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1. The effects of mosaicism on biological and clinical markers of Alzheimer's disease in adults with Down syndrome

Author

Xicota, Laura, Dang, Lam-Ha T, Lee, Alice, Krinsky-McHale, Sharon, Pang, Deborah, Melilli, Lisa, O'Bryant, Sid, Henson, Rachel L, Laymon, Charles, Lai, Florence, Rosas, H Diana, Ances, Beau, Lott, Ira, Hom, Christy, Christian, Bradley, Hartley, Sigan, Zaman, Shahid, Head, Elizabeth, Mapstone, Mark, Jin, Zhezhen, Silverman, Wayne, Schupf, Nicole, Handen, Benjamin, Lee, Joseph H, Syndrome, Alzheimer's Biomarker Consortium–Down, Aizenstein, Howard J, Ances, Beau M, Andrews, Howard F, Bell, Karen, Birn, Rasmus, Brickman, Adam M, Bulova, Peter, Cheema, Amrita, Chen, Kewei, Christian, Bradley T, Clare, Isabel, Clark, Lorraine, Cohen, Ann D, Constantino, John N, Doran, Eric W, Fagan, Anne, Feingold, Eleanor, Foroud, Tatiana M, Handen, Benjamin L, Harp, Jordan, Hartley, Sigan L, Henson, Rachel, Honig, Lawrence, Ikonomovic, Milos D, Johnson, Sterling C, Jordan, Courtney, Kamboh, M Ilyas, Keator, David, Klunk, William E, Kofler, Julia K, Kreisl, William Charles, Krinsky-McHale, Sharon J, Lao, Patrick, Lott, Ira T, Lupson, Victoria, Mathis, Chester A, Minhas, Davneet Singh, Nadkarni, Neelesh, O’Bryant, Sid, Parisi, Melisa, Pettersen, Melissa, Price, Julie C, Pulsifer, Margaret, Rafii, Michael S, Reiman, Eric, Rizvi, Batool, Ryan, Laurie, Schmitt, Frederick, Silverman, Wayne P, Tudorascu, Dana L, Tumuluru, Rameshwari, Tycko, Benjamin, Varadarajan, Badri, White, Desiree A, Yassa, Michael A, and Zhang, Fan

Subjects
Epidemiology, Health Sciences, Alzheimer's Disease, Clinical Research, Down Syndrome, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Acquired Cognitive Impairment, Aging, Neurosciences, Dementia, Prevention, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, 2.1 Biological and endogenous factors, 4.2 Evaluation of markers and technologies, Neurological, Congenital, Down syndrome, Mosaicism, Alzheimer's disease, Plasma biomarkers, CSF, PET, Alzheimer's Biomarker Consortium – Down Syndrome, mosaicism, Alzheimer&#x27, s disease, plasma biomarkers, Clinical Sciences, Public Health and Health Services, Clinical sciences
Abstract

BackgroundIndividuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21.MethodsWe examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium-Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma AD biomarkers (Aβ40, Aβ42, tau, and NfL) and longitudinal cognitive measures. A subset had cerebrospinal fluid biomarkers (Aβ40, Aβ42, tau, ptau181, and NfL) and amyloid and tau PET data.FindingsFor both cohorts, the prevalence of mosaicism was

Published
2024

2. Cerebrovascular disease is associated with Alzheimer’s plasma biomarker concentrations in adults with Down syndrome

Author

Edwards, Natalie C, Lao, Patrick J, Alshikho, Mohamad J, Ericsson, Olivia M, Rizvi, Batool, Petersen, Melissa E, O’Bryant, Sid, Aguilar, Lisi Flores, 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, Aizenstein, Howard J, Ances, Beau M, Andrews, Howard F, Bell, Karen, Birn, Rasmus M, Brickman, Adam M, Bulova, Peter, Cheema, Amrita, Chen, Kewei, Clare, Isabel, Cohen, Ann D, Constantino, John N, Doran, Eric W, Fagan, Anne, Feingold, Eleanor, Foroud, Tatiana M, Harp, Jordan, Hartley, Sigan L, Head, Elizabeth, Henson, Rachel, Hom, Christy, Honig, Lawrence, Ikonomovic, Milos D, Johnson, Sterling C, Jordan, Courtney, Kamboh, M Ilyas, Keator, David, Klunk, William E, Kofler, Julia K, Kreisl, William Charles, Krinsky-McHale, Sharon J, Lao, Patrick, Laymon, Charles, Lupson, Victoria, Mathis, Chester A, Minhas, Davneet Singh, Nadkarni, Neelesh, Parisi, Melissa, Pang, Deborah, Petersen, Melissa, Price, Julie C, Pulsifer, Margaret, Rafii, Michael S, Reiman, Eric, Rosas, Herminia Diana, Ryan, Laurie, Schmitt, Frederick, Schupf, Nicole, Silverman, Wayne P, Tumuluru, Rameshwari, Tycko, Benjamin, Varadarajan, Badri, White, Desiree A, Zhang, Fan, Gutierrez, José, and Wilcock, Donna M

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Dementia, Neurodegenerative, Brain Disorders, Vascular Cognitive Impairment/Dementia, Acquired Cognitive Impairment, Alzheimer's Disease, Aging, Alzheimer's Disease Related Dementias (ADRD), Biomedical Imaging, Cerebrovascular, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Prevention, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Neurological, Alzheimer's disease, Down syndrome, cerebrovascular disease, magnetic resonance imaging, biomarkers, Alzheimer’s Biomarkers Consortium–Down Syndrome (ABC-DS) Investigators, Alzheimer’s disease, Clinical sciences, Biological psychology
Abstract

By age 40 years, over 90% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome.

Published
2024

3. The 2022 symposium on dementia and brain aging in low‐ and middle‐income countries: Highlights on research, diagnosis, care, and impact

Author

Kalaria, Raj, Maestre, Gladys, Mahinrad, Simin, Acosta, Daisy M, Akinyemi, Rufus Olusola, Alladi, Suvarna, Allegri, Ricardo F, Arshad, Faheem, Babalola, David Oluwasayo, Baiyewu, Olusegun, Bak, Thomas H, Bellaj, Tarek, Brodie‐Mends, David K, Carrillo, Maria C, Celestin, Kaputu‐Kalala‐Malu, Damasceno, Albertino, de Silva, Ranil Karunamuni, de Silva, Rohan, Djibuti, Mamuka, Dreyer, Anna Jane, Ellajosyula, Ratnavalli, Farombi, Temitope H, Friedland, Robert P, Garza, Noe, Gbessemehlan, Antoine, Georgiou, Eliza Eleni‐Zacharoula, Govia, Ishtar, Grinberg, Lea T, Guerchet, Maëlenn, Gugssa, Seid Ali, Gumikiriza‐Onoria, Joy Louise, Hogervorst, Eef, Hornberger, Michael, Ibanez, Agustin, Ihara, Masafumi, Issac, Thomas Gregor, Jönsson, Linus, Karanja, Wambui M, Lee, Joseph H, Leroi, Iracema, Livingston, Gill, Manes, Facundo Francisco, Mbakile‐Mahlanza, Lingani, Miller, Bruce L, Musyimi, Christine Wayua, Mutiso, Victoria N, Nakasujja, Noeline, Ndetei, David M, Nightingale, Sam, Novotni, Gabriela, Nyamayaro, Primrose, Nyame, Solomon, Ogeng'o, Julius A, Ogunniyi, Adesola, de Oliveira, Maira Okada, Okubadejo, Njideka U, Orrell, Martin, Paddick, Stella‐Maria, Pericak‐Vance, Margaret A, Pirtosek, Zvezdan, Potocnik, Felix Claude Victor, Raman, Rema, Rizig, Mie, Rosselli, Mónica, Salokhiddinov, Marufjon, Satizabal, Claudia L, Sepulveda‐Falla, Diego, Seshadri, Sudha, Sexton, Claire E, Skoog, Ingmar, St George‐Hyslop, Peter H, Suemoto, Claudia Kimie, Thapa, Prekshy, Udeh‐Momoh, Chinedu Theresa, Valcour, Victor, Vance, Jeffery M, Varghese, Mathew, Vera, Jaime H, Walker, Richard W, Zetterberg, Henrik, Zewde, Yared Z, and Ismail, Ozama

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Brain Disorders, Dementia, Aging, Neurodegenerative, Prevention, Acquired Cognitive Impairment, Neurological, Good Health and Well Being, Humans, Developing Countries, Brain, Congresses as Topic, Biomedical Research, Alzheimer's disease, dementia, diversity, high‐income countries, low‐ and middle‐income countries, risk factors, vascular dementia, Geriatrics, Clinical sciences, Biological psychology
Abstract

Two of every three persons living with dementia reside in low- and middle-income countries (LMICs). The projected increase in global dementia rates is expected to affect LMICs disproportionately. However, the majority of global dementia care costs occur in high-income countries (HICs), with dementia research predominantly focusing on HICs. This imbalance necessitates LMIC-focused research to ensure that characterization of dementia accurately reflects the involvement and specificities of diverse populations. Development of effective preventive, diagnostic, and therapeutic approaches for dementia in LMICs requires targeted, personalized, and harmonized efforts. Our article represents timely discussions at the 2022 Symposium on Dementia and Brain Aging in LMICs that identified the foremost opportunities to advance dementia research, differential diagnosis, use of neuropsychometric tools, awareness, and treatment options. We highlight key topics discussed at the meeting and provide future recommendations to foster a more equitable landscape for dementia prevention, diagnosis, care, policy, and management in LMICs. HIGHLIGHTS: Two-thirds of persons with dementia live in LMICs, yet research and costs are skewed toward HICs. LMICs expect dementia prevalence to more than double, accompanied by socioeconomic disparities. The 2022 Symposium on Dementia in LMICs addressed advances in research, diagnosis, prevention, and policy. The Nairobi Declaration urges global action to enhance dementia outcomes in LMICs.

Published
2024

4. Whole genome‐wide sequence analysis of long‐lived families (Long‐Life Family Study) identifies MTUS2 gene associated with late‐onset Alzheimer's disease

Author

Xicota, Laura, Cosentino, Stephanie, Vardarajan, Badri, Mayeux, Richard, Perls, Thomas T, Andersen, Stacy L, Zmuda, Joseph M, Thyagarajan, Bharat, Yashin, Anatoli, Wojczynski, Mary K, Krinsky‐McHale, Sharon, Handen, Benjamin L, Christian, Bradley T, Head, Elizabeth, Mapstone, Mark E, Schupf, Nicole, Lee, Joseph H, Barral, Sandra, Study, the Long‐Life Family, Abner, Erin, Adams, Perrie M, Aguirre, Alyssa, Albert, Marilyn S, Albin, Roger L, Allen, Mariet, Alvarez, Lisa, Andrews, Howard, Apostolova, Liana G, Arnold, Steven E, Asthana, Sanjay, Atwood, Craig S, Ayres, Gayle, Barber, Robert C, Barnes, Lisa L, Bartlett, Jackie, Beach, Thomas G, Becker, James T, Beecham, Gary W, Benchek, Penelope, Bennett, David A, Bertelson, John, Biber, Sarah A, Bird, Thomas D, Blacker, Deborah, Boeve, Bradley F, Bowen, James D, Boxer, Adam, Brewer, James B, Burke, James R, Burns, Jeffrey M, Bush, William S, Buxbaum, Joseph D, Byrd, Goldie, Cantwell, Laura B, Cao, Chuanhai, Carlsson, Cynthia M, Carrasquillo, Minerva M, Chan, Kwun C, Chasse, Scott, Chen, Yen‐Chi, Chesselet, Marie‐Francoise, Chin, Nathaniel A, Chui, Helena C, Chung, Jaeyoon, Craft, Suzanne, Crane, Paul K, Cranney, Marissa, Cruchaga, Carlos, Cuccaro, Michael L, Culhane, Jessica, Cullum, C Munro, Darby, Eveleen, Davis, Barbara, De Jager, Philip L, DeCarli, Charles, DeToledo, John C, Dickson, Dennis W, Dobbins, Nic, Duara, Ranjan, Ertekin‐Taner, Nilufer, Evans, Denis A, Faber, Kelley M, Fairchild, Thomas J, Fallin, Daniele, Fallon, Kenneth B, Fardo, David W, Farlow, Martin R, Farrell, John, Farrer, Lindsay A, Fernandez‐Hernandez, Victoria, Foroud, Tatiana M, Frosch, Matthew P, Galasko, Douglas R, Gamboa, Adriana, Gauthreaux, Kathryn M, Gefen, Tamar, Geschwind, Daniel H, Ghetti, Bernardino, and Gilbert, John R

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Neurodegenerative, Brain Disorders, Dementia, Alzheimer's Disease, Human Genome, Biotechnology, Aging, Genetics, 2.1 Biological and endogenous factors, Aetiology, Neurological, Humans, Alzheimer Disease, Amyloid beta-Peptides, Genetic Predisposition to Disease, Genome-Wide Association Study, Microtubule-Associated Proteins, Polymorphism, Single Nucleotide, Sequence Analysis, genetic risk, late-onset Alzheimer's disease, microtubule protein, MTUS2 gene, whole genome sequence, Long‐Life Family Study, Alzheimer's Disease Genetic Consortium, Alzheimer's Biomarkers Consortium‐Down Syndrome, late‐onset Alzheimer's disease, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionLate-onset Alzheimer's disease (LOAD) has a strong genetic component. Participants in Long-Life Family Study (LLFS) exhibit delayed onset of dementia, offering a unique opportunity to investigate LOAD genetics.MethodsWe conducted a whole genome sequence analysis of 3475 LLFS members. Genetic associations were examined in six independent studies (N = 14,260) with a wide range of LOAD risk. Association analysis in a sub-sample of the LLFS cohort (N = 1739) evaluated the association of LOAD variants with beta amyloid (Aβ) levels.ResultsWe identified several single nucleotide polymorphisms (SNPs) in tight linkage disequilibrium within the MTUS2 gene associated with LOAD (rs73154407, p = 7.6 × 10-9). Association of MTUS2 variants with LOAD was observed in the five independent studies and was significantly stronger within high levels of Aβ42/40 ratio compared to lower amyloid.DiscussionMTUS2 encodes a microtubule associated protein implicated in the development and function of the nervous system, making it a plausible candidate to investigate LOAD biology.HighlightsLong-Life Family Study (LLFS) families may harbor late onset Alzheimer's dementia (LOAD) variants. LLFS whole genome sequence analysis identified MTUS2 gene variants associated with LOAD. The observed LLFS variants generalized to cohorts with wide range of LOAD risk. The association of MTUS2 with LOAD was stronger within high levels of beta amyloid. Our results provide evidence for MTUS2 gene as a novel LOAD candidate locus.

Published
2024

5. Cognitive and functional performance and plasma biomarkers of early Alzheimer's disease in Down syndrome

Author

Schworer, Emily K, Handen, Benjamin L, Petersen, Melissa, O'Bryant, Sid, Peven, Jamie C, Tudorascu, Dana L, Lee, Laisze, Krinsky‐McHale, Sharon J, Hom, Christy L, Clare, Isabel CH, Christian, Bradley T, Schupf, Nicole, Lee, Joseph H, Head, Elizabeth, Mapstone, Mark, Lott, Ira, Ances, Beau M, Zaman, Shahid, Brickman, Adam M, Lai, Florence, Rosas, H Diana, Hartley, Sigan L, and Syndrome, the Alzheimer Biomarker Consortium‐Down

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Brain Disorders, Mental Health, Aging, Down Syndrome, Acquired Cognitive Impairment, Clinical Research, Alzheimer's Disease, Prevention, Intellectual and Developmental Disabilities (IDD), Behavioral and Social Science, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Neurological, Congenital, adaptive behavior, adults, cognitive performance, functional abilities, neurofilament light chain, plasma amyloid beta, plasma total tau, trisomy 21, Alzheimer Biomarker Consortium‐Down Syndrome, Genetics, Biological psychology
Abstract

IntroductionPeople with Down syndrome (DS) have a 75% to 90% lifetime risk of Alzheimer's disease (AD). AD pathology begins a decade or more prior to onset of clinical AD dementia in people with DS. It is not clear if plasma biomarkers of AD pathology are correlated with early cognitive and functional impairments in DS, and if these biomarkers could be used to track the early stages of AD in DS or to inform inclusion criteria for clinical AD treatment trials.MethodsThis large cross-sectional cohort study investigated the associations between plasma biomarkers of amyloid beta (Aβ)42/40, total tau, and neurofilament light chain (NfL) and cognitive (episodic memory, visual-motor integration, and visuospatial abilities) and functional (adaptive behavior) impairments in 260 adults with DS without dementia (aged 25-81 years).ResultsIn general linear models lower plasma Aβ42/40 was related to lower visuospatial ability, higher total tau was related to lower episodic memory, and higher NfL was related to lower visuospatial ability and lower episodic memory.DiscussionPlasma biomarkers may have utility in tracking AD pathology associated with early stages of cognitive decline in adults with DS, although associations were modest.HighlightsPlasma Alzheimer's disease (AD) biomarkers correlate with cognition prior to dementia in Down syndrome.Lower plasma amyloid beta 42/40 was related to lower visuospatial abilities.Higher plasma total tau and neurofilament light chain were associated with lower cognitive performance.Plasma biomarkers show potential for tracking early stages of AD symptomology.

Published
2024

6. Comparison of amyloid burden in individuals with Down syndrome versus autosomal dominant Alzheimer's disease: a cross-sectional study

Author

Boerwinkle, Anna H, Gordon, Brian A, Wisch, Julie, Flores, Shaney, Henson, Rachel L, Butt, Omar H, McKay, Nicole, Chen, Charles D, Benzinger, Tammie LS, Fagan, Anne M, Handen, Benjamin L, Christian, Bradley T, Head, Elizabeth, Mapstone, Mark, Rafii, Michael S, O'Bryant, Sid, Lai, Florence, Rosas, H Diana, Lee, Joseph H, Silverman, Wayne, Brickman, Adam M, Chhatwal, Jasmeer P, Cruchaga, Carlos, Perrin, Richard J, Xiong, Chengjie, Hassenstab, Jason, McDade, Eric, Bateman, Randall J, Ances, Beau M, Syndrome, Alzheimer's Biomarker Consortium-Down, Aizenstein, Howard J, Andrews, Howard F, Bell, Karen, Birn, Rasmus M, Bulova, Peter, Cheema, Amrita, Chen, Kewei, Clare, Isabel, Clark, Lorraine, Cohen, Ann D, Constantino, John N, Doran, Eric W, Feingold, Eleanor, Foroud, Tatiana M, Hartley, Sigan L, Hom, Christy, Honig, Lawrence, Ikonomovic, Milos D, Johnson, Sterling C, Jordan, Courtney, Kamboh, M Ilyas, Keator, David, Klunk, William E, Kofler, Julia K, Kreisl, William C, McHale, Sharon J Krinsky-, Lao, Patrick, Laymon, Charles, Lott, Ira T, Lupson, Victoria, Mathis, Chester A, Minhas, Davneet S, Nadkarni, Neelesh, Pang, Deborah, Petersen, Melissa, Price, Julie C, Pulsifer, Margaret, Reiman, Eric, Rizvi, Batool, Sabbagh, Marwan N, Schupf, Nicole, Tudorascu, Dana L, Tumuluru, Rameshwari, Tycko, Benjamin, Varadarajan, Badri, White, Desiree A, Yassa, Michael A, Zaman, Shahid, Zhang, Fan, Network, Dominantly Inherited Alzheimer, Adams, Sarah, Allegri, Ricardo, Araki, Aki, Barthelemy, Nicolas, Bechara, Jacob, Berman, Sarah, Bodge, Courtney, Brandon, Susan, Brooks, William, Brosch, Jared, Buck, Jill, Buckles, Virginia, Carter, Kathleen, Cash, Lisa, Mendez, Patricio C, Chua, Jasmin, Chui, Helena, Courtney, Laura, Day, Gregory, and DeLaCruz, Chrismary

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Biomedical Imaging, Aging, Alzheimer's Disease, Clinical Research, Neurodegenerative, Brain Disorders, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Intellectual and Developmental Disabilities (IDD), Genetics, Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adult, Aged, Humans, Middle Aged, Alzheimer Disease, Amyloid beta-Peptides, Apolipoproteins E, Biomarkers, Cross-Sectional Studies, Down Syndrome, Positron-Emission Tomography, Cerebral Cortex, Alzheimer's Biomarker Consortium-Down Syndrome, Dominantly Inherited Alzheimer Network, Neurology & Neurosurgery, Clinical sciences
Abstract

BackgroundImportant insights into the early pathogenesis of Alzheimer's disease can be provided by studies of autosomal dominant Alzheimer's disease and Down syndrome. However, it is unclear whether the timing and spatial distribution of amyloid accumulation differs between people with autosomal dominant Alzheimer's disease and those with Down syndrome. We aimed to directly compare amyloid changes between these two groups of people.MethodsIn this cross-sectional study, we included participants (aged ≥25 years) with Down syndrome and sibling controls who had MRI and amyloid PET scans in the first data release (January, 2020) of the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study. We also included carriers of autosomal dominant Alzheimer's disease genetic mutations and non-carrier familial controls who were within a similar age range to ABC-DS participants (25-73 years) and had MRI and amyloid PET scans at the time of a data freeze (December, 2020) of the Dominantly Inherited Alzheimer Network (DIAN) study. Controls from the two studies were combined into a single group. All DIAN study participants had genetic testing to determine PSEN1, PSEN2, or APP mutation status. APOE genotype was determined from blood samples. CSF samples were collected in a subset of ABC-DS and DIAN participants and the ratio of amyloid β42 (Aβ42) to Aβ40 (Aβ42/40) was measured to evaluate its Spearman's correlation with amyloid PET. Global PET amyloid burden was compared with regards to cognitive status, APOE ɛ4 status, sex, age, and estimated years to symptom onset. We further analysed amyloid PET deposition by autosomal dominant mutation type. We also assessed regional patterns of amyloid accumulation by estimated number of years to symptom onset. Within a subset of participants the relationship between amyloid PET and CSF Aβ42/40 was evaluated.Findings192 individuals with Down syndrome and 33 sibling controls from the ABC-DS study and 265 carriers of autosomal dominant Alzheimer's disease mutations and 169 non-carrier familial controls from the DIAN study were included in our analyses. PET amyloid centiloid and CSF Aβ42/40 were negatively correlated in carriers of autosomal dominant Alzheimer's disease mutations (n=216; r=-0·565; p

Published
2023

7. The effects of mosaicism on biological and clinical markers of Alzheimer's disease in adults with Down syndrome

Author

Aizenstein, Howard J., Ances, Beau M., Andrews, Howard F., Bell, Karen, Birn, Rasmus, Brickman, Adam M., Bulova, Peter, Cheema, Amrita, Chen, Kewei, Christian, Bradley T., Clare, Isabel, Clark, Lorraine, Cohen, Ann D., Constantino, John N., Doran, Eric W., Fagan, Anne, Feingold, Eleanor, Foroud, Tatiana M., Handen, Benjamin L., Harp, Jordan, Hartley, Sigan L., Head, Elizabeth, Henson, Rachel, Hom, Christy, Honig, Lawrence, Ikonomovic, Milos D., Johnson, Sterling C., Jordan, Courtney, Kamboh, M.Ilyas, Keator, David, Klunk, William E., Kofler, Julia K., Kreisl, William Charles, Krinsky-McHale, Sharon J., Lai, Florence, Lao, Patrick, Laymon, Charles, Lee, Joseph H., Lott, Ira T., Lupson, Victoria, Mapstone, Mark, Mathis, Chester A., Minhas, Davneet Singh, Nadkarni, Neelesh, O’Bryant, Sid, Parisi, Melisa, Pang, Deborah, Pettersen, Melissa, Price, Julie C., Pulsifer, Margaret, Rafii, Michael S., Reiman, Eric, Rizvi, Batool, Rosas, H. Diana, Ryan, Laurie, Schmitt, Frederick, Schupf, Nicole, Silverman, Wayne P., Tudorascu, Dana L., Tumuluru, Rameshwari, Tycko, Benjamin, Varadarajan, Badri, White, Desiree A., Yassa, Michael A., Zaman, Shahid, Zhang, Fan, Xicota, Laura, Dang, Lam-Ha T., Lee, Alice, Krinsky-McHale, Sharon, Melilli, Lisa, O'Bryant, Sid, Henson, Rachel L., Ances, Beau, Lott, Ira, Christian, Bradley, Hartley, Sigan, Jin, Zhezhen, Silverman, Wayne, and Handen, Benjamin

Published
2024
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8. Probing the proteome to explore potential correlates of increased Alzheimer's‐related cerebrovascular disease in adults with Down syndrome

Author

Moni, Fahmida, Petersen, Melissa E, Zhang, Fan, Lao, Patrick J, Zimmerman, Molly E, Gu, Yian, Gutierrez, José, Rizvi, Batool, Laing, Krystal K, Igwe, Kay C, Sathishkumar, Mithra, Keator, David, Andrews, Howard, Krinsky‐McHale, Sharon, Head, Elizabeth, Lee, Joseph H, Lai, Florence, Yassa, Michael A, Rosas, H Diana, Silverman, Wayne, Lott, Ira T, Schupf, Nicole, O'Bryant, Sid, and Brickman, Adam M

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Vascular Cognitive Impairment/Dementia, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Acquired Cognitive Impairment, Down Syndrome, Neurodegenerative, Biomedical Imaging, Alzheimer's Disease, Intellectual and Developmental Disabilities (IDD), Alzheimer's Disease Related Dementias (ADRD), Cerebrovascular, Brain Disorders, 4.2 Evaluation of markers and technologies, 4.1 Discovery and preclinical testing of markers and technologies, 2.1 Biological and endogenous factors, Neurological, Adult, Humans, Middle Aged, Alzheimer Disease, Proteome, Proteomics, Cerebrovascular Disorders, Biomarkers, Geriatrics, Clinical sciences, Biological psychology
Abstract

Cerebrovascular disease is associated with symptoms and pathogenesis of Alzheimer's disease (AD) among adults with Down syndrome (DS). The cause of increased dementia-related cerebrovascular disease in DS is unknown. We explored whether protein markers of neuroinflammation are associated with markers of cerebrovascular disease among adults with DS. Participants from the Alzheimer's disease in Down syndrome (ADDS) study with magnetic resonance imaging (MRI) scans and blood biomarker data were included. Support vector machine (SVM) analyses examined the relationship of blood-based proteomic biomarkers with MRI-defined cerebrovascular disease among participants characterized as having cognitive decline (n = 36, mean age ± SD = 53 ± 6.2) and as being cognitively stable (n = 78, mean age = 49 ± 6.4). Inflammatory and AD markers were associated with cerebrovascular disease, particularly among symptomatic individuals. The pattern suggested relatively greater inflammatory involvement among cognitively stable individuals and greater AD involvement among those with cognitively decline. The findings help to generate hypotheses that both inflammatory and AD markers are implicated in cerebrovascular disease among those with DS and point to potential mechanistic pathways for further examination.

Published
2022

9. Comparison of tau spread in people with Down syndrome versus autosomal-dominant Alzheimer's disease: a cross-sectional study

Author

Aizenstein, Howard J., Andrews, Howard F., Bell, Karen, Birn, Rasmus M., Bulova, Peter, Cheema, Amrita, Chen, Kewei, Clare, Isabel, Clark, Lorraine, Cohen, Ann D., Constantino, John N., Doran, Eric W., Feingold, Eleanor, Foroud, Tatiana M., Hartley, Sigan L., Hom, Christy, Honig, Lawrence, Ikonomovic, Milos D., Johnson, Sterling C., Jordan, Courtney, Kamboh, M. Ilyas, Keator, David, Klunk, William E., Kofler, Julia K., Kreisl, William C., Krinsky-McHale, Sharon J., Lao, Patrick, Laymon, Charles, Lott, Ira T., Lupson, Victoria, Mathis, Chester A., Minhas, Davneet S., Nadkarni, Neelesh, Pang, Deborah, Petersen, Melissa, Price, Julie C., Pulsifer, Margaret, Reiman, Eric, Rizvi, Batool, Sabbagh, Marwan N., Schupf, Nicole, Tudorascu, Dana L., Tumuluru, Rameshwari, Tycko, Benjamin, Varadarajan, Badri, White, Desiree A., Yassa, Michael A., Zaman, Shahid, Zhang, Fan, Bateman, Randall, Daniels, Alisha J., Courtney, Laura, McDade, Eric, Llibre-Guerra, Jorge J., Supnet-Bell, Charlene, Xiong, Chengie, Xu, Xiong, Lu, Ruijin, Wang, Guoqiao, Li, Yan, Gremminger, Emily, Perrin, Richard J., Franklin, Erin, Ibanez, Laura, Jerome, Gina, Herries, Elizabeth, Stauber, Jennifer, Baker, Bryce, Minton, Matthew, Cruchaga, Carlos, Goate, Alison M., Renton, Alan E., Picarello, Danielle M., Benzinger, Tammie, Gordon, Brian A., Hornbeck, Russall, Hassenstab, Jason, Smith, Jennifer, Stout, Sarah, Aschenbrenner, Andrew J., Karch, Celeste M., Marsh, Jacob, Morris, John C., Holtzman, David M., Barthelemy, Nicolas, Xu, Jinbin, Noble, James M., Berman, Sarah B., Ikonomovic, Snezana, Nadkarni, Neelesh K., Day, Gregory, Graff-Radford, Neill R., Farlow, Martin, Chhatwal, Jasmeer P., Ikeuchi, Takeshi, Kasuga, Kensaku, Niimi, Yoshiki, Huey, Edward D., Salloway, Stephen, Schofield, Peter R., Brooks, William S., Bechara, Jacob A., Martins, Ralph, Fox, Nick C., Cash, David M., Ryan, Natalie S., Jucker, Mathias, Laske, Christoph, Hofmann, Anna, Kuder-Buletta, Elke, Graber-Sultan, Susanne, Obermueller, Ulrike, Levin, Johannes, Roedenbeck, Yvonne, Vöglein, Jonathan, Lee, Jae-Hong, Roh, Jee Hoon, Sanchez-Valle, Raquel, Rosa-Neto, Pedro, Allegri, Ricardo F., Chrem Mendez, Patricio, Surace, Ezequiel, Vazquez, Silvia, Lopera, Francisco, Leon, Yudy Milena, Ramirez, Laura, Aguillon, David, Levey, Allan I., Johnson, Erik C.B, Seyfried, Nicholas T., Ringman, John, Mori, Hiroshi, Wisch, Julie K, McKay, Nicole S, Boerwinkle, Anna H, Kennedy, James, Flores, Shaney, Handen, Benjamin L, Christian, Bradley T, Head, Elizabeth, Mapstone, Mark, Rafii, Michael S, O’Bryant, Sid E, Price, Julie C, Laymon, Charles M, Krinsky-McHale, Sharon J, Lai, Florence, Rosas, H Diana, Hartley, Sigan L, Lott, Ira T, Tudorascu, Dana, Zammit, Matthew, Brickman, Adam M, Lee, Joseph H, Bird, Thomas D, Cohen, Annie, Chrem, Patricio, Daniels, Alisha, Chhatwal, Jasmeer P, Karch, Celeste M, Day, Gregory S, Llibre-Guerra, Jorge, Ringman, John M, van Dyck, Christopher H, Xiong, Chengjie, Morris, John C, Bateman, Randall J, Benzinger, Tammie L S, Gordon, Brian A, and Ances, Beau M

Published
2024
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10. Obstructive sleep apnea, cerebrovascular disease, and amyloid in older adults with Down syndrome across the Alzheimer’s continuum

Author

Lao, Patrick, Zimmerman, Molly E, Hartley, Sigan L, Gutierrez, José, Keator, David, Igwe, Kay C, Laing, Krystal K, Cotton-Samuel, Dejania, Sathishkumar, Mithra, Moni, Fahmida, Andrews, Howard, Krinsky-McHale, Sharon, Head, Elizabeth, Lee, Joseph H, Lai, Florence, Yassa, Michael A, Rosas, H Diana, Silverman, Wayne, Lott, Ira T, Schupf, Nicole, and Brickman, Adam M

Subjects
Allied Health and Rehabilitation Science, Health Sciences, Prevention, Brain Disorders, Neurodegenerative, Acquired Cognitive Impairment, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Sleep Research, Neurosciences, Down Syndrome, Lung, Biomedical Imaging, Aging, Clinical Research, Intellectual and Developmental Disabilities (IDD), Dementia, Neurological, Alzheimer’s disease, Cerebrovascular disease, Down syndrome, Obstructive sleep apnea, Allied health and rehabilitation science
Abstract

We determined the extent to which obstructive sleep apnea (OSA) is associated with increased cerebrovascular disease and amyloid burden, and the relation of the two processes across clinical Alzheimer's disease (AD) diagnostic groups in adults with Down syndrome (DS). Adults with DS from the Biomarkers of Alzheimer's Disease in Down Syndrome (ADDS) study were included given available research MRI (n = 116; 50 ± 8 years; 42% women) and amyloid PET scans (n = 71; 50 ± 7 years; 39% women) at the time of analysis. Participants were characterized as cognitively stable (CS; 64%), with mild cognitive impairment-DS (MCI-DS; 23%), with possible AD dementia (5%), or with definite AD dementia (8%). OSA was determined via medical records and interviews. Models tested the effect of OSA on MRI-derived cerebrovascular biomarkers and PET-derived amyloid burden, and the moderating effect of OSA and AD diagnosis on biomarkers. OSA was reported in 39% of participants, which did not differ by clinical AD diagnostic group. OSA was not associated with cerebrovascular biomarkers but was associated with greater cortical amyloid burden. White matter hyperintensity (WMH) volume (primarily in the parietal lobe), enlarged perivascular spaces, and cortical and striatal amyloid burden were greater across clinical AD diagnostic groups (CS

Published
2022

11. Plasma Total-Tau and Neurofilament Light Chain as Diagnostic Biomarkers of Alzheimer’s Disease Dementia and Mild Cognitive Impairment in Adults with Down Syndrome

Author

Petersen, Melissa E, Rafii, Michael S, Zhang, Fan, Hall, James, Julovich, David, Ances, Beau M, Schupf, Nicole, Krinsky-McHale, Sharon J, Mapstone, Mark, Silverman, Wayne, Lott, Ira, Klunk, William, Head, Elizabeth, Christian, Brad, Foroud, Tatiana, Lai, Florence, Rosas, H Diana, Zaman, Shahid, Wang, Mei-Cheng, Tycko, Benjamin, Lee, Joseph H, Handen, Benjamin, Hartley, Sigan, Fortea, Juan, O’Bryant, Sid, and Syndrome, for the Alzheimer’s Biomarker Consortium–Down

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Aging, Alzheimer's Disease, Dementia, Brain Disorders, Neurodegenerative, Prevention, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Down Syndrome, Intellectual and Developmental Disabilities (IDD), Acquired Cognitive Impairment, 4.1 Discovery and preclinical testing of markers and technologies, Neurological, Congenital, Adult, Aged, Aged, 80 and over, Alzheimer Disease, Biomarkers, Cognitive Dysfunction, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Neurofilament Proteins, tau Proteins, Neurofilament light chain, proteomics, sensitivity, specificity, total-tau, trisomy 21, Alzheimer’s Biomarker Consortium –Down Syndrome, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences, Biological psychology
Abstract

BackgroundThe need for diagnostic biomarkers of cognitive decline is particularly important among aging adults with Down syndrome (DS). Growing empirical support has identified the utility of plasma derived biomarkers among neurotypical adults with mild cognitive impairment (MCI) and Alzheimer's disease (AD); however, the application of such biomarkers has been limited among the DS population.ObjectiveThis study aimed to investigate the cross-sectional diagnostic performance of plasma neurofilament light chain (Nf-L) and total-tau, individually and in combination among a cohort of DS adults.MethodsPlasma samples were analyzed from n = 305 (n = 225 cognitively stable (CS); n = 44 MCI-DS; n = 36 DS-AD) participants enrolled in the Alzheimer's Biomarker Consortium -Down Syndrome.ResultsIn distinguishing DS-AD participants from CS, Nf-L alone produced an AUC of 90%, total-tau alone reached 74%, and combined reached an AUC of 86%. When age and gender were included, AUC increased to 93%. Higher values of Nf-L, total-tau, and age were all shown to be associated with increased risk for DS-AD. When distinguishing MCI-DS participants from CS, Nf-L alone produced an AUC of 65%, while total-tau alone reached 56%. A combined model with Nf-L, total-tau, age, and gender produced an AUC of 87%. Both higher values in age and total-tau were found to increase risk for MCI-DS; Nf-L levels were not associated with increased risk for MCI-DS.ConclusionAdvanced assay techniques make total-tau and particularly Nf-L useful biomarkers of both AD pathology and clinical status in DS and have the potential to serve as outcome measures in clinical trials for future disease-modifying drugs.

Published
2021

12. Alzheimer‐Related Cerebrovascular Disease in Down Syndrome

Author

Lao, Patrick J, Gutierrez, José, Keator, David, Rizvi, Batool, Banerjee, Arit, Igwe, Kay C, Laing, Krystal K, Sathishkumar, Mithra, Moni, Fahmida, Andrews, Howard, Krinsky‐McHale, Sharon, Head, Elizabeth, Lee, Joseph H, Lai, Florence, Yassa, Michael A, Rosas, H Diana, Silverman, Wayne, Lott, Ira T, Schupf, Nicole, and Brickman, Adam M

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Neurodegenerative, Prevention, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Biomedical Imaging, Intellectual and Developmental Disabilities (IDD), Clinical Research, Alzheimer's Disease, Acquired Cognitive Impairment, Down Syndrome, Aging, Brain Disorders, Dementia, Vascular Cognitive Impairment/Dementia, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Aetiology, Detection, screening and diagnosis, Neurological, Alzheimer Disease, Amyloid, Cerebrovascular Disorders, Cognitive Dysfunction, Female, Hemorrhage, Humans, Hypertrophy, Infarction, Magnetic Resonance Imaging, Male, Middle Aged, Neuroimaging, Positron-Emission Tomography, White Matter, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveAdults with Down syndrome (DS) develop Alzheimer disease (AD) pathology by their 5th decade. Compared with the general population, traditional vascular risks in adults with DS are rare, allowing examination of cerebrovascular disease in this population and insight into its role in AD without the confound of vascular risk factors. We examined in vivo magnetic resonance imaging (MRI)-based biomarkers of cerebrovascular pathology in adults with DS, and determined their cross-sectional relationship with age, beta-amyloid pathology, and mild cognitive impairment or clinical AD diagnostic status.MethodsParticipants from the Biomarkers of Alzheimer's Disease in Down Syndrome study (n = 138, 50 ± 7 years, 39% women) with MRI data and a subset (n = 90) with amyloid positron emission tomography (PET) were included. We derived MRI-based biomarkers of cerebrovascular pathology, including white matter hyperintensities (WMH), infarcts, cerebral microbleeds, and enlarged perivascular spaces (PVS), as well as PET-based biomarkers of amyloid burden. Participants were characterized as cognitively stable (CS), mild cognitive impairment-DS (MCI-DS), possible AD dementia, or definite AD dementia based on in-depth assessments of cognition, function, and health status.ResultsThere were detectable WMH, enlarged PVS, infarcts, and microbleeds as early as the 5th decade of life. There was a monotonic increase in WMH volume, enlarged PVS, and presence of infarcts across diagnostic groups (CS < MCI-DS < possible AD dementia < definite AD dementia). Higher amyloid burden was associated with a higher likelihood of an infarct.InterpretationThe findings highlight the prevalence of cerebrovascular disease in adults with DS and add to a growing body of evidence that implicates cerebrovascular disease as a core feature of AD and not simply a comorbidity. ANN NEUROL 2020;88:1165-1177.

Published
2020

13. Proteomic profiles of prevalent mild cognitive impairment and Alzheimer's disease among adults with Down syndrome.

Author

Petersen, Melissa, Zhang, Fan, Krinsky-McHale, Sharon J, Silverman, Wayne, Lee, Joseph H, Pang, Deborah, Hall, James, Schupf, Nicole, and O'Bryant, Sid E

Subjects
Alzheimer's disease, Down syndrome, biomarkers, blood based, plasma, Alzheimers disease, Genetics, Neurosciences
Abstract

IntroductionWe sought to determine if a proteomic profile approach developed to detect Alzheimer's disease (AD) in the general population would apply to adults with Down syndrome (DS).MethodsPlasma samples were obtained from 398 members of a community-based cohort of adults with DS. A total of n = 186 participants were determined to be non-demented and without mild cognitive impairment (MCI) at baseline and throughout follow-up; n = 50 had prevalent MCI; n = 42 had prevalent AD.ResultsThe proteomic profile yielded an area under the curve (AUC) of 0.92, sensitivity (SN) = 0.80, and specificity (SP) = 0.98 detecting prevalent MCI. For detecting prevalent AD, the proteomic profile yielded an AUC of 0.89, SN = 0.81, and SP = 0.97. The overall profile closely resembled our previously published profile of AD in the general population.DiscussionThese data provide evidence of the applicability of our blood-based algorithm for detecting MCI/AD among adults with DS.

Published
2020

14. Proteomic profiles for Alzheimer's disease and mild cognitive impairment among adults with Down syndrome spanning serum and plasma: An Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study.

Author

Petersen, Melissa E, Zhang, Fan, Schupf, Nicole, Krinsky-McHale, Sharon J, Hall, James, Mapstone, Mark, Cheema, Amrita, Silverman, Wayne, Lott, Ira, Rafii, Michael S, Handen, Benjamin, Klunk, William, Head, Elizabeth, Christian, Brad, Foroud, Tatiana, Lai, Florence, Rosas, H Diana, Zaman, Shahid, Ances, Beau M, Wang, Mei-Cheng, Tycko, Benjamin, Lee, Joseph H, O'Bryant, Sid, and Alzheimer's Biomarker Consortium – Down Syndrome (ABC‐DS)

Subjects
Alzheimer's Biomarker Consortium – Down Syndrome, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Aging, Acquired Cognitive Impairment, Brain Disorders, Down Syndrome, Intellectual and Developmental Disabilities (IDD), Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Genetics, Neurosciences
Abstract

IntroductionPreviously generated serum and plasma proteomic profiles were examined among adults with Down syndrome (DS) to determine whether these profiles could discriminate those with mild cognitive impairment (MCI-DS) and Alzheimer's disease (DS-AD) from those cognitively stable (CS).MethodsData were analyzed on n = 305 (n = 225 CS; n = 44 MCI-DS; n = 36 DS-AD) enrolled in the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS).ResultsDistinguishing MCI-DS from CS, the serum profile produced an area under the curve (AUC) = 0.95 (sensitivity [SN] = 0.91; specificity [SP] = 0.99) and an AUC = 0.98 (SN = 0.96; SP = 0.97) for plasma when using an optimized cut-off score. Distinguishing DS-AD from CS, the serum profile produced an AUC = 0.93 (SN = 0.81; SP = 0.99) and an AUC = 0.95 (SN = 0.86; SP = 1.0) for plasma when using an optimized cut-off score. AUC remained unchanged to slightly improved when age and sex were included. Eotaxin3, interleukin (IL)-10, C-reactive protein, IL-18, serum amyloid A , and FABP3 correlated fractions at r2 > = 0.90.DiscussionProteomic profiles showed excellent detection accuracy for MCI-DS and DS-AD.

Published
2020

15. The Alzheimer's Biomarker Consortium-Down Syndrome: Rationale and methodology.

Author

Handen, Benjamin L, Lott, Ira T, Christian, Bradley T, Schupf, Nicole, OBryant, Sid, Mapstone, Mark, Fagan, Anne M, Lee, Joseph H, Tudorascu, Dana, Wang, Mei-Cheng, Head, Elizabeth, Klunk, William, Ances, Beau, Lai, Florence, Zaman, Shahid, Krinsky-McHale, Sharon, Brickman, Adam M, Rosas, H Diana, Cohen, Annie, Andrews, Howard, Hartley, Sigan, Silverman, Wayne, and Alzheimer's Biomarker Consortium‐Down Syndrome (ABC‐DS)

Subjects
Alzheimer's Biomarker Consortium‐Down Syndrome, ABC‐DS, Alzheimer's disease, Down syndrome, dementia, Prevention, Alzheimer's Disease, Neurodegenerative, Acquired Cognitive Impairment, Clinical Research, Neurosciences, Down Syndrome, Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Dementia, Intellectual and Developmental Disabilities (IDD), Biomedical Imaging, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Aetiology, 2.1 Biological and endogenous factors, Neurological, ABC-DS, Genetics
Abstract

IntroductionAdults with Down syndrome (DS) are at exceptionally high risk for Alzheimer's disease (AD), with virtually all individuals developing key neuropathological features by age 40. Identifying biomarkers of AD progression in DS can provide valuable insights into pathogenesis and suggest targets for disease modifying treatments.MethodsWe describe the development of a multi-center, longitudinal study of biomarkers of AD in DS. The protocol includes longitudinal examination of clinical, cognitive, blood and cerebrospinal fluid-based biomarkers, magnetic resonance imaging and positron emission tomography measures (at 16-month intervals), as well as genetic modifiers of AD risk and progression.ResultsApproximately 400 individuals will be enrolled in the study (more than 370 to date). The methodological approach from the administrative, clinical, neuroimaging, omics, neuropathology, and statistical cores is provided.DiscussionThis represents the largest U.S.-based, multi-site, biomarker initiative of AD in DS. Findings can inform other multidisciplinary networks studying AD in the general population.

Published
2020

17. Comparison of amyloid burden in individuals with Down syndrome versus autosomal dominant Alzheimer's disease: a cross-sectional study

Author

Aizenstein, Howard J, Andrews, Howard F, Bell, Karen, Birn, Rasmus M, Bulova, Peter, Cheema, Amrita, Chen, Kewei, Clare, Isabel, Clark, Lorraine, Cohen, Ann D, Constantino, John N, Doran, Eric W, Feingold, Eleanor, Foroud, Tatiana M, Hartley, Sigan L, Hom, Christy, Honig, Lawrence, Ikonomovic, Milos D, Johnson, Sterling C, Jordan, Courtney, Kamboh, M Ilyas, Keator, David, Klunk MD, William E, Kofler, Julia K, Kreisl, William C, Krinsky- McHale, Sharon J, Lao, Patrick, Laymon, Charles, Lott, Ira T, Lupson, Victoria, Mathis, Chester A, Minhas, Davneet S, Nadkarni, Neelesh, Pang, Deborah, Petersen, Melissa, Price, Julie C, Pulsifer, Margaret, Reiman, Eric, Rizvi, Batool, Sabbagh, Marwan N, Schupf, Nicole, Tudorascu, Dana L, Tumuluru, Rameshwari, Tycko, Benjamin, Varadarajan, Badri, White, Desiree A, Yassa, Michael A, Zaman, Shahid, Zhang, Fan, Adams, Sarah, Allegri, Ricardo, Araki, Aki, Barthelemy, Nicolas, Bechara, Jacob, Berman, Sarah, Bodge, Courtney, Brandon, Susan, Brooks, William, Brosch, Jared, Buck, Jill, Buckles, Virginia, Carter, Kathleen, Cash, Lisa, Mendez, Patricio C, Chua, Jasmin, Chui, Helena, Courtney, Laura, Day, Gregory, DeLaCruz, Chrismary, Denner, Darcy, Diffenbacher, Anna, Dincer, Aylin, Donahue, Tamara, Douglas, Jane, Duong, Duc, Egido, Noelia, Esposito, Bianca, Farlow, Marty, Feldman, Becca, Fitzpatrick, Colleen, Fox, Nick, Franklin, Erin, Joseph-Mathurin, Nelly, Fujii, Hisako, Gardener, Samantha, Ghetti, Bernardino, Goate, Alison, Goldberg, Sarah, Goldman, Jill, Gonzalez, Alyssa, Gräber-Sultan, Susanne, Graff-Radford, Neill, Graham, Morgan, Gray, Julia, Gremminger, Emily, Grilo, Miguel, Groves, Alex, Haass, Christian, Häslerc, Lisa, Hellm, Cortaiga, Herries, Elizabeth, Hoechst-Swisher, Laura, Hofmann, Anna, Holtzman, David, Hornbeck, Russ, Igor, Yakushev, Ihara, Ryoko, Ikeuchi, Takeshi, Ikonomovic, Snezana, Ishii, Kenji, Jack, Clifford, Jerome, Gina, Johnson, Erik, Jucker, Mathias, Karch, Celeste, Käser, Stephan, Kasuga, Kensaku, Keefe, Sarah, Klunk, William, Koeppe, Robert, Koudelis, Deb, Kuder-Buletta, Elke, Laske, Christoph, Levey, Allan, Levin, Johannes, Li, Yan, Lopez, Oscar, Marsh, Jacob, Martins, Ralph, Mason, Neal S, Masters, Colin, Mawuenyega, Kwasi, McCullough, Austin, Mejia, Arlene, Morenas-Rodriguez, Estrella, Morris, John C, Mountz, James, Mummery, Catherine, Nagamatsu, Akemi, Neimeyer, Katie, Niimi, Yoshiki, Noble, James, Norton, Joanne, Nuscher, Brigitte, Obermüller, Ulricke, O'Connor, Antoinette, Patira, Riddhi, Ping, Lingyan, Preische, Oliver, Renton, Alan, Ringman, John, Salloway, Stephen, Schofield, Peter, Senda, Michio, Seyfried, Nicholas T, Shady, Kristine, Shimada, Hiroyuki, Sigurdson, Wendy, Smith, Jennifer, Smith, Lori, Snitz, Beth, Sohrabi, Hamid, Stephens, Sochenda, Taddei, Kevin, Thompson, Sarah, Vöglein, Jonathan, Wang, Peter, Wang, Qing, Weamer, Elise, Xu, Jinbin, Xu, Xiong, Boerwinkle, Anna H, Gordon, Brian A, Wisch, Julie, Flores, Shaney, Henson, Rachel L, Butt, Omar H, McKay, Nicole, Chen, Charles D, Benzinger, Tammie L S, Fagan, Anne M, Handen, Benjamin L, Christian, Bradley T, Head, Elizabeth, Mapstone, Mark, Rafii, Michael S, O'Bryant, Sid, Lai, Florence, Rosas, H Diana, Lee, Joseph H, Silverman, Wayne, Brickman, Adam M, Chhatwal, Jasmeer P, Cruchaga, Carlos, Perrin, Richard J, Xiong, Chengjie, Hassenstab, Jason, McDade, Eric, Bateman, Randall J, and Ances, Beau M

Published
2023
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18. Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions

Author

de Vries, Paul S, Brown, Michael R, Bentley, Amy R, Sung, Yun J, Winkler, Thomas W, Ntalla, Ioanna, Schwander, Karen, Kraja, Aldi T, Guo, Xiuqing, Franceschini, Nora, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Huffman, Jennifer E, Musani, Solomon K, Li, Changwei, Feitosa, Mary F, Richard, Melissa A, Noordam, Raymond, Aschard, Hugues, Bartz, Traci M, Bielak, Lawrence F, Deng, Xuan, Dorajoo, Rajkumar, Lohman, Kurt K, Manning, Alisa K, Rankinen, Tuomo, Smith, Albert V, Tajuddin, Salman M, Evangelou, Evangelos, Graff, Mariaelisa, Alver, Maris, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gandin, Ilaria, Gao, Chuan, Goel, Anuj, Hagemeijer, Yanick, Harris, Sarah E, Hartwig, Fernando P, He, Meian, Horimoto, Andrea RVR, Hsu, Fang-Chi, Jackson, Anne U, Kasturiratne, Anuradhani, Komulainen, Pirjo, Kühnel, Brigitte, Laguzzi, Federica, Lee, Joseph H, Luan, Jian'an, Lyytikäinen, Leo-Pekka, Matoba, Nana, Nolte, Ilja M, Pietzner, Maik, Riaz, Muhammad, Said, M Abdullah, Scott, Robert A, Sofer, Tamar, Stančáková, Alena, Takeuchi, Fumihiko, Tayo, Bamidele O, van der Most, Peter J, Varga, Tibor V, Wang, Yajuan, Ware, Erin B, Wen, Wanqing, Yanek, Lisa R, Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Amin, Najaf, Amini, Marzyeh, Arking, Dan E, Aung, Tin, Ballantyne, Christie, Boerwinkle, Eric, Broeckel, Ulrich, Campbell, Archie, Canouil, Mickaël, Charumathi, Sabanayagam, Chen, Yii-Der Ida, Connell, John M, de Faire, Ulf, de las Fuentes, Lisa, de Mutsert, Renée, de Silva, H Janaka, Ding, Jingzhong, Dominiczak, Anna F, Duan, Qing, Eaton, Charles B, Eppinga, Ruben N, Faul, Jessica D, Fisher, Virginia, Forrester, Terrence, Franco, Oscar H, Friedlander, Yechiel, Ghanbari, Mohsen, and Giulianini, Franco

Subjects
Epidemiology, Health Sciences, Substance Misuse, Alcoholism, Alcohol Use and Health, Human Genome, Prevention, Genetics, Aetiology, 2.1 Biological and endogenous factors, Cardiovascular, Adolescent, Adult, Aged, Alcohol Drinking, Cholesterol, HDL, Cholesterol, LDL, Female, Genome-Wide Association Study, Genotype, Humans, Life Style, Lipids, Male, Middle Aged, Phenotype, Racial Groups, Triglycerides, Vascular Endothelial Growth Factor B, Young Adult, alcohol consumption, cholesterol, gene-environment interactions, gene-lifestyle interactions, genome-wide association studies, lipids, triglycerides, InterAct Consortium, Lifelines Cohort, Groningen, The Netherlands, Mathematical Sciences, Medical and Health Sciences
Abstract

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.

Published
2019

21. Excess Synaptojanin 1 Contributes to Place Cell Dysfunction and Memory Deficits in the Aging Hippocampus in Three Types of Alzheimer’s Disease

Author

Miranda, Andre M, Herman, Mathieu, Cheng, Rong, Nahmani, Eden, Barrett, Geoffrey, Micevska, Elizabeta, Fontaine, Gaelle, Potier, Marie-Claude, Head, Elizabeth, Schmitt, Frederick A, Lott, Ira T, Jiménez-Velázquez, Ivonne Z, Antonarakis, Stylianos E, Di Paolo, Gilbert, Lee, Joseph H, Hussaini, S Abid, and Marquer, Catherine

Subjects
Biochemistry and Cell Biology, Biological Sciences, Dementia, Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease, Aging, Neurosciences, Brain Disorders, Neurodegenerative, Genetics, Aetiology, 2.1 Biological and endogenous factors, Neurological, Alzheimer Disease, Animals, Cognition Disorders, Haplotypes, Hippocampus, Memory Disorders, Mice, Inbred C57BL, Mice, Transgenic, Mutant Proteins, Nerve Tissue Proteins, Phosphoric Monoester Hydrolases, Place Cells, Polymorphism, Single Nucleotide, Synapses, Long-term memory, SYNJ1, hyperexcitability, in vivo electrophysiology, neurodegenerative disorders, single nucleotide polymorphisms, synaptic dysfunction, Medical Physiology, Biological sciences
Abstract

The phosphoinositide phosphatase synaptojanin 1 (SYNJ1) is a key regulator of synaptic function. We first tested whether SYNJ1 contributes to phenotypic variations in familial Alzheimer's disease (FAD) and show that SYNJ1 polymorphisms are associated with age of onset in both early- and late-onset human FAD cohorts. We then interrogated whether SYNJ1 levels could directly affect memory. We show that increased SYNJ1 levels in autopsy brains from adults with Down syndrome (DS/AD) are inversely correlated with synaptophysin levels, a direct readout of synaptic integrity. We further report age-dependent cognitive decline in a mouse model overexpressing murine Synj1 to the levels observed in human sporadic AD, triggered through hippocampal hyperexcitability and defects in the spatial reproducibility of place fields. Taken together, our findings suggest that SYNJ1 contributes to memory deficits in the aging hippocampus in all forms of AD.

Published
2018

22. A Novel Gene ARHGAP44 for Longitudinal Changes in Glycated Hemoglobin (HbA1c) in Subjects without Type 2 Diabetes: Evidence from the Long Life Family Study (LLFS) and the Framingham Offspring Study (FOS)

Author

Wang, Siyu, primary, Lenzini, Petra, additional, Thygarajan, Bharat, additional, Lee, Joseph H., additional, Vardarajan, Badri N., additional, Yashin, Anatoli, additional, Miljkovic, Iva, additional, Daw, E. Warwick, additional, Lin, Shiow J., additional, Patti, Gary, additional, Brent, Michael, additional, Zmuda, Joseph M., additional, Perls, Thomas T., additional, Christensen, Kaare, additional, Province, Michael A., additional, and An, Ping, additional

Published
2024
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24. Comparison of CSF biomarkers in Down syndrome and autosomal dominant Alzheimer's disease: a cross-sectional study

Author

Fagan, Anne M, Henson, Rachel L, Li, Yan, Boerwinkle, Anna H, Xiong, Chengjie, Bateman, Randall J, Goate, Alison, Ances, Beau M, Doran, Eric, Christian, Bradley T, Lai, Florence, Rosas, H Diana, Schupf, Nicole, Krinsky-McHale, Sharon, Silverman, Wayne, Lee, Joseph H, Klunk, William E, Handen, Benjamin L, Allegri, Ricardo F, Chhatwal, Jasmeer P, Day, Gregory S, Graff-Radford, Neill R, Jucker, Mathias, Levin, Johannes, Martins, Ralph N, Masters, Colin L, Mori, Hiroshi, Mummery, Catherine J, Niimi, Yoshiki, Ringman, John M, Salloway, Stephen, Schofield, Peter R, Shoji, Mikio, and Lott, Ira T

Published
2021
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25. Contributors

Author

Brickman, Adam M., primary, Butterfield, D. Allan, additional, Capone, George, additional, Carmona-Iragui, María, additional, Chicoine, Brian, additional, Christian, Bradley T., additional, Dang, Lam-Ha T., additional, Di Domenico, Fabio, additional, DiProspero, Natalie D., additional, Esbensen, Anna J., additional, Fortea, Juan, additional, Granholm, Ann-Charlotte, additional, Gross, Thomas, additional, Hamlett, Eric D., additional, Handen, Benjamin L., additional, Hartley, Sigan L., additional, Head, Elizabeth, additional, Iulita, M. Florencia, additional, Jones, Lydia, additional, Kim, Soyun, additional, Kloske, Courtney, additional, Krinsky-McHale, Sharon J., additional, Lai, Florence, additional, Ledreux, Aurélie, additional, Lee, Joseph H., additional, Lott, Ira T., additional, Mapstone, Mark, additional, Martini, Alessandra C., additional, Miguel, Jennifer C., additional, Mufson, Elliott J., additional, O’Bryant, Sid E., additional, Pang, Deborah, additional, Pape, Sarah, additional, Perez, Sylvia E., additional, Perluigi, Marzia, additional, Petersen, Melissa, additional, Rafii, Michael S., additional, Rizvi, Batool, additional, Rosas, H. Diana, additional, Sadheura, Kirpal, additional, Schupf, Nicole, additional, Silverman, Wayne, additional, Strydom, Andre, additional, Wilcock, Donna M., additional, Yassa, Michael A., additional, and Zaman, Shahid, additional

Published
2022
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28. Transcriptome profiling and analysis of patients with esophageal squamous cell carcinoma from Kazakhstan

Author

Sharip, Aigul, primary, Rakhimova, Saule, additional, Molkenov, Askhat, additional, Ashenova, Ainur, additional, Kozhamkulov, Ulan, additional, Akhmetollayev, Ilyas, additional, Zinovyev, Andrei, additional, Zhukov, Yuri, additional, Omarov, Marat, additional, Tuleutaev, Mukhtar, additional, Rakhmetova, Venera, additional, Terwilliger, Joseph D., additional, Lee, Joseph H., additional, Zhumadilov, Zhaxybay, additional, Akilzhanova, Ainur, additional, and Kairov, Ulykbek, additional

Published
2024
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29. Association of Variability and Hypertensive Loads in 24-h Blood Pressure with Mortality and Cardiovascular Risk

Author

Melgarejo, Jesus D, primary, Patil, Dhrumil, additional, Mena, Luis J, additional, Vatcheva, Kristina P, additional, Garcia, Jose A, additional, Satizabal, Claudia L, additional, Chavez, Carlos A, additional, Pirela, Rosa V, additional, Silva, Egle, additional, Calmon, Gustavo, additional, Lee, Joseph H, additional, Terwilliger, Joseph D, additional, Seshadri, Sudha, additional, and Maestre, Gladys E, additional

Published
2024
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31. Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals

Author

Ghani, Mahdi, Reitz, Christiane, Cheng, Rong, Vardarajan, Badri Narayan, Jun, Gyungah, Sato, Christine, Naj, Adam, Rajbhandary, Ruchita, Wang, Li-San, Valladares, Otto, Lin, Chiao-Feng, Larson, Eric B, Graff-Radford, Neill R, Evans, Denis, De Jager, Philip L, Crane, Paul K, Buxbaum, Joseph D, Murrell, Jill R, Raj, Towfique, Ertekin-Taner, Nilufer, Logue, Mark, Baldwin, Clinton T, Green, Robert C, Barnes, Lisa L, Cantwell, Laura B, Fallin, M Daniele, Go, Rodney CP, Griffith, Patrick A, Obisesan, Thomas O, Manly, Jennifer J, Lunetta, Kathryn L, Kamboh, M Ilyas, Lopez, Oscar L, Bennett, David A, Hendrie, Hugh, Hall, Kathleen S, Goate, Alison M, Byrd, Goldie S, Kukull, Walter A, Foroud, Tatiana M, Haines, Jonathan L, Farrer, Lindsay A, Pericak-Vance, Margaret A, Lee, Joseph H, Schellenberg, Gerard D, St George-Hyslop, Peter, Mayeux, Richard, and Rogaeva, Ekaterina

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Clinical Research, Aging, Acquired Cognitive Impairment, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Brain Disorders, Neurodegenerative, Genetics, 2.1 Biological and endogenous factors, Aetiology, Neurological, Black or African American, Aged, Alzheimer Disease, Case-Control Studies, Chicago, Genes, Recessive, Genome-Wide Association Study, Homozygote, Humans, Indiana, Polymorphism, Single Nucleotide, Alzheimer’s Disease Genetics Consortium
Abstract

ImportanceMutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays.ObjectiveTo evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals.Design, setting, and participantsCase-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals.Main outcomes and measuresThe ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses.ResultsThe African American cohort had a low degree of inbreeding (F ~ 0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb (P = .004) or greater than 3 Mb (P = .02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 = .04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 = .02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 = .03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs >2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs >3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 = .006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 = .01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers.Conclusions and relevanceTo our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.

Published
2015

35. Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

Author

Kraja, Aldi T., Liu, Chunyu, Fetterman, Jessica L., Graff, Mariaelisa, Have, Christian Theil, Gu, Charles, Yanek, Lisa R., Feitosa, Mary F., Arking, Dan E., Chasman, Daniel I., Young, Kristin, Ligthart, Symen, Hill, W. David, Weiss, Stefan, Luan, Jian’an, Giulianini, Franco, Li-Gao, Ruifang, Hartwig, Fernando P., Lin, Shiow J., Wang, Lihua, Richardson, Tom G., Yao, Jie, Fernandez, Eliana P., Ghanbari, Mohsen, Wojczynski, Mary K., Lee, Wen-Jane, Argos, Maria, Armasu, Sebastian M., Barve, Ruteja A., Ryan, Kathleen A., An, Ping, Baranski, Thomas J., Bielinski, Suzette J., Bowden, Donald W., Broeckel, Ulrich, Christensen, Kaare, Chu, Audrey Y., Corley, Janie, Cox, Simon R., Uitterlinden, Andre G., Rivadeneira, Fernando, Cropp, Cheryl D., Daw, E. Warwick, van Heemst, Diana, de las Fuentes, Lisa, Gao, He, Tzoulaki, Ioanna, Ahluwalia, Tarunveer S., de Mutsert, Renée, Emery, Leslie S., Erzurumluoglu, A. Mesut, Perry, James A., Fu, Mao, Forouhi, Nita G., Gu, Zhenglong, Hai, Yang, Harris, Sarah E., Hemani, Gibran, Hunt, Steven C., Irvin, Marguerite R., Jonsson, Anna E., Justice, Anne E., Kerrison, Nicola D., Larson, Nicholas B., Lin, Keng-Hung, Love-Gregory, Latisha D., Mathias, Rasika A., Lee, Joseph H., Nauck, Matthias, Noordam, Raymond, Ong, Ken K., Pankow, James, Patki, Amit, Pattie, Alison, Petersmann, Astrid, Qi, Qibin, Ribel-Madsen, Rasmus, Rohde, Rebecca, Sandow, Kevin, Schnurr, Theresia M., Sofer, Tamar, Starr, John M., Taylor, Adele M., Teumer, Alexander, Timpson, Nicholas J., de Haan, Hugoline G., Wang, Yujie, Weeke, Peter E., Williams, Christine, Wu, Hongsheng, Yang, Wei, Zeng, Donglin, Witte, Daniel R., Weir, Bruce S., Wareham, Nicholas J., Vestergaard, Henrik, Turner, Stephen T., Torp-Pedersen, Christian, Stergiakouli, Evie, Sheu, Wayne Huey-Herng, Rosendaal, Frits R., Ikram, M. Arfan, Franco, Oscar H., Ridker, Paul M., Perls, Thomas T., Pedersen, Oluf, Nohr, Ellen A., Newman, Anne B., Linneberg, Allan, Langenberg, Claudia, Kilpeläinen, Tuomas O., Kardia, Sharon L.R., Jørgensen, Marit E., Jørgensen, Torben, Sørensen, Thorkild I.A., Homuth, Georg, Hansen, Torben, Goodarzi, Mark O., Deary, Ian J., Christensen, Cramer, Chen, Yii-Der Ida, Chakravarti, Aravinda, Brandslund, Ivan, Bonnelykke, Klaus, Taylor, Kent D., Wilson, James G., Rodriguez, Santiago, Davies, Gail, Horta, Bernardo L., Thyagarajan, Bharat, Rao, D.C., Grarup, Niels, Davila-Roman, Victor G., Hudson, Gavin, Guo, Xiuqing, Arnett, Donna K., Hayward, Caroline, Vaidya, Dhananjay, Mook-Kanamori, Dennis O., Tiwari, Hemant K., Levy, Daniel, Loos, Ruth J.F., Dehghan, Abbas, Elliott, Paul, Malik, Afshan N., Scott, Robert A., Becker, Diane M., de Andrade, Mariza, Province, Michael A., Meigs, James B., Rotter, Jerome I., and North, Kari E.

Published
2019
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37. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease

Author

Nalls, Mike A, Pankratz, Nathan, Lill, Christina M, Do, Chuong B, Hernandez, Dena G, Saad, Mohamad, DeStefano, Anita L, Kara, Eleanna, Bras, Jose, Sharma, Manu, Schulte, Claudia, Keller, Margaux F, Arepalli, Sampath, Letson, Christopher, Edsall, Connor, Stefansson, Hreinn, Liu, Xinmin, Pliner, Hannah, Lee, Joseph H, Cheng, Rong, Ikram, M Arfan, Ioannidis, John PA, Hadjigeorgiou, Georgios M, Bis, Joshua C, Martinez, Maria, Perlmutter, Joel S, Goate, Alison, Marder, Karen, Fiske, Brian, Sutherland, Margaret, Xiromerisiou, Georgia, Myers, Richard H, Clark, Lorraine N, Stefansson, Kari, Hardy, John A, Heutink, Peter, Chen, Honglei, Wood, Nicholas W, Houlden, Henry, Payami, Haydeh, Brice, Alexis, Scott, William K, Gasser, Thomas, Bertram, Lars, Eriksson, Nicholas, Foroud, Tatiana, and Singleton, Andrew B

Subjects
Aging, Parkinson's Disease, Neurosciences, Prevention, Genetics, Brain Disorders, Human Genome, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Neurological, Case-Control Studies, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Parkinson Disease, Polymorphism, Single Nucleotide, Risk Factors, International Parkinson's Disease Genomics Consortium, Parkinson's Study Group (PSG) Parkinson's Research: The Organized GENetics Initiative, 23andMe, GenePD, NeuroGenetics Research Consortium, Hussman Institute of Human Genomics, Ashkenazi Jewish Dataset Investigator, Cohorts for Health and Aging Research in Genetic Epidemiology, North American Brain Expression Consortium, United Kingdom Brain Expression Consortium, Greek Parkinson's Disease Consortium, Alzheimer Genetic Analysis Group, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55-4.30; P = 2 × 10(-16)). We also show six risk loci associated with proximal gene expression or DNA methylation.

Published
2014

38. Examination of Genetic Risk Factors for Alzheimer’s Disease in a Cohort of Familial Longevity: the Long Life Family Study

Author

Xicota, Laura, primary, Cheng, Rong, additional, Barral, Sandra, additional, Honig, Lawrence S., additional, Schupf, Nicole, additional, Gu, Yian, additional, Cosentino, Stephanie, additional, Zmuda, Joseph M, additional, Perls, Thomas T., additional, Christensen, Kaare, additional, Province, Michael A, additional, and Lee, Joseph H., additional

Published
2023
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41. Effects of structural and social determinants of health and comorbidities on ethno‐racial differences in ATN plasma biomarkers of Alzheimer’s disease: A HABS‐HD study

Author

Meeker, Karin L., primary, Ances, Beau, additional, Petersen, Melissa, additional, Barber, Robert, additional, Yaffe, Kristine, additional, Zhou, Zhengyang, additional, Llibre‐Guerra, Jorge J, additional, Zhang, Fan, additional, Hall, James, additional, Kind, Amy J., additional, Lee, Joseph H., additional, Vardarajan, Badri N, additional, Cohen, Annie, additional, Mielke, Michelle M., additional, Mapstone, Mark, additional, Babulal, Ganesh M., additional, and O'Bryant, Sid E., additional

Published
2023
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42. Genome‐wide association meta‐analysis of plasma neurofilament light levels in high‐risk adults with Down Syndrome

Author

Dang, Lam‐Ha T, primary, Petersen, Melissa, additional, Xicota, Laura, additional, O'Bryant, Sid E., additional, Krinsky‐McHale, Sharon J, additional, Mapstone, Mark, additional, Kamboh, M. Ilyas, additional, Cruchaga, Carlos, additional, Handen, Benjamin L., additional, Pang, Deborah, additional, Silverman, Wayne, additional, Schupf, Nicole, additional, and Lee, Joseph H., additional

Published
2023
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43. Cerebrovascular disease drives Alzheimer plasma biomarker concentrations in adults with Down syndrome

Author

Edwards, Natalie C, primary, Lao, Patrick C, additional, Alshikho, Mohamad J, additional, Ericsson, Olivia M, additional, Rizvi, Batool, additional, Petersen, Melissa E, additional, O'Bryant, Sid, additional, Flores-Aguilar, Lisi, additional, Simoes, Sabrina, additional, Mapstone, Mark, additional, Tudorascu, Dana L, additional, Janelidze, Shorena, additional, Hansson, Oskar, additional, Handen, Benjamin L, additional, Christian, Bradley T, additional, Lee, Joseph H, additional, Lai, Florence, additional, Rosas, H Diana, additional, Zaman, Shahid, additional, Lott, Ira T, additional, Yassa, Michael A, additional, Gutierrez, José, additional, Wilcock, Donna M, additional, Head, Elizabeth, additional, and Brickman, Adam M., additional

Published
2023
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44. Role of Genetic Polymorphisms in the Development of Complications in Patients with Implanted Left Ventricular Assist Devices: HeartWare, HeartMate II, and HeartMate 3

Author

Zhalbinova, Madina R., primary, Rakhimova, Saule E., additional, Kozhamkulov, Ulan A., additional, Akilzhanova, Gulbanu A., additional, Chinybayeva, Assel A., additional, Akilzhanov, Kenes R., additional, Shaimardanov, Nurlan K., additional, Kuanysheva, Anargul G., additional, Lee, Joseph H., additional, Kairov, Ulykbek Y., additional, Bekbossynova, Makhabbat S., additional, and Akilzhanova, Ainur R., additional

Published
2023
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45. List of contributors

Author

Ah Mew, Nicholas, primary, Akamatsu, Wado, additional, Akman, Hasan Orhan, additional, AlHakeem, Afnan, additional, Aoyama, Koji, additional, Artuch, Rafael, additional, Beck, Michael, additional, Bennett, C. Frank, additional, Berry, Gerard T., additional, Bissell, D. Montgomery, additional, Canine, Brenda, additional, Caskey, C. Thomas, additional, Casy, Widler, additional, Chinnery, Patrick F., additional, Chuang, David T., additional, Cook, Emily K., additional, Cox, Rody P., additional, De Jager, Philip L., additional, Demirbas, Didem, additional, Desnick, Robert J., additional, DiMauro, Salvatore, additional, Eichler, Florian S., additional, Elger, Bernice, additional, Emmanuele, Valentina, additional, Evans, Patricia, additional, Fogel, Brent L., additional, García-Cazorla, Àngels, additional, Gellera, Cinzia, additional, Golla, Sailaja, additional, Goodspeed, Kimberly, additional, Gospe, Sidney M., additional, Gray, Steven J., additional, Gropman, Andrea L., additional, Gu, Yian, additional, Guerrini, Renzo, additional, Gunn, Teresa M., additional, Hadziahmetovic, Una, additional, Haffner, Darrah, additional, Hagerman, R.J., additional, Harel, Tamar, additional, Head, Elizabeth, additional, Horvath, Rita, additional, Hosoi, Yasushi, additional, Hou, Ying-Chen Claire, additional, Hsiao, Jane, additional, Ishiura, Hiroyuki, additional, Jack, Clifford R., additional, Jakkamsetti, Vikram, additional, Johnson†, William G., additional, Jotterand, Fabrice, additional, Kane, John P., additional, Khorkova, Olga, additional, Kinoshita, Chisato, additional, Klompe, Sanne E., additional, Koehl, Lisa M., additional, Kruer, Michael C., additional, Kukull, Walter A., additional, Lane, Roger M., additional, Lee, Joseph H., additional, Leigh, M.J., additional, Ling, Qinglan, additional, Lupski, James R., additional, Luzi, Paola, additional, Ma, Qian, additional, Maegawa, Gustavo H.B., additional, Malloy, Mary J., additional, Margolis, Seth S., additional, Marin-Valencia, Isaac, additional, Mastrianni, James A., additional, Matalon, Dena, additional, Matalon, Reuben, additional, Matalon Rd, Kimberlee Michals, additional, Mathews, Jennifer M., additional, Mayeux, Richard, additional, McCurdy, Jennifer, additional, Meltzer, Meira R., additional, Menkes†, John H., additional, Miron, Justin, additional, Mitsui, Jun, additional, Miyajima, Hiroaki, additional, Monteggia, Lisa M., additional, Morris, Mary Ann, additional, Moser†, Hugo W., additional, Murray, Melissa E., additional, Nakaki, Toshio, additional, Nilsson, Nathalie, additional, Nishino, Ichizo, additional, Nordlie, Sandra M.H., additional, Nussbaum, Robert L., additional, Nyhan, William L., additional, Okano, Hideyuki, additional, Padilla-Lopez, Sergio, additional, Parrini, Elena, additional, Pascual, Juan M., additional, Pastores, Gregory M., additional, Patel, Shailendra B., additional, Patterson, Marc C., additional, Pena, Izabella A., additional, Picard, Cynthia, additional, Poirier, Judes, additional, Posey, Jennifer E., additional, Raymond, Gerald V., additional, Renthal, William, additional, Rosenblatt, David S., additional, Rossignol, Francis, additional, Salen, Gerald, additional, Sandhoff, Konrad, additional, Schiffmann, Raphael, additional, Schindler, Detlev, additional, Schmitt, Frederick A., additional, Schneider, Susanne A., additional, Schon, Eric A., additional, Schuchman, Edward H., additional, Seashore, Margretta Reed, additional, Shaffo, Frances C., additional, Shevell, Michael, additional, Sinnett, Sarah E., additional, Srour, Myriam, additional, Sternberg, Samuel H., additional, Sugie, Kazuma, additional, Szabla, Kristen L., additional, Taroni, Franco, additional, Tedeschi Dauar, Marina, additional, Tsuji, Shoji, additional, Uhlmann, Wendy R., additional, van Karnebeek, Clara, additional, Van Pelt, Kathryn L., additional, Vemuri, Prashanthi, additional, Venditti, Charles P., additional, Wahlestedt, Claes, additional, Wang, Bruce, additional, Watkins, David, additional, Wenger, David A., additional, Williams, Charles A., additional, Wilson, Golder N., additional, Wolf, Barry, additional, Wynn, R. Max, additional, and Yu, Hung-Chun, additional

Published
2020
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