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Browsing by Author "Karch, Celeste M."
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Item Awareness of Genetic Risk in the Dominantly Inherited Alzheimer Network (DIAN)(Wiley, 2020-01) Aschenbrenner, Andrew J.; James, Bryan D.; McDade, Eric; Wang, Guoqiao; Lim, Yen Ying; Benzinger, Tammie L.S.; Cruchaga, Carlos; Goate, Alison; Xiong, Chengjie; Perrin, Richard; Buckles, Virginia; Allegri, Ricardo; Berman, Sarah B.; Chhatwal, Jasmeer P.; Fagan, Anne; Farlow, Martin; O'Connor, Antoinette; Ghetti, Bernardino; Graff-Radford, Neill; Goldman, Jill; Gräber, Susanne; Karch, Celeste M.; Lee, Jae-Hong; Levin, Johannes; Martins, Ralph N.; Masters, Colin; Mori, Hiroshi; Noble, James; Salloway, Stephen; Schofield, Peter; Morris, John C.; Bateman, Randall J.; Hassenstab, Jason; Neurology, School of MedicineIntroduction: Although some members of families with autosomal dominant Alzheimer's disease mutations learn their mutation status, most do not. How knowledge of mutation status affects clinical disease progression is unknown. This study quantifies the influence of mutation awareness on clinical symptoms, cognition, and biomarkers. Methods: Mutation carriers and non-carriers from the Dominantly Inherited Alzheimer Network (DIAN) were stratified based on knowledge of mutation status. Rates of change on standard clinical, cognitive, and neuroimaging outcomes were examined. Results: Mutation knowledge had no associations with cognitive decline, clinical progression, amyloid deposition, hippocampal volume, or depression in either carriers or non-carriers. Carriers who learned their status mid-study had slightly higher levels of depression and lower cognitive scores. Discussion: Knowledge of mutation status does not affect rates of change on any measured outcome. Learning of status mid-study may confer short-term changes in cognitive functioning, or changes in cognition may influence the determination of mutation status.Item Change in Cerebrospinal Fluid Tau Microtubule Binding Region Detects Symptom Onset, Cognitive Decline, Tangles, and Atrophy in Dominantly Inherited Alzheimer's Disease(Wiley, 2023) Horie, Kanta; Li, Yan; Barthélemy, Nicolas R.; Gordon, Brian; Hassenstab, Jason; Benzinger, Tammie L. S.; Fagan, Anne M.; Morris, John C.; Karch, Celeste M.; Xiong, Chengjie; Allegri, Ricardo; Mendez, Patricio Chrem; Ikeuchi, Takeshi; Kasuga, Kensaku; Noble, James; Farlow, Martin; Chhatwal, Jasmeer; Day, Gregory; Schofield, Peter R.; Masters, Colin L.; Levin, Johannes; Jucker, Mathias; Lee, Jae-Hong; Roh, Jee Hoon; Sato, Chihiro; Sachdev, Pallavi; Koyama, Akihiko; Reyderman, Larisa; Bateman, Randall J.; McDade, Eric; Dominantly Inherited Alzheimer Network; Neurology, School of MedicineObjective: Identifying cerebrospinal fluid measures of the microtubule binding region of tau (MTBR-tau) species that reflect tau aggregation could provide fluid biomarkers that track Alzheimer's disease related neurofibrillary tau pathological changes. We examined the cerebrospinal fluid (CSF) MTBR-tau species in dominantly inherited Alzheimer's disease (DIAD) mutation carriers to assess the association with Alzheimer's disease (AD) biomarkers and clinical symptoms. Methods: Cross-sectional and longitudinal CSF from 229 DIAD mutation carriers and 130 mutation non-carriers had sequential characterization of N-terminal/mid-domain phosphorylated tau (p-tau) followed by MTBR-tau species and tau positron emission tomography (tau PET), other soluble tau and amyloid biomarkers, comprehensive clinical and cognitive assessments, and brain magnetic resonance imaging of atrophy. Results: CSF MTBR-tau species located within the putative "border" region and one species corresponding to the "core" region of aggregates in neurofibrillary tangles (NFTs) increased during the presymptomatic stage and decreased during the symptomatic stage. The "border" MTBR-tau species were associated with amyloid pathology and CSF p-tau; whereas the "core" MTBR-tau species were associated stronger with tau PET and CSF measures of neurodegeneration. The ratio of the border to the core species provided a continuous measure of increasing amounts that tracked clinical progression and NFTs. Interpretation: Changes in CSF soluble MTBR-tau species preceded the onset of dementia, tau tangle increase, and atrophy in DIAD. The ratio of 4R-specific MTBR-tau (border) to the NFT (core) MTBR-tau species corresponds to the pathology of NFTs in DIAD and change with disease progression. The dynamics between different MTBR-tau species in the CSF may serve as a marker of tau-related disease progression and target engagement of anti-tau therapeutics.Item Comparing cortical signatures of atrophy between late-onset and autosomal dominant Alzheimer disease(Elsevier, 2020) Dincer, Aylin; Gordon, Brian A.; Hari-Raj, Amrita; Keefe, Sarah J.; Flores, Shaney; McKay, Nicole S.; Paulick, Angela M.; Shady Lewis, Kristine E.; Feldman, Rebecca L.; Hornbeck, Russ C.; Allegri, Ricardo; Ances, Beau M.; Berman, Sarah B.; Brickman, Adam M.; Brooks, William S.; Cash, David M.; Chhatwal, Jasmeer P.; Farlow, Martin R.; la Fougère, Christian; Fox, Nick C.; Fulham, Michael J.; Jack, Clifford R., Jr.; Joseph-Mathurin, Nelly; Karch, Celeste M.; Lee, Athene; Levin, Johannes; Masters, Colin L.; McDade, Eric M.; Oh, Hwamee; Perrin, Richard J.; Raji, Cyrus; Salloway, Stephen P.; Schofield, Peter R.; Su, Yi; Villemagne, Victor L.; Wang, Qing; Weiner, Michael W.; Xiong, Chengjie; Yakushev, Igor; Morris, John C.; Bateman, Randall J.; Benzinger, Tammie L.S.; Neurology, School of MedicineDefining a signature of cortical regions of interest preferentially affected by Alzheimer disease (AD) pathology may offer improved sensitivity to early AD compared to hippocampal volume or mesial temporal lobe alone. Since late-onset Alzheimer disease (LOAD) participants tend to have age-related comorbidities, the younger-onset age in autosomal dominant AD (ADAD) may provide a more idealized model of cortical thinning in AD. To test this, the goals of this study were to compare the degree of overlap between the ADAD and LOAD cortical thinning maps and to evaluate the ability of the ADAD cortical signature regions to predict early pathological changes in cognitively normal individuals. We defined and analyzed the LOAD cortical maps of cortical thickness in 588 participants from the Knight Alzheimer Disease Research Center (Knight ADRC) and the ADAD cortical maps in 269 participants from the Dominantly Inherited Alzheimer Network (DIAN) observational study. Both cohorts were divided into three groups: cognitively normal controls (nADRC = 381; nDIAN = 145), preclinical (nADRC = 153; nDIAN = 76), and cognitively impaired (nADRC = 54; nDIAN = 48). Both cohorts underwent clinical assessments, 3T MRI, and amyloid PET imaging with either 11C-Pittsburgh compound B or 18F-florbetapir. To generate cortical signature maps of cortical thickness, we performed a vertex-wise analysis between the cognitively normal controls and impaired groups within each cohort using six increasingly conservative statistical thresholds to determine significance. The optimal cortical map among the six statistical thresholds was determined from a receiver operating characteristic analysis testing the performance of each map in discriminating between the cognitively normal controls and preclinical groups. We then performed within-cohort and cross-cohort (e.g. ADAD maps evaluated in the Knight ADRC cohort) analyses to examine the sensitivity of the optimal cortical signature maps to the amyloid levels using only the cognitively normal individuals (cognitively normal controls and preclinical groups) in comparison to hippocampal volume. We found the optimal cortical signature maps were sensitive to early increases in amyloid for the asymptomatic individuals within their respective cohorts and were significant beyond the inclusion of hippocampus volume, but the cortical signature maps performed poorly when analyzing across cohorts. These results suggest the cortical signature maps are a useful MRI biomarker of early AD-related neurodegeneration in preclinical individuals and the pattern of decline differs between LOAD and ADAD.Item Comparison of amyloid accumulation between Down syndrome and autosomal-dominant Alzheimer disease(Wiley, 2022) Boerwinkle, Anna H.; Gordon, Brian A.; Wisch, Julie K.; Flores, Shaney; Henson, Rachel L.; Butt, Omar Hameed; Chen, Charles D.; Benzinger, Tammie L. S.; Fagan, Anne M.; Handen, Benjamin L.; Christian, Bradley T.; Head, Elizabeth; Mapstone, Mark; Klunk, William E.; Rafii, Michael S.; O’Bryant, Sid E.; Price, Julie C.; Schupf, Nicole; Laymon, Charles M.; Krinsky-McHale, Sharon J.; Lai, Florence; Rosas, H. Diana; Hartley, Sigan L.; Zaman, Shahid; Lott, Ira T.; Silverman, Wayne; Brickman, Adam M.; Lee, Joseph H.; Allegri, Ricardo Francisco; Berman, Sarah; Chhatwal, Jasmeer P.; Chui, Helena C.; Cruchaga, Carlos; Farlow, Martin R.; Fox, Nick C.; Goate, Alison; Day, Gregory S.; Graff-Radford, Neill R.; Jucker, Mathias; Lee, Jae-Hong; Levin, Johannes; Martins, Ralph N.; Mori, Hiroshi; Perrin, Richard J.; Salloway, Stephen P.; Sanchez-Valle, Raquel; Schofield, Peter R.; Xiong, Chengjie; Karch, Celeste M.; Hassenstab, Jason J.; McDade, Eric; Bateman, Randall J.; Ances, Beau M.; Neurology, School of MedicineBackground: Given the triplication of chromosome 21 and the location of the amyloid precursor protein gene on chromosome 21, almost all adults with Down syndrome (DS) develop Alzheimer disease (AD)-like pathology and dementia during their lifetime. Comparing amyloid accumulation in DS to autosomal dominant AD (ADAD), another genetic form of AD, may improve our understanding of early AD pathology development. Method: We assessed amyloid positron emission tomography (PET) imaging in 192 participants with DS and 33 sibling controls from the Alzheimer’s Biomarker Consortium-Down Syndrome (ABC-DS) and 265 mutation-carriers (MC) and 169 familial controls from the Dominantly Inherited Alzheimer Network (DIAN) (Table 1). We calculated regional standard uptake value ratios (SUVR) using a cerebellar cortex reference region and converted global amyloid burden SUVR to centiloids. We compared amyloid PET by cognitive status and estimated-years-to-symptom-onset (EYO). EYO was calculated for DIAN participants by subtracting their age from parental age of symptom onset and for ABC-DS participants by subtracting their age from 50.2 years, a published average age of symptom onset in a large sample of individuals with DS (Fortea et al., 2020). In a subset of participants, we assessed the relationship between amyloid PET and CSF Aβ42/40. Result: The relationship between CSF Aβ42/40 and amyloid PET was similar in DS and MC participants (Figure 1). We did not observe significant differences between MC and DS grouped by cognitive status (Figure 2). However, when assessed over EYO, global amyloid burden was significantly elevated in MC at EYO ≥ -23 but was not elevated in DS until EYO ≥ -15 (Figure 3). We observed early cortical and subcortical amyloid PET increases in both groups, but we also measured some regional differences in amyloid PET changes between MC and DS, specifically in the medial occipital region (Figure 4 and 5). Conclusion: These results demonstrate similarities in the relationship between amyloid biomarkers and the levels of amyloid accumulation in ADAD and DS. However, we also observed a 5-10 year delay and some regional differences in amyloid accumulation in DS. This is important for future clinical trials to consider when recruiting participants and determining treatment efficacy.Item Human fibroblast and stem cell resource from the Dominantly Inherited Alzheimer Network(BMC, 2018-07-25) Karch, Celeste M.; Hernández, Damián Hernández; Wang, Jen-Chyong; Marsh, Jacob; Hewit, Alex W.; Hsu, Simon; Norton, Joanne; Levitch, Denise; Donahue, Tamara; Sigurdson, Wendy; Ghetti, Bernardino; Farlow, Martin; Chhatwal, Jasmeer; Berman, Sarah; Cruchaga, Carlos; Morris, John C.; Bateman, Randall J.; Dominantly Inherited Alzheimer Network (DIAN); Pébay, Alice; Goate, Alison M.; Pathology and Laboratory Medicine, School of MedicineBACKGROUND: Mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) cause autosomal dominant forms of Alzheimer disease (ADAD). More than 280 pathogenic mutations have been reported in APP, PSEN1, and PSEN2. However, understanding of the basic biological mechanisms that drive the disease are limited. The Dominantly Inherited Alzheimer Network (DIAN) is an international observational study of APP, PSEN1, and PSEN2 mutation carriers with the goal of determining the sequence of changes in presymptomatic mutation carriers who are destined to develop Alzheimer disease. RESULTS: We generated a library of 98 dermal fibroblast lines from 42 ADAD families enrolled in DIAN. We have reprogrammed a subset of the DIAN fibroblast lines into patient-specific induced pluripotent stem cell (iPSC) lines. These cells were thoroughly characterized for pluripotency markers. CONCLUSIONS: This library represents a comprehensive resource that can be used for disease modeling and the development of novel therapeutics.Item Longitudinal Accumulation of Cerebral Microhemorrhages in Dominantly Inherited Alzheimer Disease(American Academy of Neurology, 2021-03-23) Joseph-Mathurin, Nelly; Wang, Guoqiao; Kantarci, Kejal; Jack, Clifford R., Jr.; McDade, Eric; Hassenstab, Jason; Blazey, Tyler M.; Gordon, Brian A.; Su, Yi; Chen, Gengsheng; Massoumzadeh, Parinaz; Hornbeck, Russ C.; Allegri, Ricardo F.; Ances, Beau M.; Berman, Sarah B.; Brickman, Adam M.; Brooks, William S.; Cash, David M.; Chhatwal, Jasmeer P.; Chui, Helena C.; Correia, Stephen; Cruchaga, Carlos; Farlow, Martin R.; Fox, Nick C.; Fulham, Michael; Ghetti, Bernardino; Graff-Radford, Neill R.; Johnson, Keith A.; Karch, Celeste M.; Laske, Christoph; Lee, Athene K.W.; Levin, Johannes; Masters, Colin L.; Noble, James M.; O’Connor, Antoinette; Perrin, Richard J.; Preboske, Gregory M.; Ringman, John M.; Rowe, Christopher C.; Salloway, Stephen; Saykin, Andrew J.; Schofield, Peter R.; Shimada, Hiroyuki; Shoji, Mikio; Suzuki, Kazushi; Villemagne, Victor L.; Xiong, Chengjie; Yakushev, Igor; Morris, John C.; Bateman, Randall J.; Benzinger, Tammie L.S.; Pathology and Laboratory Medicine, School of MedicineObjective: To investigate the inherent clinical risks associated with the presence of cerebral microhemorrhages (CMHs) or cerebral microbleeds and characterize individuals at high risk for developing hemorrhagic amyloid-related imaging abnormality (ARIA-H), we longitudinally evaluated families with dominantly inherited Alzheimer disease (DIAD). Methods: Mutation carriers (n = 310) and noncarriers (n = 201) underwent neuroimaging, including gradient echo MRI sequences to detect CMHs, and neuropsychological and clinical assessments. Cross-sectional and longitudinal analyses evaluated relationships between CMHs and neuroimaging and clinical markers of disease. Results: Three percent of noncarriers and 8% of carriers developed CMHs primarily located in lobar areas. Carriers with CMHs were older, had higher diastolic blood pressure and Hachinski ischemic scores, and more clinical, cognitive, and motor impairments than those without CMHs. APOE ε4 status was not associated with the prevalence or incidence of CMHs. Prevalent or incident CMHs predicted faster change in Clinical Dementia Rating although not composite cognitive measure, cortical thickness, hippocampal volume, or white matter lesions. Critically, the presence of 2 or more CMHs was associated with a significant risk for development of additional CMHs over time (8.95 ± 10.04 per year). Conclusion: Our study highlights factors associated with the development of CMHs in individuals with DIAD. CMHs are a part of the underlying disease process in DIAD and are significantly associated with dementia. This highlights that in participants in treatment trials exposed to drugs, which carry the risk of ARIA-H as a complication, it may be challenging to separate natural incidence of CMHs from drug-related CMHs.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 Metabolomic and lipidomic signatures in autosomal dominant and late-onset Alzheimer's disease brains(Wiley, 2023) Novotny, Brenna C.; Fernandez, Maria Victoria; Wang, Ciyang; Budde, John P.; Bergmann, Kristy; Eteleeb, Abdallah M.; Bradley, Joseph; Webster, Carol; Ebl, Curtis; Norton, Joanne; Gentsch, Jen; Dube, Umber; Wang, Fengxian; Morris, John C.; Bateman, Randall J.; Perrin, Richard J.; McDade, Eric; Xiong, Chengjie; Chhatwal, Jasmeer; Dominantly Inherited Alzheimer Network (DIAN) Study Group; Alzheimer's Disease Neuroimaging Initiative; Alzheimer's Disease Metabolomics Consortium (ADMC); Goate, Alison; Farlow, Martin; Schofield, Peter; Chui, Helena; Karch, Celeste M.; Cruchaga, Carlos; Benitez, Bruno A.; Harari, Oscar; Neurology, School of MedicineIntroduction: The identification of multiple genetic risk factors for Alzheimer's disease (AD) suggests that many pathways contribute to AD onset and progression. However, the metabolomic and lipidomic profiles in carriers of distinct genetic risk factors are not fully understood. The metabolome can provide a direct image of dysregulated pathways in the brain. Methods: We interrogated metabolomic signatures in the AD brain, including carriers of pathogenic variants in APP, PSEN1, and PSEN2 (autosomal dominant AD; ADAD), APOE ɛ4, and TREM2 risk variant carriers, and sporadic AD (sAD). Results: We identified 133 unique and shared metabolites associated with ADAD, TREM2, and sAD. We identified a signature of 16 metabolites significantly altered between groups and associated with AD duration. Discussion: AD genetic variants show distinct metabolic perturbations. Investigation of these metabolites may provide greater insight into the etiology of AD and its impact on clinical presentation. Highlights: APP/PSEN1/PSEN2 and TREM2 variant carriers show distinct metabolic changes. A total of 133 metabolites were differentially abundant in AD genetic groups. β-citrylglutamate is differentially abundant in autosomal dominant, TREM2, and sporadic AD. A 16-metabolite profile shows differences between Alzheimer's disease (AD) genetic groups. The identified metabolic profile is associated with duration of disease.Item Novel avenues of tau research(Wiley, 2024) Sexton, Claire E.; Bitan, Gal; Bowles, Kathryn R.; Brys, Miroslaw; Buée, Luc; Bukar Maina, Mahmoud; Clelland, Claire D.; Cohen, Ann D.; Crary, John F.; Dage, Jeffrey L.; Diaz, Kristophe; Frost, Bess; Gan, Li; Goate, Alison M.; Golbe, Lawrence I.; Hansson, Oskar; Karch, Celeste M.; Kolb, Hartmuth C.; La Joie, Renaud; Lee, Suzee E.; Matallana, Diana; Miller, Bruce L.; Onyike, Chiadi U.; Quiroz, Yakeel T.; Rexach, Jessica E.; Rohrer, Jonathan D.; Rommel, Amy; Sadri-Vakili, Ghazaleh; Schindler, Suzanne E.; Schneider, Julie A.; Sperling, Reisa A.; Teunissen, Charlotte E.; Weninger, Stacie C.; Worley, Susan L.; Zheng, Hui; Carrillo, Maria C.; Neurology, School of MedicineIntroduction: The pace of innovation has accelerated in virtually every area of tau research in just the past few years. Methods: In February 2022, leading international tau experts convened to share selected highlights of this work during Tau 2022, the second international tau conference co-organized and co-sponsored by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation. Results: Representing academia, industry, and the philanthropic sector, presenters joined more than 1700 registered attendees from 59 countries, spanning six continents, to share recent advances and exciting new directions in tau research. Discussion: The virtual meeting provided an opportunity to foster cross-sector collaboration and partnerships as well as a forum for updating colleagues on research-advancing tools and programs that are steadily moving the field forward.Item Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid(Springer, 2022-11-09) Drieu, Antoine; Du, Siling; Storck, Steffen E.; Rustenhoven, Justin; Papadopoulos, Zachary; Dykstra, Taitea; Zhong, Fenghe; Kim, Kyungdeok; Blackburn, Susan; Mamuladze, Tornike; Harari, Oscar; Karch, Celeste M.; Bateman, Randall J.; Perrin, Richard; Farlow, Martin; Chhatwal, Jasmeer; Dominantly Inherited Alzheimer Network; Hu, Song; Randolph, Gwendalyn J.; Smirnov, Igor; Kipnis, Jonathan; Neurology, School of MedicineMacrophages are important players for the maintenance of tissue homeostasis1. Perivascular and leptomeningeal macrophages reside in close proximity to the central nervous system (CNS) parenchyma2, and their role in CNS physiology has not been well enough studied to date. Given their continuous interaction with the cerebrospinal fluid (CSF) and strategic positioning, we refer to these cells collectively as parenchymal border macrophages (PBMs). Here, we demonstrate that PBMs regulate CSF flow dynamics. We identify a subpopulation of PBMs expressing high levels of CD163 and Lyve1 (scavenger receptor proteins), located in close proximity to the brain arterial tree, and show that Lyve1+ PBMs regulate arterial motion that drives CSF flow. Pharmacological or genetic depletion of PBMs led to accumulation of extracellular matrix proteins, obstructing CSF access to perivascular spaces hence impairing CNS perfusion and clearance. Aging-associated alterations in PBMs and impairment of CSF dynamics were restored upon intracisternal injection of macrophage colony-stimulating growth factor (M-CSF). Human single-nuclei RNA sequencing data obtained from Alzheimer’s disease (AD) patients and healthy controls point to changes in phagocytosis/endocytosis and interferon-gamma (IFNγ) signaling on PBMs, pathways that are corroborated in a mouse AD model. Collectively, our results identify PBMs as novel cellular regulators of CSF flow dynamics, which could potentially be targeted pharmacologically to alleviate brain clearance deficits associated with aging and AD.