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Item A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's disease(Springer Nature, 2021) Salloway, Stephen; Farlow, Martin; McDade, Eric; Clifford, David B.; Wang, Guoqiao; Llibre-Guerra, Jorge J.; Hitchcock, Janice M.; Mills, Susan L.; Santacruz, Anna M.; Aschenbrenner, Andrew J.; Hassenstab, Jason; Benzinger, Tammie L.S.; Gordon, Brian A.; Fagan, Anne M.; Coalier, Kelley A.; Cruchaga, Carlos; Goate, Alison A.; Perrin, Richard J.; Xiong, Chengjie; Li, Yan; Morris, John C.; Snider, B. Joy; Mummery, Catherine; Surti, G. Mustafa; Hannequin, Didier; Wallon, David; Berman, Sarah B.; Lah, James J.; Jimenez-Velazquez, Ivonne Z.; Roberson, Erik D.; van Dyck, Christopher H.; Honig, Lawrence S.; Sánchez-Valle, Raquel; Brooks, William S.; Gauthier, Serge; Galasko, Douglas R.; Masters, Colin L.; Brosch, Jared R.; Hsiung, Ging-Yuek Robin; Jayadev, Suman; Formaglio, Maité; Masellis, Mario; Clarnette, Roger; Pariente, Jérémie; Dubois, Bruno; Pasquier, Florence; Jack, Clifford R., Jr.; Koeppe, Robert; Snyder, Peter J.; Aisen, Paul S.; Thomas, Ronald G.; Berry, Scott M.; Wendelberger, Barbara A.; Andersen, Scott W.; Holdridge, Karen C.; Mintun, Mark A.; Yaari, Roy; Sims, John R.; Baudler, Monika; Delmar, Paul; Doody, Rachelle S.; Fontoura, Paulo; Giacobino, Caroline; Kerchner, Geoffrey A.; Bateman, Randall J.; Dominantly Inherited Alzheimer Network–Trials Unit; Neurology, School of MedicineDominantly inherited Alzheimer's disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4-7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aβ targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses.Item Amyloid-Related Imaging Abnormalities in the DIAN-TU-001 Trial of Gantenerumab and Solanezumab: Lessons from a Trial in Dominantly Inherited Alzheimer Disease(Wiley, 2022) Joseph-Mathurin, Nelly; Llibre-Guerra, Jorge J.; Li, Yan; McCullough, Austin A.; Hofmann, Carsten; Wojtowicz, Jakub; Park, Ethan; Wang, Guoqiao; Preboske, Gregory M.; Wang, Qing; Gordon, Brian A.; Chen, Charles D.; Flores, Shaney; Aggarwal, Neelum T.; Berman, Sarah B.; Bird, Thomas D.; Black, Sandra E.; Borowski, Bret; Brooks, William S.; Chhatwal, Jasmeer P.; Clarnette, Roger; Cruchaga, Carlos; Fagan, Anne M.; Farlow, Martin; Fox, Nick C.; Gauthier, Serge; Hassenstab, Jason; Hobbs, Diana A.; Holdridge, Karen C.; Honig, Lawrence S.; Hornbeck, Russ C.; Hsiung, Ging-Yuek R.; Jack, Clifford R., Jr.; Jimenez-Velazquez, Ivonne Z.; Jucker, Mathias; Klein, Gregory; Levin, Johannes; Mancini, Michele; Masellis, Mario; McKay, Nicole S.; Mummery, Catherine J.; Ringman, John M.; Shimada, Hiroyuki; Snider, B. Joy; Suzuki, Kazushi; Wallon, David; Xiong, Chengjie; Yaari, Roy; McDade, Eric; Perrin, Richard J.; Bateman, Randall J.; Salloway, Stephen P.; Benzinger, Tammie L. S.; Clifford, David B.; Dominantly Inherited Alzheimer Network Trials Unit; Neurology, School of MedicineObjective: To determine the characteristics of participants with amyloid-related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD). Methods: 142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, β-amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross-sectional and longitudinal analyses evaluated potential ARIA-related risk factors. Results: Eleven participants developed ARIA-E, including 3 with mild symptoms. No ARIA-E was reported under solanezumab while gantenerumab was associated with ARIA-E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE-ɛ4 carriers were more likely to develop ARIA-E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA-E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. At first ARIA-E occurrence, all ARIA-E participants were amyloid-PET+, 60% were CDR >0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA-H. Most ARIA-E radiologically resolved after dose adjustment and developing ARIA-E did not significantly increase odds of trial discontinuation. ARIA-E was more frequently observed in the occipital lobe (90%). ARIA-E severity was associated with age at time of ARIA-E. Interpretation: In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA-E risk, with additional risk for individuals APOE-ɛ4(+) or with microhemorrhage. ARIA-E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation.Item Autosomal dominant and sporadic late onset Alzheimer's disease share a common in vivo pathophysiology(Oxford University Press, 2022) Morris, John C.; Weiner, Michael; Xiong, Chengjie; Beckett, Laurel; Coble, Dean; Saito, Naomi; Aisen, Paul S.; Allegri, Ricardo; Benzinger, Tammie L. S.; Berman, Sarah B.; Cairns, Nigel J.; Carrillo, Maria C.; Chui, Helena C.; Chhatwal, Jasmeer P.; Cruchaga, Carlos; Fagan, Anne M.; Farlow, Martin; Fox, Nick C.; Ghetti, Bernardino; Goate, Alison M.; Gordon, Brian A.; Graff-Radford, Neill; Day, Gregory S.; Hassenstab, Jason; Ikeuchi, Takeshi; Jack, Clifford R.; Jagust, William J.; Jucker, Mathias; Levin, Johannes; Massoumzadeh, Parinaz; Masters, Colin L.; Martins, Ralph; McDade, Eric; Mori, Hiroshi; Noble, James M.; Petersen, Ronald C.; Ringman, John M.; Salloway, Stephen; Saykin, Andrew J.; Schofield, Peter R.; Shaw, Leslie M.; Toga, Arthur W.; Trojanowski, John Q.; Vöglein, Jonathan; Weninger, Stacie; Bateman, Randall J.; Buckles, Virginia D.; Dominantly Inherited Alzheimer Network; Alzheimer’s Disease Neuroimaging and Initiative; Neurology, School of MedicineThe extent to which the pathophysiology of autosomal dominant Alzheimer's disease corresponds to the pathophysiology of 'sporadic' late onset Alzheimer's disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer's disease to late onset Alzheimer's disease. We compared brain MRI and amyloid PET data, as well as CSF concentrations of amyloid-β42, amyloid-β40, tau and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer's disease from the Dominantly Inherited Alzheimer Network, with corresponding data from 559 participants from the Alzheimer's Disease Neuroimaging Initiative. Imaging data and CSF samples were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer's disease, allowing the alignment of the ∼30-year age difference between the cohorts on a clinically meaningful anchor point, namely the participant age at symptomatic onset. Biomarker profiles were similar for both autosomal dominant Alzheimer's disease and late onset Alzheimer's disease. Both groups demonstrated accelerated rates of decline in cognitive performance and in regional brain volume loss after symptomatic onset. Although amyloid burden accumulation as determined by PET was greater after symptomatic onset in autosomal dominant Alzheimer's disease than in late onset Alzheimer's disease participants, CSF assays of amyloid-β42, amyloid-β40, tau and p-tau181 were largely overlapping in both groups. Rates of change in cognitive performance and hippocampal volume loss after symptomatic onset were more aggressive for autosomal dominant Alzheimer's disease participants. These findings suggest a similar pathophysiology of autosomal dominant Alzheimer's disease and late onset Alzheimer's disease, supporting a shared pathobiological construct.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 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 Pittsburgh compound B and florbetapir in cross-sectional and longitudinal studies(Elsevier, 2019-02-22) Su, Yi; Flores, Shaney; Wang, Guoqiao; Hornbeck, Russ C.; Speidel, Benjamin; Joseph-Mathurin, Nelly; Vlassenko, Andrei G.; Gordon, Brian A.; Koeppe, Robert A.; Klunk, William E.; Clifford, R. Jack, Jr.; Farlow, Martin R.; Salloway, Stephen; Snider, Barbara J.; Berman, Sarah B.; Roberson, Erik D.; Broschi, Jared; Jimenez-Velazques, Ivonne; van Dyck, Christopher H.; Galasko, Douglas; Yuan, Shauna H.; Jayadev, Suman; Honig, Lawrence S.; Gauthier, Serge; Hsiung, Ging-Yuek R.; Masellis, Mario; Brooks, William S.; Fulham, Michael; Clarnette, Roger; Masters, Colin L.; Wallon, David; Hannequin, Didier; Dubois, Bruno; Pariente, Jeremie; Sanchez-Valle, Raquel; Mummery, Catherine; Ringman, John M.; Bottlaender, Michel; Klein, Gregory; Milosavljevic-Ristic, Smiljana; McDade, Eric; Xiong, Chengjie; Morris, John C.; Bateman, Randall J.; Benzinger, Tammie L.S.; Neurology, School of MedicineIntroduction: Quantitative in vivo measurement of brain amyloid burden is important for both research and clinical purposes. However, the existence of multiple imaging tracers presents challenges to the interpretation of such measurements. This study presents a direct comparison of Pittsburgh compound B-based and florbetapir-based amyloid imaging in the same participants from two independent cohorts using a crossover design. Methods: Pittsburgh compound B and florbetapir amyloid PET imaging data from three different cohorts were analyzed using previously established pipelines to obtain global amyloid burden measurements. These measurements were converted to the Centiloid scale to allow fair comparison between the two tracers. The mean and inter-individual variability of the two tracers were compared using multivariate linear models both cross-sectionally and longitudinally. Results: Global amyloid burden measured using the two tracers were strongly correlated in both cohorts. However, higher variability was observed when florbetapir was used as the imaging tracer. The variability may be partially caused by white matter signal as partial volume correction reduces the variability and improves the correlations between the two tracers. Amyloid burden measured using both tracers was found to be in association with clinical and psychometric measurements. Longitudinal comparison of the two tracers was also performed in similar but separate cohorts whose baseline amyloid load was considered elevated (i.e., amyloid positive). No significant difference was detected in the average annualized rate of change measurements made with these two tracers. Discussion: Although the amyloid burden measurements were quite similar using these two tracers as expected, difference was observable even after conversion into the Centiloid scale. Further investigation is warranted to identify optimal strategies to harmonize amyloid imaging data acquired using different tracers.Item Different rates of cognitive decline in autosomal dominant and late-onset Alzheimer disease(Wiley, 2022-10) Buckles, Virginia D.; Xiong , Chengjie; Bateman, Randall J.; Hassenstab, Jason; Allegri, Ricardo; Berman, Sarah B.; Chhatwal, Jasmeer P.; Danek, Adrian; Fagan, Anne M.; Ghetti, Bernardino; Goate, Alison; Graff-Radford, Neill; Jucker, Mathias; Levin, Johannes; Marcus, Daniel S.; Masters, Colin L.; McCue, Lena; McDade, Eric; Mori, Hiroshi; Moulder, Krista L.; Noble, James M.; Paumier , Katrina; Preische, Oliver; Ringman, John M.; Fox, Nick C.; Salloway, Stephen; Schofield, Peter R.; Martins, Ralph; Vöglein, Jonathan; Morris, John C.; Dominantly Inherited Alzheimer Network; Pathology and Laboratory Medicine, School of MedicineAs prevention trials advance with autosomal dominant Alzheimer disease (ADAD) participants, understanding the similarities and differences between ADAD and “sporadic” late-onset AD (LOAD) is critical to determine generalizability of findings between these cohorts. Cognitive trajectories of ADAD mutation carriers (MCs) and autopsy-confirmed LOAD individuals were compared to address this question. Longitudinal rates of change on cognitive measures were compared in ADAD MCs (n=310) and autopsy-confirmed LOAD participants (n=163) before and after symptom onset (estimated/observed). LOAD participants declined more rapidly in the presymptomatic (preclinical) period and performed more poorly at symptom onset than ADAD participants on a cognitive composite. After symptom onset, however, the younger ADAD MCs declined more rapidly. The similar but not identical cognitive trajectories (declining but at different rates) for ADAD and LOAD suggest common AD pathologies but with some differences.Item Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease: The DIAN-TU-001 Randomized Clinical Trial(American Medical Association, 2024) Wagemann, Olivia; Liu, Haiyan; Wang, Guoqiao; Shi, Xinyu; Bittner, Tobias; Scelsi, Marzia A.; Farlow, Martin R.; Clifford, David B.; Supnet-Bell, Charlene; Santacruz, Anna M.; Aschenbrenner, Andrew J.; Hassenstab, Jason J.; Benzinger, Tammie L. S.; Gordon, Brian A.; Coalier, Kelley A.; Cruchaga, Carlos; Ibanez, Laura; Perrin, Richard J.; Xiong, Chengjie; Li, Yan; Morris, John C.; Lah, James J.; Berman, Sarah B.; Roberson, Erik D.; van Dyck, Christopher H.; Galasko, Douglas; Gauthier, Serge; Hsiung, Ging-Yuek R.; Brooks, William S.; Pariente, Jérémie; Mummery, Catherine J.; Day, Gregory S.; Ringman, John M.; Mendez, Patricio Chrem; St. George-Hyslop, Peter; Fox, Nick C.; Suzuki, Kazushi; Okhravi, Hamid R.; Chhatwal, Jasmeer; Levin, Johannes; Jucker, Mathias; Sims, John R.; Holdridge, Karen C.; Proctor, Nicholas K.; Yaari, Roy; Andersen, Scott W.; Mancini, Michele; Llibre-Guerra, Jorge; Bateman, Randall J.; McDade, Eric; Dominantly Inherited Alzheimer Network–Trials Unit; Neurology, School of MedicineImportance: Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). Objective: To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. Design, setting, and participants: From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. Interventions: In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. Main outcomes and measures: Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3-like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. Results: Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] β = -242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] β = -0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] β = -0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] β = -0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] β = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] β = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] β = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. Conclusions and relevance: This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification.Item Investigation of sex differences in mutation carriers of the Dominantly Inherited Alzheimer Network(Wiley, 2024) Wagemann, Olivia; Li, Yan; Hassenstab, Jason; Aschenbrenner, Andrew J.; McKay, Nicole S.; Gordon, Brian A.; Benzinger, Tammie L. S.; Xiong, Chengjie; Cruchaga, Carlos; Renton, Alan E.; Perrin, Richard J.; Berman, Sarah B.; Chhatwal, Jasmeer P.; Farlow, Martin R.; Day, Gregory S.; Ikeuchi, Takeshi; Jucker, Mathias; Lopera, Francisco; Mori, Hiroshi; Noble, James M.; Sánchez-Valle, Raquel; Schofield, Peter R.; Morris, John C.; Daniels, Alisha; Levin, Johannes; Bateman, Randall J.; McDade, Eric; Llibre-Guerra, Jorge J.; Dominantly Inherited Alzheimer Network; Neurology, School of MedicineIntroduction: Studies suggest distinct differences in the development, presentation, progression, and response to treatment of Alzheimer's disease (AD) between females and males. We investigated sex differences in cognition, neuroimaging, and fluid biomarkers in dominantly inherited AD (DIAD). Methods: Three hundred twenty-five mutation carriers (55% female) and one hundred eighty-six non-carriers (58% female) of the Dominantly Inherited Alzheimer Network Observational Study were analyzed. Linear mixed models and Spearman's correlation explored cross-sectional sex differences in cognition, cerebrospinal fluid (CSF) biomarkers, Pittsburgh compound B positron emission tomography (11 C-PiB PET) and structural magnetic resonance imaging (MRI). Results: Female carriers performed better than males on delayed recall and processing speed despite similar hippocampal volumes. As the disease progressed, symptomatic females revealed higher increases in MRI markers of neurodegeneration and memory impairment. PiB PET and established CSF AD markers revealed no sex differences. Discussion: Our findings suggest an initial cognitive reserve in female carriers followed by a pronounced increase in neurodegeneration coupled with worse performance on delayed recall at later stages of DIAD.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.