Browsing by Author "Holtzman, David M."
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Item Aducanumab anti-amyloid immunotherapy induces sustained microglial and immune alterations(Rockefeller University, 2024) Cadiz, Mika P.; Gibson, Katelin A.; Todd, Kennedi T.; Nascari, David G.; Massa, Nashali; Lilley, Meredith T.; Olney, Kimberly C.; Al-Amin, Md Mamun; Jiang, Hong; Holtzman, David M.; Fryer, John D.; Medical and Molecular Genetics, School of MedicineAducanumab, an anti-amyloid immunotherapy for Alzheimer's disease, efficiently reduces Aβ, though its plaque clearance mechanisms, long-term effects, and effects of discontinuation are not fully understood. We assessed the effect of aducanumab treatment and withdrawal on Aβ, neuritic dystrophy, astrocytes, and microglia in the APP/PS1 amyloid mouse model. We found that reductions in amyloid and neuritic dystrophy during acute treatment were accompanied by microglial and astrocytic activation, and microglial recruitment to plaques and adoption of an aducanumab-specific pro-phagocytic and pro-degradation transcriptomic signature, indicating a role for microglia in aducanumab-mediated Aβ clearance. Reductions in Aβ and dystrophy were sustained 15 but not 30 wk after discontinuation, and reaccumulation of plaques coincided with loss of the microglial aducanumab signature and failure of microglia to reactivate. This suggests that despite the initial benefit from treatment, microglia are unable to respond later to restrain plaque reaccumulation, making further studies on the effect of amyloid-directed immunotherapy withdrawal crucial for assessing long-term safety and efficacy.Item Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference(Wiley, 2024) Kloske, Courtney M.; Belloy, Michael E.; Blue, Elizabeth E.; Bowman, Gregory R.; Carrillo, Maria C.; Chen, Xiaoying; Chiba-Falek, Ornit; Davis, Albert A.; Di Paolo, Gilbert; Garretti, Francesca; Gate, David; Golden, Lesley R.; Heinecke, Jay W.; Herz, Joachim; Huang, Yadong; Iadecola, Costantino; Johnson, Lance A.; Kanekiyo, Takahisa; Karch, Celeste M.; Khvorova, Anastasia; Koppes-den Hertog, Sascha J.; Lamb, Bruce T.; Lawler, Paige E.; Le Guen, Yann; Litvinchuk, Alexandra; Liu, Chia-Chen; Mahinrad, Simin; Marcora, Edoardo; Marino, Claudia; Michaelson, Danny M.; Miller, Justin J.; Morganti, Josh M.; Narayan, Priyanka S.; Naslavsky, Michel S.; Oosthoek, Marlies; Ramachandran, Kapil V.; Ramakrishnan, Abhirami; Raulin, Ana-Caroline; Robert, Aiko; Saleh, Rasha N. M.; Sexton, Claire; Shah, Nilomi; Shue, Francis; Sible, Isabel J.; Soranno, Andrea; Strickland, Michael R.; Tcw, Julia; Thierry, Manon; Tsai, Li-Huei; Tuckey, Ryan A.; Ulrich, Jason D.; van der Kant, Rik; Wang, Na; Wellington, Cheryl L.; Weninger, Stacie C.; Yassine, Hussein N.; Zhao, Na; Bu, Guojun; Goate, Alison M.; Holtzman, David M.; Neurology, School of MedicineIntroduction: The apolipoprotein E gene (APOE) is an established central player in the pathogenesis of Alzheimer's disease (AD), with distinct apoE isoforms exerting diverse effects. apoE influences not only amyloid-beta and tau pathologies but also lipid and energy metabolism, neuroinflammation, cerebral vascular health, and sex-dependent disease manifestations. Furthermore, ancestral background may significantly impact the link between APOE and AD, underscoring the need for more inclusive research. Methods: In 2023, the Alzheimer's Association convened multidisciplinary researchers at the "AAIC Advancements: APOE" conference to discuss various topics, including apoE isoforms and their roles in AD pathogenesis, progress in apoE-targeted therapeutic strategies, updates on disease models and interventions that modulate apoE expression and function. Results: This manuscript presents highlights from the conference and provides an overview of opportunities for further research in the field. Discussion: Understanding apoE's multifaceted roles in AD pathogenesis will help develop targeted interventions for AD and advance the field of AD precision medicine. Highlights: APOE is a central player in the pathogenesis of Alzheimer's disease. APOE exerts a numerous effects throughout the brain on amyloid-beta, tau, and other pathways. The AAIC Advancements: APOE conference encouraged discussions and collaborations on understanding the role of APOE.Item Apolipoprotein E4 influences amyloid deposition but not cell loss after traumatic brain injury in a mouse model of Alzheimer's disease(Society for Neuroscience, 2002-12) Hartman, Richard E.; Laurer, Helmut; Longhi, Luca; Bales, Kelly R.; Paul, Steven M.; McIntosh, Tracy K.; Holtzman, David M.; Pharmacology and Toxicology, School of MedicineThe epsilon4 allele of apolipoprotein E (APOE) and traumatic brain injury (TBI) are both risk factors for the development of Alzheimer's disease (AD). These factors may act synergistically, in that APOE4+ individuals are more likely to develop dementia after TBI. Because the mechanism underlying these effects is unclear, we questioned whether APOE4 and TBI interact either through effects on amyloid-beta (Abeta) or by enhancing cell death/tissue injury. We assessed the effects of TBI in PDAPP mice (transgenic mice that develop AD-like pathology) expressing human APOE3 (PDAPP:E3), human APOE4 (PDAPP:E4), or no APOE (PDAPP:E-/-). Mice were subjected to a unilateral cortical impact injury at 9-10 months of age and allowed to survive for 3 months. Abeta load, hippocampal/cortical volumes, and hippocampal CA3 cell loss were quantified using stereological methods. All of the groups contained mice with Abeta-immunoreactive deposits (56% PDAPP:E4, 20% PDAPP:E3, 75% PDAPP:E-/-), but thioflavine-S-positive Abeta (amyloid) was present only in the molecular layer of the dentate gyrus in the PDAPP:E4 mice (44%). In contrast, our previous studies showed that in the absence of TBI, PDAPP:E3 and PDAPP:E4 mice have little to no Abeta deposition at this age. After TBI, all of the Abeta deposits present in PDAPP:E3 and PDAPP:E-/- mice were diffuse plaques. In contrast to the effect of APOE4 on amyloid, PDAPP:E3, PDAPP:E4, and PDAPP:E-/- mice did not differ in the amount of brain tissue or cell loss. These data support the hypothesis that APOE4 influences the neurodegenerative cascade after TBI via an effect on Abeta.Item BDNF Val66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer’s disease(Oxford, 2016-10) Lim, Yen Ying; Hassenstab, Jason; Cruchaga, Carlos; Goate, Alison; Fagan, Anne M.; Benzinger, Tammie L. S.; Maruff, Paul; Snyder, Peter J.; Masters, Colin L.; Allegri, Ricardo; Chhatwal, Jasmeer; Farlow, Martin R.; Graff-Radford, Neill R.; Laske, Christoph; Levin, Johannes; McDade, Eric; Ringman, John M.; Rossor, Martin N.; Salloway, Stephen; Schofield, Peter R.; Holtzman, David M.; Morris, John C.; Bateman, Randall J.; Department of Neurology, IU School of MedicineThe brain-derived neurotrophic factor ( BDNF ) Val66Met polymorphism is implicated in synaptic excitation and neuronal integrity, and has previously been shown to moderate amyloid-β-related memory decline and hippocampal atrophy in preclinical sporadic Alzheimer’s disease. However, the effect of BDNF in autosomal dominant Alzheimer’s disease is unknown. We aimed to determine the effect of BDNF Val66Met on cognitive function, hippocampal function, tau and amyloid-β in preclinical autosomal dominant Alzheimer’s disease. We explored effects of apolipoprotein E ( APOE ) ε4 on these relationships. The Dominantly Inherited Alzheimer Network conducted clinical, neuropsychological, genetic, biomarker and neuroimaging measures at baseline in 131 mutation non-carriers and 143 preclinical autosomal dominant Alzheimer’s disease mutation carriers on average 12 years before clinical symptom onset. BDNF genotype data were obtained for mutation carriers (95 Val 66 homozygotes, 48 Met 66 carriers). Among preclinical mutation carriers, Met 66 carriers had worse memory performance, lower hippocampal glucose metabolism and increased levels of cerebrospinal fluid tau and phosphorylated tau (p-tau) than Val 66 homozygotes. Cortical amyloid-β and cerebrospinal fluid amyloid-β 42 levels were significantly different from non-carriers but did not differ between preclinical mutation carrier Val 66 homozygotes and Met 66 carriers. There was an effect of APOE on amyloid-β levels, but not cognitive function, glucose metabolism or tau. As in sporadic Alzheimer’s disease, the deleterious effects of amyloid-β on memory, hippocampal function, and tau in preclinical autosomal dominant Alzheimer’s disease mutation carriers are greater in Met 66 carriers. To date, this is the only genetic factor found to moderate downstream effects of amyloid-β in autosomal dominant Alzheimer’s disease.Item Genome-wide association study identifies four novel loci associated with Alzheimer's endophenotypes and disease modifiers(Springer Verlag, 2017-05) Deming, Yuetiva; Li, Zeran; Kapoor, Manav; Harari, Oscar; Del-Aguila, Jorge L.; Black, Kathleen; Carrell, David; Cai, Yefei; Fernandez, Maria Victoria; Budde, John; Ma, Shengmei; Saef, Benjamin; Howells, Bill; Huang, Kuanlin; Bertelsen, Sarah; Fagan, Anne M.; Holtzman, David M.; Morris, John C.; Kim, Sungeun; Saykin, Andrew J.; De Jager, Philip L.; Albert, Marilyn; Moghekar, Abhay; O’Brien, Richard; Riemenschneider, Matthias; Petersen, Ronald C.; Blennow, Kaj; Zetterberg, Henrik; Minthon, Lennart; Van Deerlin, Vivianna M.; Lee, Virginia Man-Yee; Shaw, Leslie M.; Trojanowski, John Q.; Schellenberg, Gerard; Haines, Jonathan L.; Mayeux, Richard; Pericak-Vance, Margaret A.; Farrer, Lindsay A.; Peskind, Elaine R.; Li, Ge; Di Narzo, Antonio F.; Alzheimer’s Disease Neuroimaging Initiative (ADGC). The Alzheimer Disease Genetic Consortium (ADGC); Kauwe, John S. K.; Goate, Alison M.; Cruchaga, Carlos; Medicine, School of MedicineMore than 20 genetic loci have been associated with risk for Alzheimer's disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased statistical power to identify variants that may not pass the stringent multiple test correction in case-control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS). We conducted GWAS of amyloid beta (Aβ42), tau, and phosphorylated tau (ptau181) levels in cerebrospinal fluid (CSF) from 3146 participants across nine studies to identify novel variants associated with AD. Five genome-wide significant loci (two novel) were associated with ptau181, including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with Aβ42 near GLIS1 on 1p32.3 (β = -0.059, P = 2.08 × 10-8) and within SERPINB1 on 6p25 (β = -0.025, P = 1.72 × 10-8) were also associated with AD risk (GLIS1: OR = 1.105, P = 3.43 × 10-2), disease progression (GLIS1: β = 0.277, P = 1.92 × 10-2), and age at onset (SERPINB1: β = 0.043, P = 4.62 × 10-3). Bioinformatics indicate that the intronic SERPINB1 variant (rs316341) affects expression of SERPINB1 in various tissues, including the hippocampus, suggesting that SERPINB1 influences AD through an Aβ-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF Aβ42 (P = 0.001 and P = 0.009, respectively) and the INPP5D locus may affect ptau181 levels (P = 0.009); larger studies are necessary to verify these results. Together the findings from this study can be used to inform future AD studies.Item Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy(Springer Nature, 2021) Da Mesquita, Sandro; Papadopoulos, Zachary; Dykstra, Taitea; Brase, Logan; Farias, Fabiana Geraldo; Wall, Morgan; Jiang, Hong; Kodira, Chinnappa Dilip; de Lima, Kalil Alves; Herz, Jasmin; Louveau, Antoine; Goldman, Dylan H.; Salvador, Andrea Francesca; Onengut-Gumuscu, Suna; Farber, Emily; Dabhi, Nisha; Kennedy, Tatiana; Milam, Mary Grace; Baker, Wendy; Smirnov, Igor; Rich, Stephen S.; Dominantly Inherited Alzheimer Network; Benitez, Bruno A.; Karch, Celeste M.; Perrin, Richard J.; Farlow, Martin; Chhatwal, Jasmeer P.; Holtzman, David M.; Cruchaga, Carlos; Harari, Oscar; Kipnis, Jonathan; Neurology, School of MedicineAlzheimer's disease (AD) is the most prevalent cause of dementia1. Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aβ) is a promising therapeutic strategy2,3. Meningeal lymphatic drainage has an important role in the accumulation of Aβ in the brain4, but it is not known whether modulation of meningeal lymphatic function can influence the outcome of immunotherapy in AD. Here we show that ablation of meningeal lymphatic vessels in 5xFAD mice (a mouse model of amyloid deposition that expresses five mutations found in familial AD) worsened the outcome of mice treated with anti-Aβ passive immunotherapy by exacerbating the deposition of Aβ, microgliosis, neurovascular dysfunction, and behavioural deficits. By contrast, therapeutic delivery of vascular endothelial growth factor C improved clearance of Aβ by monoclonal antibodies. Notably, there was a substantial overlap between the gene signature of microglia from 5xFAD mice with impaired meningeal lymphatic function and the transcriptional profile of activated microglia from the brains of individuals with AD. Overall, our data demonstrate that impaired meningeal lymphatic drainage exacerbates the microglial inflammatory response in AD and that enhancement of meningeal lymphatic function combined with immunotherapies could lead to better clinical outcomes.Item Resting-State Functional Connectivity Disruption as a Pathological Biomarker in Autosomal Dominant Alzheimer Disease(Mary Ann Liebert, 2021) Smith, Robert X.; Strain, Jeremy F.; Tanenbaum, Aaron; Fagan, Anne M.; Hassenstab, Jason; McDade, Eric; Schindler, Suzanne E.; Gordon, Brian A.; Xiong, Chengjie; Chhatwal, Jasmeer; Jack, Clifford, Jr.; Karch, Celeste; Berman, Sarah; Brosch, Jared R.; Lah, James J.; Brickman, Adam M.; Cash, David M.; Fox, Nick C.; Graff-Radford, Neill R.; Levin, Johannes; Noble, James; Holtzman, David M.; Masters, Colin L.; Farlow, Martin R.; Laske, Christoph; Schofield, Peter R.; Marcus, Daniel S.; Morris, John C.; Benzinger, Tammie L. S.; Bateman, Randall J.; Ances, Beau M.; Neurology, School of MedicineAim: Identify a global resting-state functional connectivity (gFC) signature in mutation carriers (MC) from the Dominantly Inherited Alzheimer Network (DIAN). Assess the gFC with regard to amyloid (A), tau (T), and neurodegeneration (N) biomarkers, and estimated years to symptom onset (EYO). Introduction: Cross-sectional measures were assessed in MC (n = 171) and mutation noncarrier (NC) (n = 70) participants. A functional connectivity (FC) matrix that encompassed multiple resting-state networks was computed for each participant. Methods: A global FC was compiled as a single index indicating FC strength. The gFC signature was modeled as a nonlinear function of EYO. The gFC was linearly associated with other biomarkers used for assessing the AT(N) framework, including cerebrospinal fluid (CSF), positron emission tomography (PET) molecular biomarkers, and structural magnetic resonance imaging. Results: The gFC was reduced in MC compared with NC participants. When MC participants were differentiated by clinical dementia rating (CDR), the gFC was significantly decreased in MC CDR >0 (demented) compared with either MC CDR 0 (cognitively normal) or NC participants. The gFC varied nonlinearly with EYO and initially decreased at EYO = −24 years, followed by a stable period followed by a further decline near EYO = 0 years. Irrespective of EYO, a lower gFC associated with values of amyloid PET, CSF Aβ1–42, CSF p-tau, CSF t-tau, 18F-fluorodeoxyglucose, and hippocampal volume. Conclusions: The gFC correlated with biomarkers used for defining the AT(N) framework. A biphasic change in the gFC suggested early changes associated with CSF amyloid and later changes associated with hippocampal volume.Item White matter hyperintensities and the mediating role of cerebral amyloid angiopathy in dominantly-inherited Alzheimer's disease(Public Library of Science, 2018-05-09) Lee, Seonjoo; Zimmerman, Molly E.; Narkhede, Atul; Nasrabady, Sara E.; Tosto, Giuseppe; Meier, Irene B.; Benzinger, Tammie L. S.; Marcus, Daniel S.; Fagan, Anne M.; Fox, Nick C.; Cairns, Nigel J.; Holtzman, David M.; Buckles, Virginia; Ghetti, Bernardino; McDade, Eric; Martins, Ralph N.; Saykin, Andrew J.; Masters, Colin L.; Ringman, John M.; Fӧrster, Stefan; Schofield, Peter R.; Sperling, Reisa A. n; Johnson, Keith A. n; Chhatwal, Jasmeer P.; Salloway, Stephen; Correia, Stephen; Jack, Clifford R., Jr.; Weiner, Michael; Bateman, Randall J.; Morris, John C.; Mayeux, Richard; Brickman, Adam M.; Dominantly Inherited Alzheimer Network; Pathology and Laboratory Medicine, School of MedicineINTRODUCTION: White matter hyperintensity (WMH) volume on MRI is increased among presymptomatic individuals with autosomal dominant mutations for Alzheimer's disease (AD). One potential explanation is that WMH, conventionally considered a marker of cerebrovascular disease, are a reflection of cerebral amyloid angiopathy (CAA) and that increased WMH in this population is a manifestation of this vascular form of primary AD pathology. We examined whether the presence of cerebral microbleeds, a marker of CAA, mediates the relationship between WMH and estimated symptom onset in individuals with and without autosomal dominant mutations for AD. PARTICIPANTS AND METHODS: Participants (n = 175, mean age = 41.1 years) included 112 with an AD mutation and 63 first-degree non-carrier controls. We calculated the estimated years from expected symptom onset (EYO) and analyzed baseline MRI data for WMH volume and presence of cerebral microbleeds. Mixed effects regression and tests of mediation were used to examine microbleed and WMH differences between carriers and non-carriers and to test the whether the association between WMH and mutation status is dependent on the presence of microbleeds. RESULTS: Mutation carriers were more likely to have microbleeds than non-carriers (p<0.05) and individuals with microbleeds had higher WMH volume than those without (p<0.05). Total WMH volume was increased in mutation carriers compared with non-carriers, up to 20 years prior to EYO, after controlling for microbleed status, as we demonstrated previously. Formal testing of mediation demonstrated that 21% of the association between mutation status and WMH was mediated by presence of microbleeds (p = 0.03) but a significant direct effect of WMH remained (p = 0.02) after controlling for presence of microbleeds. DISCUSSION: Although there is some co-dependency between WMH and microbleeds, the observed increases in WMH among mutation carriers does not appear to be fully mediated by this marker of CAA. The findings highlight the possibility that WMH represent a core feature of AD independent of vascular forms of beta amyloid.Item White matter hyperintensities are a core feature of Alzheimer's disease: Evidence from the dominantly inherited Alzheimer network(Wiley, 2016-06) Lee, Seonjoo; Viqar, Fawad; Zimmerman, Molly E.; Narkhede, Atul; Tosto, Giuseppe; Benzinger, Tammie L.S.; Marcus, Daniel S.; Fagan, Anne M.; Goate, Alison; Fox, Nick C.; Cairns, Nigel J.; Holtzman, David M.; Buckles, Virginia; Ghetti, Bernardino; McDade, Eric; Martins, Ralph N.; Saykin, Andrew J.; Masters, Colin L.; Ringman, John M.; Ryan, Natalie S.; Förster, Stefan; Laske, Christoph; Schofield, Peter R.; Sperling, Reisa A.; Salloway, Stephen; Correia, Stephen; Jack, Clifford; Weiner, Michael; Bateman, Randall J.; Morris, John C.; Mayeux, Richard; Brickman, Adam M.; Dominantly Inherited Alzheimer Network; Department of Pathology and Laboratory Medicine, School of MedicineWhite matter hyperintensities (WMHs) are areas of increased signal on T2-weighted magnetic resonance imaging (MRI) scans that most commonly reflect small vessel cerebrovascular disease. Increased WMH volume is associated with risk and progression of Alzheimer's disease (AD). These observations are typically interpreted as evidence that vascular abnormalities play an additive, independent role contributing to symptom presentation, but not core features of AD. We examined the severity and distribution of WMH in presymptomatic PSEN1, PSEN2, and APP mutation carriers to determine the extent to which WMH manifest in individuals genetically determined to develop AD.