{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:11:53Z","timestamp":1785435113004,"version":"3.56.0"},"reference-count":120,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T00:00:00Z","timestamp":1762560000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T00:00:00Z","timestamp":1762560000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institutes of Health, United States"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Acta Neuropathol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Alzheimer\u2019s disease is the most common form of dementia; however, its molecular mechanisms are not fully understood. We recently identified polymeric\u00a0glycine\u2013arginine-containing (polyGR+) aggregates as a novel type of proteinopathy in AD autopsy brains. Here, we performed a comprehensive analysis to study if polyGR+\u2009aggregates are associated with AD neuropathological changes (ADNC) and clinical features of AD cases. We show polyGR+ aggregates are detected in\u2009~\u200960% of AD postmortem brains from three AD cohorts but not age-similar controls or disease controls with primary age-related tauopathy (PART). A subtype of polyGR+\u2009aggregates with a clustered-punctate morphology that is positive for the markers of dystrophic neurites is associated with earlier onset and shortened survival in AD cases. Increased levels of A\u03b2 plaques and phosphorylated\u00a0tau (pTau)\u00a0tangles are detected in the hippocampus of AD autopsy brains with high levels of polyGR+\u2009aggregates compared to AD autopsy brains with minimal polyGR+\u2009staining. In addition to ADNC, a subset of polyGR+\u2009aggregates coexists with limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC) or Lewy body pathology (LBP). Hippocampal polyGR+\u2009aggregate levels are\u2009~\u20093.8- and\u2009~\u20093.71-fold higher in late-onset AD cases who experienced stroke or high blood pressure, respectively. In SH-SY5Y cells, hydrogen peroxide treatment which mimics oxidative stress leads to increased levels of polyGR+\u2009proteins produced by the\n                    <jats:italic>CASP8<\/jats:italic>\n                    \u00a0GGGAGA repeat expansion, which was recently shown to associate with increased AD risk. In addition, we show the accumulation of pTau induced by\n                    <jats:italic>CASP8<\/jats:italic>\n                    polyGR+\u2009protein aggregates is elevated upon hydrogen peroxide treatment. In summary, our results demonstrate polyGR+\u2009aggregates are a frequent and understudied type of proteinopathy in AD autopsy brains and that polyGR proteinopathy is associated with ADNC.\n                  <\/jats:p>","DOI":"10.1007\/s00401-025-02954-8","type":"journal-article","created":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T11:48:00Z","timestamp":1762602480000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["PolyGR-containing aggregates link with pathology and clinical features of Alzheimer\u2019s disease"],"prefix":"10.1007","volume":"150","author":[{"given":"Huong T.","family":"Phuong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo F.","family":"Tomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cemal","family":"Akmese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Mijares","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella M.","family":"Gerstin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Logan R.","family":"Bell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross","family":"Ellwood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svitlana","family":"Yegorova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefani K.","family":"Ng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace","family":"Massey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Phillips","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Melloni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Pletnikova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"XiangYang","family":"Lou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. Brent","family":"Clark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan C.","family":"Troncoso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley T.","family":"Hyman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Prokop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura P. W.","family":"Ranum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lien","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,8]]},"reference":[{"key":"2954_CR1","doi-asserted-by":"publisher","unstructured":"(2024) 2024 Alzheimer's disease facts and figures. Alzheimers Dement 20: 3708\u20133821 https:\/\/doi.org\/10.1002\/alz.13809","DOI":"10.1002\/alz.13809"},{"key":"2954_CR2","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/j.freeradbiomed.2005.04.017","volume":"39","author":"ML Alexandrova","year":"2005","unstructured":"Alexandrova ML, Bochev PG (2005) Oxidative stress during the chronic phase after stroke. Free Radic Biol Med 39:297\u2013316. https:\/\/doi.org\/10.1016\/j.freeradbiomed.2005.04.017","journal-title":"Free Radic Biol Med"},{"key":"2954_CR3","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24043754","author":"J Andrade-Guerrero","year":"2023","unstructured":"Andrade-Guerrero J, Santiago-Balmaseda A, Jeronimo-Aguilar P, Vargas-Rodriguez I, Cadena-Suarez AR, Sanchez-Garibay C et al (2023) Alzheimer\u2019s disease: an updated overview of its genetics. Int J Mol Sci. https:\/\/doi.org\/10.3390\/ijms24043754","journal-title":"Int J Mol Sci"},{"key":"2954_CR4","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/s0006-8993(00)03082-1","volume":"888","author":"Y Arai","year":"2001","unstructured":"Arai Y, Yamazaki M, Mori O, Muramatsu H, Asano G, Katayama Y (2001) Alpha-synuclein-positive structures in cases with sporadic Alzheimer\u2019s disease: morphology and its relationship to tau aggregation. Brain Res 888:287\u2013296. https:\/\/doi.org\/10.1016\/s0006-8993(00)03082-1","journal-title":"Brain Res"},{"key":"2954_CR5","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1016\/j.neuron.2013.02.004","volume":"77","author":"PEA Ash","year":"2013","unstructured":"Ash PEA, Bieniek KF, Gendron TF, Caulfield T, Lin WL, DeJesus-Hernandez M et al (2013) Unconventional translation of GGGGCC expansion generates insoluble polypeptides specific to c9FTD\/ALS. Neuron 77:639\u2013646. https:\/\/doi.org\/10.1016\/j.neuron.2013.02.004","journal-title":"Neuron"},{"key":"2954_CR6","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.1016\/S0140-6736(10)61349-9","volume":"377","author":"C Ballard","year":"2011","unstructured":"Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E (2011) Alzheimer\u2019s disease. Lancet 377:1019\u20131031. https:\/\/doi.org\/10.1016\/S0140-6736(10)61349-9","journal-title":"Lancet"},{"key":"2954_CR7","first-page":"358","volume":"19","author":"A Baradaran","year":"2014","unstructured":"Baradaran A, Nasri H, Rafieian-Kopaei M (2014) Oxidative stress and hypertension: possibility of hypertension therapy with antioxidants. J Res Med Sci 19:358\u2013367","journal-title":"J Res Med Sci"},{"key":"2954_CR8","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1001\/jamaneurol.2013.5847","volume":"71","author":"GS Bloom","year":"2014","unstructured":"Bloom GS (2014) Amyloid-\u03b2 and Tau the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol 71:505\u2013508. https:\/\/doi.org\/10.1001\/jamaneurol.2013.5847","journal-title":"JAMA Neurol"},{"key":"2954_CR9","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1007\/s00401-006-0127-z","volume":"112","author":"H Braak","year":"2006","unstructured":"Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112:389\u2013404. https:\/\/doi.org\/10.1007\/s00401-006-0127-z","journal-title":"Acta Neuropathol"},{"key":"2954_CR10","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1007\/BF00308809","volume":"82","author":"H Braak","year":"1991","unstructured":"Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239\u2013259. https:\/\/doi.org\/10.1007\/BF00308809","journal-title":"Acta Neuropathol"},{"key":"2954_CR11","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/0197-4580(95)00021-6","volume":"16","author":"H Braak","year":"1995","unstructured":"Braak H, Braak E (1995) Staging of Alzheimer\u2019s disease-related neurofibrillary changes. Neurobiol Aging 16:271\u2013278. https:\/\/doi.org\/10.1016\/0197-4580(95)00021-6","journal-title":"Neurobiol Aging"},{"key":"2954_CR12","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/s0197-4580(02)00065-9","volume":"24","author":"H Braak","year":"2003","unstructured":"Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson\u2019s disease. Neurobiol Aging 24:197\u2013211. https:\/\/doi.org\/10.1016\/s0197-4580(02)00065-9","journal-title":"Neurobiol Aging"},{"key":"2954_CR13","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1016\/j.jalz.2016.01.012","volume":"12","author":"R Cacace","year":"2016","unstructured":"Cacace R, Sleegers K, Van Broeckhoven C (2016) Molecular genetics of early-onset Alzheimer\u2019s disease revisited. Alzheimers Dement 12:733\u2013748. https:\/\/doi.org\/10.1016\/j.jalz.2016.01.012","journal-title":"Alzheimers Dement"},{"key":"2954_CR14","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02495-z","author":"WW Cheng","year":"2018","unstructured":"Cheng WW, Wang SP, Mestre AA, Fu CL, Makarem A, Xian FF et al (2018) C9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2\u03b1 phosphorylation. Nat Commun. https:\/\/doi.org\/10.1038\/s41467-017-02495-z","journal-title":"Nat Commun"},{"key":"2954_CR15","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1093\/brain\/awad388","volume":"147","author":"Y Chu","year":"2024","unstructured":"Chu Y, Hirst WD, Federoff HJ, Harms AS, Stoessl AJ, Kordower JH (2024) Nigrostriatal tau pathology in parkinsonism and Parkinson\u2019s disease. Brain 147:444\u2013457. https:\/\/doi.org\/10.1093\/brain\/awad388","journal-title":"Brain"},{"key":"2954_CR16","doi-asserted-by":"publisher","first-page":"2129","DOI":"10.1177\/0271678x18800589","volume":"38","author":"MJ Cipolla","year":"2018","unstructured":"Cipolla MJ, Liebeskind DS, Chan SL (2018) The importance of comorbidities in ischemic stroke: impact of hypertension on the cerebral circulation. J Cereb Blood Flow Metab 38:2129\u20132149. https:\/\/doi.org\/10.1177\/0271678x18800589","journal-title":"J Cereb Blood Flow Metab"},{"key":"2954_CR17","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abb3774","author":"CN Cook","year":"2020","unstructured":"Cook CN, Wu Y, Odeh HM, Gendron TF, Jansen-West K, Del Rosso G et al (2020) C9orf72 poly(GR) aggregation induces TDP-43 proteinopathy. Sci Transl Med. https:\/\/doi.org\/10.1126\/scitranslmed.abb3774","journal-title":"Sci Transl Med"},{"key":"2954_CR18","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1126\/science.8346443","volume":"261","author":"EH Corder","year":"1993","unstructured":"Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW et al (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer\u2019s disease in late onset families. Science 261:921\u2013923. https:\/\/doi.org\/10.1126\/science.8346443","journal-title":"Science"},{"key":"2954_CR19","doi-asserted-by":"publisher","first-page":"1134090","DOI":"10.3389\/fncel.2023.1134090","volume":"17","author":"TL Dane","year":"2023","unstructured":"Dane TL, Gill AL, Vieira FG, Denton KR (2023) Reduced C9orf72 expression exacerbates polyGR toxicity in patient iPSC-derived motor neurons and a type I protein arginine methyltransferase inhibitor reduces that toxicity. Front Cell Neurosci 17:1134090. https:\/\/doi.org\/10.3389\/fncel.2023.1134090","journal-title":"Front Cell Neurosci"},{"key":"2954_CR20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0184731","volume":"12","author":"JS Dhillon","year":"2017","unstructured":"Dhillon JS, Riffe C, Moore BD, Ran Y, Chakrabarty P, Golde TE et al (2017) A novel panel of alpha-synuclein antibodies reveal distinctive staining profiles in synucleinopathies. PLoS ONE 12:e0184731. https:\/\/doi.org\/10.1371\/journal.pone.0184731","journal-title":"PLoS ONE"},{"key":"2954_CR21","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.adl1030","author":"DY Dong","year":"2024","unstructured":"Dong DY, Zhang Z, Li YN, Latallo MJ, Wang SP, Nelson B et al (2024) Poly-GR repeats associated with ALS\/FTD gene impair translation elongation and induce a ribotoxic stress response in neurons. Sci Signal. https:\/\/doi.org\/10.1126\/scisignal.adl1030","journal-title":"Sci Signal"},{"key":"2954_CR22","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1016\/S1474-4422(14)70090-0","volume":"13","author":"B Dubois","year":"2014","unstructured":"Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K et al (2014) Advancing research diagnostic criteria for Alzheimer\u2019s disease: the IWG-2 criteria. Lancet Neurol 13:614\u2013629. https:\/\/doi.org\/10.1016\/S1474-4422(14)70090-0","journal-title":"Lancet Neurol"},{"key":"2954_CR23","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1038\/s43587-023-00490-2","volume":"3","author":"JP Ferrari-Souza","year":"2023","unstructured":"Ferrari-Souza JP, Bellaver B, Ferreira PCL, Benedet AL, Povala G, Lussier FZ et al (2023) APOEepsilon4 potentiates amyloid beta effects on longitudinal tau pathology. Nat Aging 3:1210\u20131218. https:\/\/doi.org\/10.1038\/s43587-023-00490-2","journal-title":"Nat Aging"},{"key":"2954_CR24","doi-asserted-by":"publisher","first-page":"47","DOI":"10.3389\/fnagi.2014.00047","volume":"6","author":"D Ferreira","year":"2014","unstructured":"Ferreira D, Perestelo-Perez L, Westman E, Wahlund LO, Sarria A, Serrano-Aguilar P (2014) Meta-review of CSF core biomarkers in Alzheimer\u2019s disease: the state-of-the-art after the new revised diagnostic criteria. Front Aging Neurosci 6:47. https:\/\/doi.org\/10.3389\/fnagi.2014.00047","journal-title":"Front Aging Neurosci"},{"key":"2954_CR25","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1002\/alz.12371","volume":"18","author":"N Franzmeier","year":"2022","unstructured":"Franzmeier N, Ossenkoppele R, Brendel M, Rubinski A, Smith R, Kumar A et al (2022) The BIN1 rs744373 Alzheimer\u2019s disease risk SNP is associated with faster Abeta-associated tau accumulation and cognitive decline. Alzheimers Dement 18:103\u2013115. https:\/\/doi.org\/10.1002\/alz.12371","journal-title":"Alzheimers Dement"},{"key":"2954_CR26","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1111\/j.1365-2990.2010.01135.x","volume":"37","author":"KE Funk","year":"2011","unstructured":"Funk KE, Mrak RE, Kuret J (2011) Granulovacuolar degeneration (GVD) bodies of Alzheimer\u2019s disease (AD) resemble late-stage autophagic organelles. Neuropathol Appl Neurobiol 37:295\u2013306. https:\/\/doi.org\/10.1111\/j.1365-2990.2010.01135.x","journal-title":"Neuropathol Appl Neurobiol"},{"key":"2954_CR27","doi-asserted-by":"publisher","first-page":"2439","DOI":"10.1111\/ene.15373","volume":"29","author":"H Garcia-Moreno","year":"2022","unstructured":"Garcia-Moreno H, Prudencio M, Thomas-Black G, Solanky N, Jansen-West KR, AL-Shaikh RH, Heslegrave A, Zetterberg H, Santana MM, de Almeida LP et al (2022) Tau and neurofilament light-chain as fluid biomarkers in spinocerebellar ataxia type 3. Eur J Neurol 29:2439\u20132452. https:\/\/doi.org\/10.1111\/ene.15373","journal-title":"Eur J Neurol"},{"key":"2954_CR28","doi-asserted-by":"publisher","first-page":"3738","DOI":"10.1002\/alz.13057","volume":"19","author":"A Garnier-Crussard","year":"2023","unstructured":"Garnier-Crussard A, Cotton F, Krolak-Salmon P, Ch\u00e9telat G (2023) White matter hyperintensities in Alzheimer\u2019s disease: beyond vascular contribution. Alzheimers Dement 19:3738\u20133748. https:\/\/doi.org\/10.1002\/alz.13057","journal-title":"Alzheimers Dement"},{"key":"2954_CR29","doi-asserted-by":"publisher","first-page":"1491","DOI":"10.1126\/science.1062097","volume":"293","author":"J Gotz","year":"2001","unstructured":"Gotz J, Chen F, van Dorpe J, Nitsch RM (2001) Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293:1491\u20131495. https:\/\/doi.org\/10.1126\/science.1062097","journal-title":"Science"},{"key":"2954_CR30","doi-asserted-by":"publisher","first-page":"1014","DOI":"10.1093\/brain\/aww021","volume":"139","author":"M Gratuze","year":"2016","unstructured":"Gratuze M, Cisbani G, Cicchetti F, Planel E (2016) Is Huntington\u2019s disease a tauopathy? Brain 139:1014\u20131025. https:\/\/doi.org\/10.1093\/brain\/aww021","journal-title":"Brain"},{"key":"2954_CR31","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02200-0","volume":"8","author":"KM Green","year":"2017","unstructured":"Green KM, Glineburg MR, Kearse MG, Flores BN, Linsalata AE, Fedak SJ et al (2017) RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response. Nat Commun 8:2005. https:\/\/doi.org\/10.1038\/s41467-017-02200-0","journal-title":"Nat Commun"},{"key":"2954_CR32","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1038\/s41582-019-0281-2","volume":"16","author":"SM Greenberg","year":"2020","unstructured":"Greenberg SM, Bacskai BJ, Hernandez-Guillamon M, Pruzin J, Sperling R, van Veluw SJ (2020) Cerebral amyloid angiopathy and Alzheimer disease\u2014one peptide, two pathways. Nat Rev Neurol 16:30\u201342. https:\/\/doi.org\/10.1038\/s41582-019-0281-2","journal-title":"Nat Rev Neurol"},{"key":"2954_CR33","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1016\/s0197-4580(99)00063-9","volume":"20","author":"E Grober","year":"1999","unstructured":"Grober E, Dickson D, Sliwinski MJ, Buschke H, Katz M, Crystal H et al (1999) Memory and mental status correlates of modified Braak staging. Neurobiol Aging 20:573\u2013579. https:\/\/doi.org\/10.1016\/s0197-4580(99)00063-9","journal-title":"Neurobiol Aging"},{"key":"2954_CR34","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1056\/NEJMoa1211851","volume":"368","author":"R Guerreiro","year":"2013","unstructured":"Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E et al (2013) TREM2 variants in Alzheimer\u2019s disease. N Engl J Med 368:117\u2013127. https:\/\/doi.org\/10.1056\/NEJMoa1211851","journal-title":"N Engl J Med"},{"key":"2954_CR35","doi-asserted-by":"publisher","first-page":"1126","DOI":"10.1038\/s41467-025-56400-0","volume":"16","author":"MH Guo","year":"2025","unstructured":"Guo MH, Lee WP, Vardarajan B, Schellenberg GD, Phillips-Cremins JE (2025) Polygenic burden of short tandem repeat expansions promotes risk for Alzheimer\u2019s disease. Nat Commun 16:1126. https:\/\/doi.org\/10.1038\/s41467-025-56400-0","journal-title":"Nat Commun"},{"key":"2954_CR36","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1161\/Hypertensionaha.117.07802","volume":"70","author":"TJ Guzik","year":"2017","unstructured":"Guzik TJ, Touyz RM (2017) Oxidative stress, inflammation, and vascular aging in hypertension. Hypertension 70:660\u2013667. https:\/\/doi.org\/10.1161\/Hypertensionaha.117.07802","journal-title":"Hypertension"},{"key":"2954_CR37","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1111\/j.1750-3639.2000.tb00269.x","volume":"10","author":"RL Hamilton","year":"2000","unstructured":"Hamilton RL (2000) Lewy bodies in Alzheimer\u2019s disease: a neuropathological review of 145 cases using alpha-synuclein immunohistochemistry. Brain Pathol 10:378\u2013384. https:\/\/doi.org\/10.1111\/j.1750-3639.2000.tb00269.x","journal-title":"Brain Pathol"},{"key":"2954_CR38","doi-asserted-by":"publisher","first-page":"5481","DOI":"10.1038\/s41380-021-01249-0","volume":"26","author":"H Hampel","year":"2021","unstructured":"Hampel H, Hardy J, Blennow K, Chen C, Perry G, Kim SH et al (2021) The amyloid-\u03b2 pathway in Alzheimer\u2019s disease. Mol Psychiatr 26:5481\u20135503. https:\/\/doi.org\/10.1038\/s41380-021-01249-0","journal-title":"Mol Psychiatr"},{"key":"2954_CR39","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1126\/science.1566067","volume":"256","author":"JA Hardy","year":"1992","unstructured":"Hardy JA, Higgins GA (1992) Alzheimer\u2019s disease: the amyloid cascade hypothesis. Science 256:184\u2013185. https:\/\/doi.org\/10.1126\/science.1566067","journal-title":"Science"},{"key":"2954_CR40","doi-asserted-by":"publisher","first-page":"1707","DOI":"10.1001\/archneur.60.12.1707","volume":"60","author":"LS Honig","year":"2003","unstructured":"Honig LS, Tang MX, Albert S, Costa R, Luchsinger J, Manly J et al (2003) Stroke and the risk of Alzheimer disease. Arch Neurol 60:1707\u20131712. https:\/\/doi.org\/10.1001\/archneur.60.12.1707","journal-title":"Arch Neurol"},{"key":"2954_CR41","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jalz.2011.10.007","volume":"8","author":"BT Hyman","year":"2012","unstructured":"Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC et al (2012) National institute on aging-Alzheimer\u2019s association guidelines for the neuropathologic assessment of Alzheimer\u2019s disease. Alzheimers Dement 8:1\u201313. https:\/\/doi.org\/10.1016\/j.jalz.2011.10.007","journal-title":"Alzheimers Dement"},{"key":"2954_CR42","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1212\/01.wnl.0000115115.98960.37","volume":"62","author":"M Ingelsson","year":"2004","unstructured":"Ingelsson M, Fukumoto H, Newell KL, Growdon JH, Hedley-Whyte ET, Frosch MP et al (2004) Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology 62:925\u2013931. https:\/\/doi.org\/10.1212\/01.wnl.0000115115.98960.37","journal-title":"Neurology"},{"key":"2954_CR43","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1016\/j.bbadis.2004.09.008","volume":"1739","author":"K Iqbal","year":"2005","unstructured":"Iqbal K, Alonso Adel C, Chen S, Chohan MO, El-Akkad E, Gong CX et al (2005) Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta 1739:198\u2013210. https:\/\/doi.org\/10.1016\/j.bbadis.2004.09.008","journal-title":"Biochim Biophys Acta"},{"key":"2954_CR44","doi-asserted-by":"publisher","first-page":"1652","DOI":"10.1038\/s12276-020-00513-7","volume":"52","author":"M Jo","year":"2020","unstructured":"Jo M, Lee S, Jeon YM, Kim S, Kwon Y, Kim HJ (2020) The role of TDP-43 propagation in neurodegenerative diseases: integrating insights from clinical and experimental studies. Exp Mol Med 52:1652\u20131662. https:\/\/doi.org\/10.1038\/s12276-020-00513-7","journal-title":"Exp Mol Med"},{"key":"2954_CR45","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1007\/s00401-016-1537-1","volume":"131","author":"KA Josephs","year":"2016","unstructured":"Josephs KA, Murray ME, Whitwell JL, Tosakulwong N, Weigand SD, Petrucelli L et al (2016) Updated TDP-43 in Alzheimer\u2019s disease staging scheme. Acta Neuropathol 131:571\u2013585. https:\/\/doi.org\/10.1007\/s00401-016-1537-1","journal-title":"Acta Neuropathol"},{"key":"2954_CR46","doi-asserted-by":"publisher","first-page":"2712","DOI":"10.1161\/hs1101.098653","volume":"32","author":"HA Kontos","year":"2001","unstructured":"Kontos HA (2001) Oxygen radicals in cerebral ischemia: the 2001 Willis lecture. Stroke 32:2712\u20132716. https:\/\/doi.org\/10.1161\/hs1101.098653","journal-title":"Stroke"},{"key":"2954_CR47","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1385\/jmn:17:2:225","volume":"17","author":"PT Kotzbauer","year":"2001","unstructured":"Kotzbauer PT, Trojanowsk JQ, Lee VM (2001) Lewy body pathology in Alzheimer\u2019s disease. J Mol Neurosci 17:225\u2013232. https:\/\/doi.org\/10.1385\/jmn:17:2:225","journal-title":"J Mol Neurosci"},{"key":"2954_CR48","doi-asserted-by":"publisher","DOI":"10.1002\/dad2.12008","volume":"12","author":"AM Kulminski","year":"2020","unstructured":"Kulminski AM, Shu L, Loika Y, He L, Nazarian A, Arbeev K et al (2020) Genetic and regulatory architecture of Alzheimer\u2019s disease in the APOE region. Alzheimers Dement (Amst) 12:e12008. https:\/\/doi.org\/10.1002\/dad2.12008","journal-title":"Alzheimers Dement (Amst)"},{"key":"2954_CR49","doi-asserted-by":"publisher","first-page":"1416","DOI":"10.1016\/j.jalz.2018.06.3061","volume":"14","author":"E Kuzma","year":"2018","unstructured":"Kuzma E, Lourida I, Moore SF, Levine DA, Ukoumunne OC, Llewellyn DJ (2018) Stroke and dementia risk: a systematic review and meta-analysis. Alzheimers Dement 14:1416\u20131426. https:\/\/doi.org\/10.1016\/j.jalz.2018.06.3061","journal-title":"Alzheimers Dement"},{"key":"2954_CR50","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.1126\/science.1254917","volume":"345","author":"I Kwon","year":"2014","unstructured":"Kwon I, Xiang SH, Kato M, Wu L, Theodoropoulos P, Wang T et al (2014) Poly-dipeptides encoded by the repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science 345:1139\u20131145. https:\/\/doi.org\/10.1126\/science.1254917","journal-title":"Science"},{"key":"2954_CR51","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1159\/000322538","volume":"8","author":"MJ Lee","year":"2011","unstructured":"Lee MJ, Chen TF, Cheng TW, Chiu MJ (2011) Rs5848 variant of progranulin gene is a risk of Alzheimer\u2019s disease in the Taiwanese population. Neurodegener Dis 8:216\u2013220. https:\/\/doi.org\/10.1159\/000322538","journal-title":"Neurodegener Dis"},{"key":"2954_CR52","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000209715","author":"MJ Lennon","year":"2024","unstructured":"Lennon MJ, Lipnicki DM, Lam BP, Crawford JD, Schutte AE, Peters R et al (2024) Blood pressure, antihypertensive use, and late-life alzheimer and non-alzheimer dementia risk an individual participant data meta-analysis. Neurology. https:\/\/doi.org\/10.1212\/WNL.0000000000209715","journal-title":"Neurology"},{"key":"2954_CR53","doi-asserted-by":"publisher","first-page":"1928","DOI":"10.1016\/j.ajpath.2012.08.012","volume":"181","author":"K Leroy","year":"2012","unstructured":"Leroy K, Ando K, Laporte V, Dedecker R, Suain V, Authelet M et al (2012) Lack of tau proteins rescues neuronal cell death and decreases amyloidogenic processing of APP in APP\/PS1 mice. Am J Pathol 181:1928\u20131940. https:\/\/doi.org\/10.1016\/j.ajpath.2012.08.012","journal-title":"Am J Pathol"},{"key":"2954_CR54","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1172\/JCI25410","volume":"116","author":"Y Levites","year":"2006","unstructured":"Levites Y, Das P, Price RW, Rochette MJ, Kostura LA, McGowan EM et al (2006) Anti-Abeta42- and anti-Abeta40-specific mAbs attenuate amyloid deposition in an Alzheimer disease mouse model. J Clin Invest 116:193\u2013201. https:\/\/doi.org\/10.1172\/JCI25410","journal-title":"J Clin Invest"},{"key":"2954_CR55","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1080\/13854046.2016.1257069","volume":"31","author":"C LoBue","year":"2017","unstructured":"LoBue C, Wadsworth H, Wilmoth K, Clem M, Hart J, Womack KB et al (2017) Traumatic brain injury history is associated with earlier age of onset of Alzheimer disease. Clin Neuropsychol 31:85\u201398. https:\/\/doi.org\/10.1080\/13854046.2016.1257069","journal-title":"Clin Neuropsychol"},{"key":"2954_CR56","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1016\/j.neuron.2016.09.015","volume":"92","author":"R Lopez-Gonzalez","year":"2016","unstructured":"Lopez-Gonzalez R, Lu YB, Gendron TF, Karydas A, Tran H, Yang DJ et al (2016) Poly(GR) in C9ORF72-related ALS\/FTD compromises mitochondrial function and increases oxidative stress and DNA damage in iPSC-derived motor neurons. Neuron 92:383\u2013391. https:\/\/doi.org\/10.1016\/j.neuron.2016.09.015","journal-title":"Neuron"},{"key":"2954_CR57","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcae043","volume":"6","author":"AC Macedo","year":"2024","unstructured":"Macedo AC, Therriault J, Tissot C, Fernandez-Arias J, Ferreira PCL, Vitali P et al (2024) Predicting functional decline in aging and Alzheimer\u2019s disease with PET-based Braak staging. Brain Commun 6:fcae043. https:\/\/doi.org\/10.1093\/braincomms\/fcae043","journal-title":"Brain Commun"},{"key":"2954_CR58","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1016\/S1474-4422(10)70195-2","volume":"9","author":"IR Mackenzie","year":"2010","unstructured":"Mackenzie IR, Rademakers R, Neumann M (2010) TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol 9:995\u20131007. https:\/\/doi.org\/10.1016\/S1474-4422(10)70195-2","journal-title":"Lancet Neurol"},{"key":"2954_CR59","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1212\/WNL.0000000000004058","volume":"89","author":"IG McKeith","year":"2017","unstructured":"McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D et al (2017) Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB consortium. Neurology 89:88\u2013100. https:\/\/doi.org\/10.1212\/WNL.0000000000004058","journal-title":"Neurology"},{"key":"2954_CR60","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/j.jalz.2011.03.005","volume":"7","author":"GM McKhann","year":"2011","unstructured":"McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH et al (2011) The diagnosis of dementia due to Alzheimer\u2019s disease: recommendations from the National Institute on Aging-Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease. Alzheimers Dement 7:263\u2013269. https:\/\/doi.org\/10.1016\/j.jalz.2011.03.005","journal-title":"Alzheimers Dement"},{"key":"2954_CR61","doi-asserted-by":"publisher","DOI":"10.3389\/fnsyn.2023.1129036","author":"S Meftah","year":"2023","unstructured":"Meftah S, Gan J (2023) Alzheimer\u2019s disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression. Front Synaptic Neuro. https:\/\/doi.org\/10.3389\/fnsyn.2023.1129036","journal-title":"Front Synaptic Neuro"},{"key":"2954_CR62","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-021-00503-x","author":"A Meneses","year":"2021","unstructured":"Meneses A, Koga S, O\u2019Leary J, Dickson DW, Bu GJ, Zhao N (2021) TDP-43 pathology in Alzheimer\u2019s disease. Mol Neurodegener. https:\/\/doi.org\/10.1186\/s13024-021-00503-x","journal-title":"Mol Neurodegener"},{"key":"2954_CR63","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.3233\/Jad-220159","volume":"88","author":"MM Mielke","year":"2022","unstructured":"Mielke MM, Ransom JE, Mandrekar J, Turcano P, Savica R, Brown AW (2022) Traumatic brain injury and risk of Alzheimer\u2019s disease and related dementias in the population. J Alzheimers Dis 88:1049\u20131059. https:\/\/doi.org\/10.3233\/Jad-220159","journal-title":"J Alzheimers Dis"},{"key":"2954_CR64","doi-asserted-by":"publisher","first-page":"1192","DOI":"10.1126\/science.1256800","volume":"345","author":"S Mizielinska","year":"2014","unstructured":"Mizielinska S, Gr\u00f6nke S, Niccoli T, Ridler CE, Clayton EL, Devoy A et al (2014) C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich protein. Science 345:1192\u20131194. https:\/\/doi.org\/10.1126\/science.1256800","journal-title":"Science"},{"key":"2954_CR65","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1126\/science.1232927","volume":"339","author":"K Mori","year":"2013","unstructured":"Mori K, Weng SM, Arzberger T, May S, Rentzsch K, Kremmer E et al (2013) The GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD\/ALS. Science 339:1335\u20131338. https:\/\/doi.org\/10.1126\/science.1232927","journal-title":"Science"},{"key":"2954_CR66","doi-asserted-by":"publisher","first-page":"2479","DOI":"10.1038\/s44319-024-00140-7","volume":"25","author":"AT Nelson","year":"2024","unstructured":"Nelson AT, Cicardi ME, Markandaiah SS, Han JYS, Philp NJ, Welebob E et al (2024) Glucose hypometabolism prompts RAN translation and exacerbates C9orf72-related ALS\/FTD phenotypes. EMBO Rep 25:2479\u20132510. https:\/\/doi.org\/10.1038\/s44319-024-00140-7","journal-title":"EMBO Rep"},{"key":"2954_CR67","doi-asserted-by":"publisher","first-page":"1503","DOI":"10.1093\/brain\/awz099","volume":"142","author":"PT Nelson","year":"2019","unstructured":"Nelson PT, Dickson DW, Trojanowski JQ, Jack CR, Boyle PA, Arfanakis K et al (2019) Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain 142:1503\u20131527. https:\/\/doi.org\/10.1093\/brain\/awz099","journal-title":"Brain"},{"key":"2954_CR68","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2416885122","author":"L Nguyen","year":"2025","unstructured":"Nguyen L, Ajredini R, Guo S, Romano LEL, Tomas RF, Bell LR et al (2025) intronic expansion identified by poly-glycine-arginine pathology increases Alzheimer\u2019s disease risk. Proc Natl Acad Sci USA. https:\/\/doi.org\/10.1073\/pnas.2416885122","journal-title":"Proc Natl Acad Sci USA"},{"key":"2954_CR69","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1038\/s41593-024-01850-w","volume":"28","author":"TB Nguyen","year":"2025","unstructured":"Nguyen TB, Miramontes R, Chillon-Marinas C, Maimon R, Vazquez-Sanchez S, Lau AL et al (2025) Aberrant splicing in Huntington\u2019s disease accompanies disrupted TDP-43 activity and altered m6A RNA modification. Nat Neurosci 28:280\u2013292. https:\/\/doi.org\/10.1038\/s41593-024-01850-w","journal-title":"Nat Neurosci"},{"key":"2954_CR70","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1001\/jamaneurol.2022.0976","volume":"79","author":"RA Nianogo","year":"2022","unstructured":"Nianogo RA, Rosenwohl-Mack A, Yaffe K, Carrasco A, Hoffmann CM, Barnes DE (2022) Risk factors associated with Alzheimer disease and related dementias by sex and race and ethnicity in the US. JAMA Neurol 79:584\u2013591. https:\/\/doi.org\/10.1001\/jamaneurol.2022.0976","journal-title":"JAMA Neurol"},{"key":"2954_CR71","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.pneurobio.2016.01.001","volume":"144","author":"LM Osborn","year":"2016","unstructured":"Osborn LM, Kamphuis W, Wadman WJ, Hol EM (2016) Astrogliosis: an integral player in the pathogenesis of Alzheimer\u2019s disease. Prog Neurobiol 144:121\u2013141. https:\/\/doi.org\/10.1016\/j.pneurobio.2016.01.001","journal-title":"Prog Neurobiol"},{"key":"2954_CR72","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1016\/j.biopsych.2023.09.003","volume":"95","author":"V Ourry","year":"2024","unstructured":"Ourry V, Binette AP, St-Onge F, Strikwerda-Brown C, Chagnot A, Poirier J et al (2024) How do modifiable risk factors affect Alzheimer\u2019s disease pathology or mitigate its effect on clinical symptom expression? Biol Psychiat 95:1006\u20131019. https:\/\/doi.org\/10.1016\/j.biopsych.2023.09.003","journal-title":"Biol Psychiat"},{"key":"2954_CR73","doi-asserted-by":"publisher","first-page":"679","DOI":"10.3233\/JAD-122110","volume":"39","author":"T Paajanen","year":"2014","unstructured":"Paajanen T, Hanninen T, Tunnard C, Hallikainen M, Mecocci P, Sobow T et al (2014) CERAD neuropsychological compound scores are accurate in detecting prodromal Alzheimer\u2019s disease: a prospective AddNeuroMed study. J Alzheimers Dis 39:679\u2013690. https:\/\/doi.org\/10.3233\/JAD-122110","journal-title":"J Alzheimers Dis"},{"key":"2954_CR74","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1007\/s40292-015-0115-2","volume":"23","author":"F Pistoia","year":"2016","unstructured":"Pistoia F, Sacco S, Degan D, Tiseo C, Ornello R, Carolei A (2016) Hypertension and stroke: epidemiological aspects and clinical evaluation. High Blood Press Cardiovasc Prev 23:9\u201318. https:\/\/doi.org\/10.1007\/s40292-015-0115-2","journal-title":"High Blood Press Cardiovasc Prev"},{"key":"2954_CR75","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1016\/s0891-5849(98)00085-9","volume":"25","author":"MC Polidori","year":"1998","unstructured":"Polidori MC, Frei B, Cherubini A, Nelles G, Rordorf G, Keaney JF Jr. et al (1998) Increased plasma levels of lipid hydroperoxides in patients with ischemic stroke. Free Radic Biol Med 25:561\u2013567. https:\/\/doi.org\/10.1016\/s0891-5849(98)00085-9","journal-title":"Free Radic Biol Med"},{"key":"2954_CR76","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1002\/ana.410430617","volume":"43","author":"P Poorkaj","year":"1998","unstructured":"Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L et al (1998) Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 43:815\u2013825. https:\/\/doi.org\/10.1002\/ana.410430617","journal-title":"Ann Neurol"},{"key":"2954_CR77","doi-asserted-by":"publisher","first-page":"25","DOI":"10.3389\/fnmol.2019.00025","volume":"12","author":"A Prasad","year":"2019","unstructured":"Prasad A, Bharathi V, Sivalingam V, Girdhar A, Patel BK (2019) Molecular mechanisms of TDP-43 misfolding and pathology in amyotrophic lateral sclerosis. Front Mol Neurosci 12:25. https:\/\/doi.org\/10.3389\/fnmol.2019.00025","journal-title":"Front Mol Neurosci"},{"key":"2954_CR78","doi-asserted-by":"publisher","first-page":"4171","DOI":"10.1016\/S0021-9258(18)34702-1","volume":"257","author":"SC Rall Jr.","year":"1982","unstructured":"Rall SC Jr., Weisgraber KH, Mahley RW (1982) Human apolipoprotein E. The complete amino acid sequence. J Biol Chem 257:4171\u20134178","journal-title":"J Biol Chem"},{"key":"2954_CR79","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21239149","author":"C Ransy","year":"2020","unstructured":"Ransy C, Vaz C, Lombes A, Bouillaud F (2020) Use of H(2)O(2) to cause oxidative stress, the catalase issue. Int J Mol Sci. https:\/\/doi.org\/10.3390\/ijms21239149","journal-title":"Int J Mol Sci"},{"key":"2954_CR80","doi-asserted-by":"publisher","first-page":"213","DOI":"10.3109\/02699059509008194","volume":"9","author":"DX Rasmusson","year":"1995","unstructured":"Rasmusson DX, Brandt J, Martin DB, Folstein MF (1995) Head-injury as a risk factor in Alzheimers-disease. Brain Inj 9:213\u2013219. https:\/\/doi.org\/10.3109\/02699059509008194","journal-title":"Brain Inj"},{"key":"2954_CR81","doi-asserted-by":"publisher","first-page":"1483","DOI":"10.1001\/jama.2013.2973","volume":"309","author":"C Reitz","year":"2013","unstructured":"Reitz C, Jun G, Naj A, Rajbhandary R, Vardarajan BN, Wang LS et al (2013) Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E \u03f54,and the risk of late-onset Alzheimer disease in African Americans. JAMA 309:1483\u20131492. https:\/\/doi.org\/10.1001\/jama.2013.2973","journal-title":"JAMA"},{"key":"2954_CR82","doi-asserted-by":"publisher","first-page":"926","DOI":"10.2174\/1570159x15666170116143743","volume":"15","author":"R Ricciarelli","year":"2017","unstructured":"Ricciarelli R, Fedele E (2017) The amyloid cascade hypothesis in Alzheimer\u2019s disease: it\u2019s time to change our mind. Curr Neuropharmacol 15:926\u2013935. https:\/\/doi.org\/10.2174\/1570159x15666170116143743","journal-title":"Curr Neuropharmacol"},{"key":"2954_CR83","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1086\/302256","volume":"64","author":"P Rizzu","year":"1999","unstructured":"Rizzu P, Van Swieten JC, Joosse M, Hasegawa M, Stevens M, Tibben A et al (1999) High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands. Am J Hum Genet 64:414\u2013421. https:\/\/doi.org\/10.1086\/302256","journal-title":"Am J Hum Genet"},{"key":"2954_CR84","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1126\/science.1141736","volume":"316","author":"ED Roberson","year":"2007","unstructured":"Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T et al (2007) Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer\u2019s disease mouse model. Science 316:750\u2013754. https:\/\/doi.org\/10.1126\/science.1141736","journal-title":"Science"},{"key":"2954_CR85","doi-asserted-by":"publisher","first-page":"2766","DOI":"10.1002\/alz.13717","volume":"20","author":"M Ruthirakuhan","year":"2024","unstructured":"Ruthirakuhan M, Swardfager W, Xiong LS, MacIntosh BJ, Rabin JS, Lanct\u00f4t KL et al (2024) Investigating the impact of hypertension with and without diabetes on Alzheimer\u2019s disease risk: a clinico-pathological study. Alzheimers Dement 20:2766\u20132778. https:\/\/doi.org\/10.1002\/alz.13717","journal-title":"Alzheimers Dement"},{"key":"2954_CR86","doi-asserted-by":"publisher","first-page":"4799","DOI":"10.1038\/s41598-022-08724-w","volume":"12","author":"S Ryan","year":"2022","unstructured":"Ryan S, Rollinson S, Hobbs E, Pickering-Brown S (2022) C9orf72 dipeptides disrupt the nucleocytoplasmic transport machinery and cause TDP-43 mislocalisation to the cytoplasm. Sci Rep 12:4799. https:\/\/doi.org\/10.1038\/s41598-022-08724-w","journal-title":"Sci Rep"},{"key":"2954_CR87","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1007\/s00401-017-1793-8","volume":"135","author":"S Saberi","year":"2018","unstructured":"Saberi S, Stauffer JE, Jiang J, Garcia SD, Taylor AE, Schulte D et al (2018) Sense-encoded poly-GR dipeptide repeat proteins correlate to neurodegeneration and uniquely co-localize with TDP-43 in dendrites of repeat-expanded C9orf72 amyotrophic lateral sclerosis. Acta Neuropathol 135:459\u2013474. https:\/\/doi.org\/10.1007\/s00401-017-1793-8","journal-title":"Acta Neuropathol"},{"key":"2954_CR88","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1186\/s40478-018-0564-7","volume":"6","author":"N Sakae","year":"2018","unstructured":"Sakae N, Bieniek KF, Zhang YJ, Ross K, Gendron TF, Murray ME et al (2018) Poly-GR dipeptide repeat polymers correlate with neurodegeneration and clinicopathological subtypes in C9ORF72-related brain disease. Acta Neuropathol Commun 6:63. https:\/\/doi.org\/10.1186\/s40478-018-0564-7","journal-title":"Acta Neuropathol Commun"},{"key":"2954_CR89","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1037\/neu0000423","volume":"32","author":"J Schaffert","year":"2018","unstructured":"Schaffert J, Lobue C, White CL, Chiang HS, Didehbani N, Lacritz L et al (2018) Traumatic brain injury history is associated with an earlier age of dementia onset in autopsy-confirmed Alzheimer\u2019s disease. Neuropsychology 32:410\u2013416. https:\/\/doi.org\/10.1037\/neu0000423","journal-title":"Neuropsychology"},{"key":"2954_CR90","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1136\/jnnp.62.2.119","volume":"62","author":"PW Schofield","year":"1997","unstructured":"Schofield PW, Tang M, Marder K, Bell K, Dooneief G, Chun M et al (1997) Alzheimer\u2019s disease after remote head injury: an incidence study. J Neurol Neurosurg Psychiatry 62:119\u2013124. https:\/\/doi.org\/10.1136\/jnnp.62.2.119","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"2954_CR91","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1126\/science.1074069","volume":"298","author":"DJ Selkoe","year":"2002","unstructured":"Selkoe DJ (2002) Alzheimer\u2019s disease is a synaptic failure. Science 298:789\u2013791. https:\/\/doi.org\/10.1126\/science.1074069","journal-title":"Science"},{"key":"2954_CR92","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1097\/JGP.0b013e3181cab764","volume":"18","author":"EH Seo","year":"2010","unstructured":"Seo EH, Lee DY, Lee JH, Choo IH, Kim JW, Kim SG et al (2010) Total scores of the CERAD neuropsychological assessment battery: validation for mild cognitive impairment and dementia patients with diverse etiologies. Am J Geriatr Psychiatry 18:801\u2013809. https:\/\/doi.org\/10.1097\/JGP.0b013e3181cab764","journal-title":"Am J Geriatr Psychiatry"},{"key":"2954_CR93","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s13024-021-00452-5","volume":"16","author":"M Seto","year":"2021","unstructured":"Seto M, Weiner RL, Dumitrescu L, Hohman TJ (2021) Protective genes and pathways in Alzheimer\u2019s disease: moving towards precision interventions. Mol Neurodegener 16:29. https:\/\/doi.org\/10.1186\/s13024-021-00452-5","journal-title":"Mol Neurodegener"},{"key":"2954_CR94","doi-asserted-by":"publisher","first-page":"2977","DOI":"10.1093\/brain\/awl203","volume":"129","author":"K Sleegers","year":"2006","unstructured":"Sleegers K, Brouwers N, Gijselinck I, Theuns J, Goossens D, Wauters J et al (2006) APP duplication is sufficient to cause early onset Alzheimer\u2019s dementia with cerebral amyloid angiopathy. Brain 129:2977\u20132983. https:\/\/doi.org\/10.1093\/brain\/awl203","journal-title":"Brain"},{"key":"2954_CR95","doi-asserted-by":"publisher","first-page":"2908","DOI":"10.1093\/brain\/awy241","volume":"141","author":"DA Solomon","year":"2018","unstructured":"Solomon DA, Stepto A, Au WH, Adachi Y, Diaper DC, Hall R et al (2018) A feedback loop between dipeptide-repeat protein, TDP-43 and karyopherin-\u03b1 mediates C9orf72-re ated neurodegeneration. Brain 141:2908\u20132924. https:\/\/doi.org\/10.1093\/brain\/awy241","journal-title":"Brain"},{"key":"2954_CR96","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1016\/j.neuron.2014.05.004","volume":"82","author":"TL Spires-Jones","year":"2014","unstructured":"Spires-Jones TL, Hyman BT (2014) The intersection of amyloid beta and Tau at synapses in Alzheimer\u2019s disease. Neuron 82:756\u2013771. https:\/\/doi.org\/10.1016\/j.neuron.2014.05.004","journal-title":"Neuron"},{"key":"2954_CR97","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-49087-0","volume":"13","author":"C Tang","year":"2023","unstructured":"Tang C, Ma YY, Lei XY, Ding YQ, Yang SS, He D (2023) Hypertension linked to Alzheimer\u2019s disease via stroke: Mendelian randomization. Sci Rep 13:21606. https:\/\/doi.org\/10.1038\/s41598-023-49087-0","journal-title":"Sci Rep"},{"key":"2954_CR98","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a006296","author":"RE Tanzi","year":"2012","unstructured":"Tanzi RE (2012) The genetics of Alzheimer disease. Cold Spring Harb Perspect Med. https:\/\/doi.org\/10.1101\/cshperspect.a006296","journal-title":"Cold Spring Harb Perspect Med"},{"key":"2954_CR99","doi-asserted-by":"publisher","first-page":"663","DOI":"10.3233\/Jad-201032","volume":"79","author":"SJ Teipel","year":"2021","unstructured":"Teipel SJ, Temp AGM, Levin F, Dyrba M, Grothe MJ, Initia ADN (2021) Association of TDP-43 pathology with global and regional <SUP>18<\/SUP>F-florbetapir PET signal in the Alzheimer\u2019s disease spectrum. J Alzheimers Dis 79:663\u2013670. https:\/\/doi.org\/10.3233\/Jad-201032","journal-title":"J Alzheimers Dis"},{"key":"2954_CR100","doi-asserted-by":"publisher","first-page":"1791","DOI":"10.1212\/wnl.58.12.1791","volume":"58","author":"DR Thal","year":"2002","unstructured":"Thal DR, Rub U, Orantes M, Braak H (2002) Phases of a beta-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791\u20131800. https:\/\/doi.org\/10.1212\/wnl.58.12.1791","journal-title":"Neurology"},{"key":"2954_CR101","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1186\/s12868-016-0288-1","volume":"17","author":"RS Thomas","year":"2016","unstructured":"Thomas RS, Henson A, Gerrish A, Jones L, Williams J, Kidd EJ (2016) Decreasing the expression of PICALM reduces endocytosis and the activity of beta-secretase: implications for Alzheimer\u2019s disease. BMC Neurosci 17:50. https:\/\/doi.org\/10.1186\/s12868-016-0288-1","journal-title":"BMC Neurosci"},{"key":"2954_CR102","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1016\/j.neuron.2013.03.026","volume":"78","author":"PK Todd","year":"2013","unstructured":"Todd PK, Oh SY, Krans A, He F, Sellier C, Frazer M et al (2013) CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome. Neuron 78:440\u2013455. https:\/\/doi.org\/10.1016\/j.neuron.2013.03.026","journal-title":"Neuron"},{"key":"2954_CR103","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1038\/nmeth.3995","volume":"13","author":"M Uhlen","year":"2016","unstructured":"Uhlen M, Bandrowski A, Carr S, Edwards A, Ellenberg J, Lundberg E et al (2016) A proposal for validation of antibodies. Nat Methods 13:823\u2013827. https:\/\/doi.org\/10.1038\/nmeth.3995","journal-title":"Nat Methods"},{"key":"2954_CR104","doi-asserted-by":"publisher","first-page":"427","DOI":"10.3233\/Jad-160527","volume":"54","author":"M Vijayan","year":"2016","unstructured":"Vijayan M, Reddy PH (2016) Stroke, vascular dementia, and Alzheimer\u2019s disease: molecular links. J Alzheimers Dis 54:427\u2013443. https:\/\/doi.org\/10.3233\/Jad-160527","journal-title":"J Alzheimers Dis"},{"key":"2954_CR105","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15701-2","author":"Vogel JW, Iturria-Medina Y, Strandberg OT, Smith R, Levitis E, Evans AC, Hansson O, Initiat ADN, Study SB","year":"2020","unstructured":"Vogel JW, Iturria-Medina Y, Strandberg OT, Smith R, Levitis E, Evans AC, Hansson O, Initiat ADN, Study SB (2020) Spread of pathological tau proteins through communicating neurons in human Alzheimer\u2019s disease. Nat Commun. https:\/\/doi.org\/10.1038\/s41467-020-15701-2","journal-title":"Nat Commun"},{"key":"2954_CR106","doi-asserted-by":"publisher","first-page":"9077","DOI":"10.1016\/S0021-9258(19)52510-8","volume":"256","author":"KH Weisgraber","year":"1981","unstructured":"Weisgraber KH, Rall SC Jr., Mahley RW (1981) Human E apoprotein heterogeneity. Cysteine-arginine interchanges in the amino acid sequence of the apo-E isoforms. J Biol Chem 256:9077\u20139083","journal-title":"J Biol Chem"},{"key":"2954_CR107","doi-asserted-by":"publisher","unstructured":"Westergard T, McAvoy K, Russell K, Wen XM, Pang Y, Morris B, Pasinelli P, Trotti D, Haeusler A (2019) Repeat-associated non-AUG translation in C9orf72-ALS\/FTD is driven by neuronal excitation and stress. Embo Mol Med. https:\/\/doi.org\/10.15252\/emmm.201809423","DOI":"10.15252\/emmm.201809423"},{"key":"2954_CR108","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1186\/s40478-019-0858-4","volume":"7","author":"Wharton SB, Wang D, Parikh C, Matthews FE, Brayne C, Ince PG, Cognitive F, Ageing Neuropathology Study G","year":"2019","unstructured":"Wharton SB, Wang D, Parikh C, Matthews FE, Brayne C, Ince PG, Cognitive F, Ageing Neuropathology Study G (2019) Epidemiological pathology of Abeta deposition in the ageing brain in CFAS: addition of multiple Abeta-derived measures does not improve dementia assessment using logistic regression and machine learning approaches. Acta Neuropathol Commun 7:198. https:\/\/doi.org\/10.1186\/s40478-019-0858-4","journal-title":"Acta Neuropathol Commun"},{"key":"2954_CR109","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1016\/j.jagp.2012.08.021","volume":"22","author":"S Wolfsgruber","year":"2014","unstructured":"Wolfsgruber S, Jessen F, Wiese B, Stein J, Bickel H, Mosch E et al (2014) The CERAD neuropsychological assessment battery total score detects and predicts Alzheimer disease dementia with high diagnostic accuracy. Am J Geriatr Psychiatry 22:1017\u20131028. https:\/\/doi.org\/10.1016\/j.jagp.2012.08.021","journal-title":"Am J Geriatr Psychiatry"},{"key":"2954_CR110","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1186\/s12864-024-10447-3","volume":"25","author":"J Xie","year":"2024","unstructured":"Xie J, Lan Y, Zou C, He J, Huang Q, Zeng J et al (2024) Single-nucleus analysis reveals microenvironment-specific neuron and glial cell enrichment in Alzheimer\u2019s disease. BMC Genomics 25:526. https:\/\/doi.org\/10.1186\/s12864-024-10447-3","journal-title":"BMC Genomics"},{"key":"2954_CR111","doi-asserted-by":"publisher","first-page":"14519","DOI":"10.1038\/s41598-022-18548-3","volume":"12","author":"X Xin","year":"2022","unstructured":"Xin X, Gong T, Hong Y (2022) Hydrogen peroxide initiates oxidative stress and proteomic alterations in meningothelial cells. Sci Rep 12:14519. https:\/\/doi.org\/10.1038\/s41598-022-18548-3","journal-title":"Sci Rep"},{"key":"2954_CR112","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1186\/s12964-024-01509-w","volume":"22","author":"X Xu","year":"2024","unstructured":"Xu X, Han Y, Zhang B, Ren Q, Ma J, Liu S (2024) Understanding immune microenvironment alterations in the brain to improve the diagnosis and treatment of diverse brain diseases. Cell Commun Signal 22:132. https:\/\/doi.org\/10.1186\/s12964-024-01509-w","journal-title":"Cell Commun Signal"},{"key":"2954_CR113","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1111\/neup.12894","volume":"43","author":"Y Yonenobu","year":"2023","unstructured":"Yonenobu Y, Beck G, Kido K, Maeda N, Yamashita R, Inoue K et al (2023) Neuropathology of spinocerebellar ataxia type 8: common features and unique tauopathy. Neuropathology 43:351\u2013361. https:\/\/doi.org\/10.1111\/neup.12894","journal-title":"Neuropathology"},{"key":"2954_CR114","doi-asserted-by":"publisher","first-page":"2181","DOI":"10.7150\/ijbs.57078","volume":"17","author":"HQ Zhang","year":"2021","unstructured":"Zhang HQ, Wei W, Zhao M, Ma LN, Jiang XF, Pei H et al (2021) Interaction between A\u03b2 and Tau in the pathogenesis of Alzheimer\u2019s disease. Int J Biol Sci 17:2181\u20132192. https:\/\/doi.org\/10.7150\/ijbs.57078","journal-title":"Int J Biol Sci"},{"key":"2954_CR115","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1038\/s41380-018-0101-x","volume":"25","author":"ST Zhang","year":"2020","unstructured":"Zhang ST, Cai F, Wu YL, Bozorgmehr T, Wang Z, Zhang S et al (2020) A presenilin-1 mutation causes Alzheimer disease without affecting Notch signaling. Mol Psychiatr 25:603\u2013613. https:\/\/doi.org\/10.1038\/s41380-018-0101-x","journal-title":"Mol Psychiatr"},{"key":"2954_CR116","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2018.00809","volume":"9","author":"X Zhang","year":"2018","unstructured":"Zhang X, Gao F, Wang DD, Li C, Fu Y, He W et al (2018) Tau pathology in Parkinson\u2019s disease. Front Neurol 9:809. https:\/\/doi.org\/10.3389\/fneur.2018.00809","journal-title":"Front Neurol"},{"key":"2954_CR117","doi-asserted-by":"publisher","first-page":"1136","DOI":"10.1038\/s41591-018-0071-1","volume":"24","author":"YJ Zhang","year":"2018","unstructured":"Zhang YJ, Gendron TF, Ebbert MTW, O\u2019Raw AD, Yue M, Jansen-West K et al (2018) Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. Nat Med 24:1136. https:\/\/doi.org\/10.1038\/s41591-018-0071-1","journal-title":"Nat Med"},{"key":"2954_CR118","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1073\/pnas.1013343108","volume":"108","author":"T Zu","year":"2011","unstructured":"Zu T, Gibbens B, Doty NS, Gomes-Pereira M, Huguet A, Stone MD et al (2011) Non-ATG-initiated translation directed by microsatellite expansions. P Natl Acad Sci USA 108:260\u2013265. https:\/\/doi.org\/10.1073\/pnas.1013343108","journal-title":"P Natl Acad Sci USA"},{"key":"2954_CR119","doi-asserted-by":"publisher","first-page":"18591","DOI":"10.1073\/pnas.2005748117","volume":"117","author":"T Zu","year":"2020","unstructured":"Zu T, Guo S, Bardhi O, Ryskamp DA, Li J, Tusi SK et al (2020) Metformin inhibits RAN translation through PKR pathway and mitigates disease in C9orf72-ALS\/FTD mice. P Natl Acad Sci USA 117:18591\u201318599. https:\/\/doi.org\/10.1073\/pnas.2005748117","journal-title":"P Natl Acad Sci USA"},{"key":"2954_CR120","doi-asserted-by":"publisher","first-page":"E4968","DOI":"10.1073\/pnas.1315438110","volume":"110","author":"T Zu","year":"2013","unstructured":"Zu T, Liu Y, Banez-Coronel M, Reid T, Pletnikova O, Lewis J et al (2013) RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc Natl Acad Sci U S A 110:E4968-4977. https:\/\/doi.org\/10.1073\/pnas.1315438110","journal-title":"Proc Natl Acad Sci U S A"}],"container-title":["Acta Neuropathologica"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00401-025-02954-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00401-025-02954-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00401-025-02954-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T17:13:55Z","timestamp":1762881235000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00401-025-02954-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,8]]},"references-count":120,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["2954"],"URL":"https:\/\/doi.org\/10.1007\/s00401-025-02954-8","relation":{},"ISSN":["1432-0533"],"issn-type":[{"value":"1432-0533","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,8]]},"assertion":[{"value":"30 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 October 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 October 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 November 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Dr. H Brent Clark served as a consultant for Janssen Research and Development in 2021 and 2022.Dr. Bradley Hyman serves on the SAB of Dewpoint and has an option for stock. Dr. Bradley Hyman serves on a scientific advisory board or is a consultant for AbbVie, Alexion, Ambagon, Aprinoia Therapeutics, Arvinas, Avrobio, AstraZeneca, Biogen, Bioinsights, BMS, Cure Alz Fund, Cell Signaling, Dewpoint, Latus, Novartis, Pfizer, Sanofi, Sofinnova, Vigil, Violet, Voyager, WaveBreak. Dr. Bradley Hyman has an option for stock in Dewpoint. Dr. Bradley Hyman owns stock in Novartis. Dr. Laura Ranum is an inventor on patents that are related to RAN translation. Dr. Lien Nguyen is an inventor on patents that are related to RAN translation.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"49"}}