, and whole blood), extensive genetic and multi-omic analyses, and brain donation upon death. This comprehensive evaluation of the human nervous system is performed longitudinally in both mutation carriers and family non-carriers, providing one of the deepest and broadest evaluations of the human brain across decades and through AD progression. These extensive data sets and samples are available for researchers to address scientific questions on the human brain, aging, and AD.Item Author Correction: Predicting Alzheimer’s disease progression using multi-modal deep learning approach(Springer Nature, 2023-08-01) Lee, Garam; Nho, Kwangsik; Kang, Byungkon; Sohn, Kyung‑Ah; Kim, Dokyoon; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of MedicineCorrection to: Scientific Reports 10.1038/s41598-018-37769-z, published online 13 February 2019 This Article contains errors. A Supplementary Information file was omitted from the original version of this Article. The Supplementary Information file is now linked to this correction notice.Item Cerebrovascular disease drives Alzheimer plasma biomarker concentrations in adults with Down syndrome(medRxiv, 2023-11-30) Edwards, Natalie C.; Lao, Patrick J.; Alshikho, Mohamad J.; Ericsson, Olivia M.; Rizvi, Batool; Petersen, Melissa E.; O’Bryant, Sid; Flores-Aguilar, Lisi; Simoes, Sabrina; Mapstone, Mark; Tudorascu, Dana L.; Janelidze, Shorena; Hansson, Oskar; Handen, Benjamin L.; Christian, Bradley T.; Lee, Joseph H.; Lai, Florence; Rosas, H. Diana; Zaman, Shahid; Lott, Ira T.; Yassa, Michael A.; Gutierrez, José; Wilcock, Donna M.; Head, Elizabeth; Brickman, Adam M.; Neurology, School of MedicineImportance: By age 40 years over 90% of adults with Down syndrome (DS) have Alzheimer's disease (AD) pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with DS have elevated cerebrovascular disease (CVD) markers that track with the clinical progression of AD, suggesting a role for CVD that is hypothesized to be mediated by inflammatory factors. Objective: To examine the pathways through which small vessel CVD contributes to AD-related pathophysiology and neurodegeneration in adults with DS. Design: Cross sectional analysis of neuroimaging, plasma, and clinical data. Setting: Participants were enrolled in Alzheimer's Biomarker Consortium - Down Syndrome (ABC-DS), a multisite study of AD in adults with DS. Participants: One hundred eighty-five participants (mean [SD] age=45.2 [9.3] years) with available MRI and plasma biomarker data were included. White matter hyperintensity (WMH) volumes were derived from T2-weighted FLAIR MRI scans and plasma biomarker concentrations of amyloid beta (Aβ42/Aβ40), phosphorylated tau (p-tau217), astrocytosis (glial fibrillary acidic protein, GFAP), and neurodegeneration (neurofilament light chain, NfL) were measured with ultrasensitive immunoassays. Main outcomes and measures: We examined the bivariate relationships of WMH, Aβ42/Aβ40, p-tau217, and GFAP with age-residualized NfL across AD diagnostic groups. A series of mediation and path analyses examined causal pathways linking WMH and AD pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. Results: There was a direct and indirect bidirectional effect through GFAP of WMH on p-tau217 concentration, which was associated with NfL concentration in the entire sample. Among cognitively stable participants, WMH was directly and indirectly, through GFAP, associated with p-tau217 concentration, and in those with MCI, there was a direct effect of WMH on p-tau217 and NfL concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. Conclusions and relevance: The findings suggest that among individuals with DS, CVD promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of AD. This work joins an emerging literature that implicates CVD and its interface with neuroinflammation as a core pathological feature of AD in adults with DS.Item Critical review of the Appropriate Use Criteria for amyloid imaging: Effect on diagnosis and patient care(Elsevier, 2016-12-18) Apostolova, Liana G.; Haider, Janelle M.; Goukasian, Naira; Rabinovici, Gil D.; Chetelat, Gael; Ringman, John M.; Kremen, Sarah; Grill, Joshua; Restrepo, Lucas; Mendez, Mario F.; Silverman, Daniel H.; Department of Neurology, IU School of MedicineINTRODUCTION: The utility of the Appropriate Use Criteria (AUC) for amyloid imaging is not established. METHODS: Fifty-three cognitively impaired patients with clinical F18-florbetapir imaging were classified as early and late onset, as well as AUC-consistent or AUC-inconsistent. Chi-square statistics and t test were used to compare demographic characteristics and clinical outcomes as appropriate. RESULTS: Early-onset patients were more likely to be amyloid positive. Change in diagnosis was more frequent in late-onset cases. Change in therapy was more common in early-onset cases. AUC-consistent and AUC-inconsistent cases had comparable rates of amyloid positivity. We saw no difference in the rate of treatment changes in the AUC-consistent group as opposed to the AUC-inconsistent group. DISCUSSION: The primary role of amyloid imaging in the early-onset group was to confirm the clinically suspected etiology, and in the late-onset group in detecting amyloid-negative cases. The rate of therapeutic changes was significantly greater in the early-onset cases.Item Effects of Vascular Risk Factors on the Association of Blood-Based Biomarkers with Alzheimer's Disease(European Society of Medicine, 2023) Hoost, S. S.; Brickman, A. M.; Manly, J. J.; Honig, L. S.; Gu, Y.; Sanchez, D.; Reyes-Dumeyer, D.; Lantigua, R. A.; Kang, M. S.; Dage, J. L.; Mayeux, R.; Neurology, School of MedicineBackground: Comorbidities may influence the levels of blood-based biomarkers for Alzheimer's disease (AD). We investigated whether differences in risk factors or comorbid conditions might explain the discordance between clinical diagnosis and biomarker classifications in a multi-ethnic cohort of elderly individuals. Aims: To evaluate the relationship of medical conditions and other characteristics, including body mass index (BMI), vascular risk factors, and head injury, with cognitive impairment and blood-based biomarkers of AD, phosphorylated tau (P-tau 181, P-tau 217), in a multi-ethnic cohort. Methods: Three-hundred individuals, aged 65 and older, were selected from a prospective community-based cohort for equal representation among three racial/ethnic groups: non-Hispanic White, Hispanic/Latino and African American/Black. Participants were classified into four groups based on absence (Asym) or presence (Sym) of cognitive impairment and low (NEG) or high (POS) P-tau 217 or P-tau 181 levels, determined previously in the same cohort: (Asym/NEG, Asym/POS, Sym/NEG, Sym/POS). We examined differences in individual characteristics across the four groups. We performed post-hoc analysis examining the differences across biomarker and cognitive status. Results: P-tau 217 or P-tau 181 positive individuals had lower BMI than P-tau negative participants, regardless of symptom status. Symptomatic and asymptomatic participants did not differ in terms of BMI. BMI was not a mediator of the effect of P-tau 217 or P-tau 181 on dementia. Frequencies of other risk factors did not differ between the four groups of individuals. Conclusions: Participants with higher levels of P-tau 217 or P-tau 181 consistent with AD had lower BMI regardless of whether the individual was symptomatic. These findings suggest that weight loss may change with AD biomarker levels before onset of cognitive decline. They do not support BMI as a confounding variable. Further longitudinal studies could explore the relationship of risk factors with clinical diagnoses and biomarkers.Item Exploring Class‐II PI3K Inhibition for the treatment of Alzheimer’s Disease: Virtual Screening for PI3KC2A Inhibitors(Wiley, 2025-01-09) Jadala, Chetna; Robo, Michael T.; Richardson, Timothy I.; Pharmacology and Toxicology, School of MedicineBackground: Focusing on novel AD treatments, the TREAT‐AD centers offer an array of free research tools, shared via the AD Knowledge Portal in a Target Enablement Package (TEP). This abstract showcases the research conducted by the IUSM‐Purdue TREAT‐AD Center, specifically focusing on Targeting class‐II PI3K’s as a potential breakthrough in AD therapy. Endocytosis within the brain encompasses diverse pathways for internalizing extracellular cargoes and receptors into cells. The prominent routes include clathrin‐mediated endocytosis and phagocytosis. Endocytosis plays a crucial role in processing amyloid precursor protein (APP) leading to abnormal production of Aβ peptides. Recycling endosomes are vital for delivering and eventually releasing Aβ into the brain. Recent research emphasizes the pivotal role of PI3K‐C2α, a class II PI3K member, in regulated endocytosis through its clathrin‐binding domain. Its localization spans clathrin‐coated pits, endocytic vesicles, early endosomes, and the trans‐Golgi network, generating phosphatidylinositol 3‐phosphate (PtdIns(3)P) and/or phosphatidylinositol 3,4‐bisphosphates (PtdIns(3,4)P2) in vivo. Targeting clathrin‐mediated endocytosis by inhibiting PI3K‐C2α, a key regulator in clathrin coated vesicle formation, could be a potential therapeutic strategy against Alzheimer’s disease. Method: We conducted extensive virtual screenings of vast compound libraries to determine potent small molecules inhibiting PI3K‐C2α. Employing shape‐based screening, and clustering techniques, we identified leading compounds for subsequent in vitro kinase assays. Compounds exhibiting nanomolar activity were selected for further investigation. Leveraging these findings, we conducted Structure‐Activity Relationship (SAR) studies, optimizing analogs to enhance binding affinity and cellular pharmacology. Result: We have identified novel PI3K‐C2α inhibitors and are in the initial stages of optimization. These compounds exhibit promising target engagement, pending further assessment for biochemical activity and cellular pharmacology. In silico assessments suggest their structures are ideal for CNS drug discovery plans. Conclusion: Inhibiting PI3K‐C2α stands as a promising therapeutic approach for Alzheimer’s disease. We've discovered unique molecular structures that inhibit the enzyme. Our findings suggest potential probe molecules for validating the target and developing lead compounds for clinical investigations.Item Human herpesvirus‐associated transposable element activation in human aging brains with Alzheimer's disease(Wiley, 2025) Feng, Yayan; Cao, Shu-Qin; Shi, Yi; Sun, Anna; Flanagan, Margaret E.; Leverenz, James B.; Pieper, Andrew A.; Jung, Jae U.; Cummings, Jeffrey; Fang, Evandro Fei; Zhang, Pengyue; Cheng, Feixiong; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthIntroduction: Human herpesvirus (HHV) has been linked to Alzheimer's disease (AD), but the underlying mechanisms remain unknown. Methods: We leveraged functional genomics data from Religious Orders Study or the Rush Memory and Aging Project (ROS/MAP) and Mount Sinai Brain Bank (MSBB) brain biobanks and single-cell RNA-sequencing data from HHV-infected forebrain organoids to investigate HHV-infection-associated transposable element (TE) dysregulation underlying AD etiologies. Results: We identified widespread TE dysregulation in HHV-positive human AD brains, including an astrocyte-specific upregulation of LINE1 subfamily TEs in HHV-positive human AD brains. We further pinpointed astrocyte-specific LINE1 upregulation that could potentially regulate target gene NEAT1 expression via long-range enhancer-promoter chromatin interactions. This LINE1 dysregulation can be partially reversed by the usage of anti-HHV drugs (valacyclovir and acyclovir) in a virus-infected human brain organoid model. Finally, we demonstrated that valacyclovir rescued tau-associated neuropathology and alleviated LINE1 activation in an experimental tau aggregation model. Discussion: Our analysis provides associations linking molecular, clinical, and neuropathological AD features with HHV infection, which warrants future clinical validation. Highlights: Via analysis of bulk RNA-seq data in two large-scale human brain biobanks, ROS/MAP (n = 109 pathologically confirmed AD and n = 44 cognitively healthy controls) and MSBB (n = 284 AD and n = 150 cognitively healthy controls), we identified widespread TE activation in HHV-positive human AD brains and significantly positive associations of HHV RNA abundance with APOE4 genotype, Braak staging score, and CERAD score. We identified cell type-specific LINE1 upregulation in both microglia and astrocytes of human AD brains via long-range enhancer-promoter chromatin interactions on lncRNA nuclear enriched abundant transcript 1 (NEAT1). We determined that usage of valacyclovir and acyclovir was significantly associated with reduced incidence of AD in a large real-world patient database. Using the HEK293 tau P301S model and U2OS mt-Keima cell model, we determined that valacyclovir treatment rescued tau-associated neuropathology and alleviated activation of LINE1 with increased cellular autophagy-level mechanistically supported clinical benefits of valacyclovir in real-world patient data.Item Individual bioenergetic capacity as a potential source of resilience to Alzheimer's disease(medRxiv, 2024-01-24) Arnold, Matthias; Buyukozkan, Mustafa; Doraiswamy, P. Murali; Nho, Kwangsik; Wu, Tong; Gudnason, Vilmundur; Launer, Lenore J.; Wang-Sattler, Rui; Adamski, Jerzy; The Alzheimer’s Disease Neuroimaging Initiative; Alzheimer’s Disease Metabolomics Consortium; De Jager, Philip L.; Ertekin-Taner, Nilüfer; Bennett, David A.; Saykin, Andrew J.; Peters, Annette; Suhre, Karsten; Kaddurah-Daouk, Rima; Kastenmüller, Gabi; Krumsiek, Jan; Radiology and Imaging Sciences, School of MedicineImpaired glucose uptake in the brain is one of the earliest presymptomatic manifestations of Alzheimer's disease (AD). The absence of symptoms for extended periods of time suggests that compensatory metabolic mechanisms can provide resilience. Here, we introduce the concept of a systemic 'bioenergetic capacity' as the innate ability to maintain energy homeostasis under pathological conditions, potentially serving as such a compensatory mechanism. We argue that fasting blood acylcarnitine profiles provide an approximate peripheral measure for this capacity that mirrors bioenergetic dysregulation in the brain. Using unsupervised subgroup identification, we show that fasting serum acylcarnitine profiles of participants from the AD Neuroimaging Initiative yields bioenergetically distinct subgroups with significant differences in AD biomarker profiles and cognitive function. To assess the potential clinical relevance of this finding, we examined factors that may offer diagnostic and therapeutic opportunities. First, we identified a genotype affecting the bioenergetic capacity which was linked to succinylcarnitine metabolism and significantly modulated the rate of future cognitive decline. Second, a potentially modifiable influence of beta-oxidation efficiency seemed to decelerate bioenergetic aging and disease progression. Our findings, which are supported by data from more than 9,000 individuals, suggest that interventions tailored to enhance energetic health and to slow bioenergetic aging could mitigate the risk of symptomatic AD, especially in individuals with specific mitochondrial genotypes.Item INPP5D expression is associated with risk for Alzheimer’s disease and induced by plaque-associated microglia(Elsevier, 2021-06) Tsai, Andy P.; Bor-Chian, Lin Peter; Dong, Chuanpeng; Moutinho, Miguel; Casali, Brad T.; Liu, Yunlong; Lamb, Bruce T.; Landreth, Gary E.; Oblak, Adrian L.; Nho, Kwangsik; Medical and Molecular Genetics, School of MedicineAlzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, robust microgliosis, neuroinflammation, and neuronal loss. Genome-wide association studies recently highlighted a prominent role for microglia in late-onset AD (LOAD). Specifically, inositol polyphosphate-5-phosphatase (INPP5D), also known as SHIP1, is selectively expressed in brain microglia and has been reported to be associated with LOAD. Although INPP5D is likely a crucial player in AD pathophysiology, its role in disease onset and progression remains unclear. We performed differential gene expression analysis to investigate INPP5D expression in AD and its association with plaque density and microglial markers using transcriptomic (RNA-Seq) data from the Accelerating Medicines Partnership for Alzheimer's Disease (AMP-AD) cohort. We also performed quantitative real-time PCR, immunoblotting, and immunofluorescence assays to assess INPP5D expression in the 5xFAD amyloid mouse model. Differential gene expression analysis found that INPP5D expression was upregulated in LOAD and positively correlated with amyloid plaque density. In addition, in 5xFAD mice, Inpp5d expression increased as the disease progressed, and selectively in plaque-associated microglia. Increased Inpp5d expression levels in 5xFAD mice were abolished entirely by depleting microglia with the colony-stimulating factor receptor-1 antagonist PLX5622. Our findings show that INPP5D expression increases as AD progresses, predominantly in plaque-associated microglia. Importantly, we provide the first evidence that increased INPP5D expression might be a risk factor in AD, highlighting INPP5D as a potential therapeutic target. Moreover, we have shown that the 5xFAD mouse model is appropriate for studying INPP5D in AD.Item Key inflammatory pathway activations in the MCI stage of Alzheimer's disease(Wiley, 2019-07) Pillai, Jagan A.; Maxwell, Sean; Bena, James; Bekris, Lynn M.; Rao, Stephen M.; Chance, Mark; Lamb, Bruce T.; Leverenz, James B.; Neurology, School of MedicineOBJECTIVE: To determine the key inflammatory pathways that are activated in the peripheral and CNS compartments at the mild cognitive impairment (MCI) stage of Alzheimer's disease (AD). METHODS: A cross-sectional study of patients with clinical and biomarker characteristics consistent with MCI-AD in a discovery cohort, with replication in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Inflammatory analytes were measured in the CSF and plasma with the same validated multiplex analyte platform in both cohorts and correlated with AD biomarkers (CSF Aβ42, total tau (t-tau), phosphorylated tau (p-tau) to identify key inflammatory pathway activations. The pathways were additionally validated by evaluating genes related to all analytes in coexpression networks of brain tissue transcriptome from an autopsy confirmed AD cohort to interrogate if the same pathway activations were conserved in the brain tissue gene modules. RESULTS: Analytes of the tumor necrosis factor (TNF) signaling pathway (KEGG ID:4668) in the CSF and plasma best correlated with CSF t-tau and p-tau levels, and analytes of the complement and coagulation pathway (KEGG ID:4610) best correlated with CSF Aβ42 levels. The top inflammatory signaling pathways of significance were conserved in the peripheral and the CNS compartments. They were also confirmed to be enriched in AD brain transcriptome gene clusters. INTERPRETATION: A cell-protective rather than a proinflammatory analyte profile predominates in the CSF in relation to neurodegeneration markers among MCI-AD patients. Analytes from the TNF signaling and the complement and coagulation pathways are relevant in evaluating disease severity at the MCI stage of AD.