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Emerging diagnostics and therapeutics for Alzheimer disease – Nature Medicine


  • World Health Organization. Ageing and health. https://www.who.int/news-room/fact-sheets/detail/ageing-and-health (2022).

  • Alzheimer’s Association. Alzheimer’s Disease Facts and Figures. Alzheimer’s Disease and Dementia https://www.alz.org/alzheimers-dementia/facts-figures

  • van Dyck, C. H. et al. Lecanemab in early Alzheimer’s disease. N. Engl. J. Med. 388, 9–21 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Sims, J. R. et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. J. Am. Med. Assoc. 330, 512–527 (2023).

    Article 
    CAS 

    Google Scholar
     

  • Nichols, E. et al. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health 7, e105–e125 (2022).

    Article 

    Google Scholar
     

  • Bateman, R. J. et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N. Engl. J. Med. 367, 795–804 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Vermunt, L. et al. Duration of preclinical, prodromal, and dementia stages of Alzheimer’s disease in relation to age, sex, and APOE genotype. Alzheimer’s Dement. 15, 888–898 (2019).

    Article 

    Google Scholar
     

  • Ossenkoppele, R., van der Kant, R. & Hansson, O. Tau biomarkers in Alzheimer’s disease: towards implementation in clinical practice and trials. Lancet Neurol. 21, 726–734 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chapleau, M., Iaccarino, L., Soleimani-Meigooni, D. & Rabinovici, G. D. The role of amyloid PET in imaging neurodegenerative disorders: a review. J. Nucl. Med. 63, 13S–19S (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Long, J. M. & Holtzman, D. M. Alzheimer disease: an update on pathobiology and treatment strategies. Cell 179, 312–339 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Glenner, G. G. & Wong, C. W. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 120, 885–890 (1984).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Masters, C. L. et al. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc. Natl Acad. Sci. USA 82, 4245–4249 (1985).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Levy, E. et al. Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248, 1124–1126 (1990).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349, 704–706 (1991).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hardy, J. & Allsop, D. Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol. Sci. 12, 383–388 (1991).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Selkoe, D. J. The molecular pathology of Alzheimer’s disease. Neuron 6, 487–498 (1991).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ossenkoppele, R. et al. Amyloid and tau PET-positive cognitively unimpaired individuals are at high risk for future cognitive decline. Nat. Med. 28, 2381–2387 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Strikwerda-Brown, C. et al. Association of elevated amyloid and tau positron emission tomography signal with near-term development of Alzheimer disease symptoms in older adults without cognitive impairment. JAMA Neurol. 79, 975–985 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, W. J. et al. Regional Aβ–tau interactions promote onset and acceleration of Alzheimer’s disease tau spreading. Neuron 110, 1932–1943 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yuan, P. et al. PLD3 affects axonal spheroids and network defects in Alzheimer’s disease. Nature 612, 328–337 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • He, Z. et al. Amyloid-β plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat. Med. 24, 29–38 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Busche, M. A. & Hyman, B. T. Synergy between amyloid-β and tau in Alzheimer’s disease. Nat. Neurosci. 23, 1183–1193 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chen, X. & Holtzman, D. M. Emerging roles of innate and adaptive immunity in Alzheimer’s disease. Immunity 55, 2236–2254 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bellenguez, C. et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat. Genet. 54, 412–436 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nutma, E. et al. Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases. Preprint at https://doi.org/10.1101/2022.05.11.491453 (2022).

  • Beaino, W. et al. Towards PET imaging of the dynamic phenotypes of microglia. Clin. Exp. Immunol. 206, 282–300 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pascoal, T. A. et al. Microglial activation and tau propagate jointly across Braak stages. Nat. Med. 27, 1592–1599 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Xiang, X. et al. Microglial activation states drive glucose uptake and FDG-PET alterations in neurodegenerative diseases. Sci. Transl. Med. 13, eabe5640 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hansson, O. et al. The Alzheimer’s Association appropriate use recommendations for blood biomarkers in Alzheimer’s disease. Alzheimers Dement. 18, 2669–2686 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lewczuk, P. et al. Cerebrospinal fluid Aβ42/40 corresponds better than Aβ42 to amyloid PET in Alzheimer’s disease. J. Alzheimer’s Dis. 55, 813–822 (2017).

    Article 
    CAS 

    Google Scholar
     

  • US Food and Drug Administration. FDA permits marketing for new test to improve diagnosis of Alzheimer’s disease. https://www.fda.gov/news-events/press-announcements/fda-permits-marketing-new-test-improve-diagnosis-alzheimers-disease (2022).

  • Li, Y. et al. Validation of plasma amyloid-β 42/40 for detecting Alzheimer disease amyloid plaques. Neurology 98, e688–e699 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Aschenbrenner, A. J. et al. Comparison of plasma and CSF biomarkers in predicting cognitive decline. Ann. Clin. Transl. Neurol. 9, 1739–1751 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wesseling, H. et al. Tau PTM profiles identify patient heterogeneity and stages of Alzheimer’s disease. Cell 183, 1699–1713 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Barthélemy, N. R. et al. A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease. Nat. Med. 26, 398–407 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Suárez-Calvet, M. et al. Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer’s continuum when only subtle changes in Aβ pathology are detected. EMBO Mol. Med. 12, e12921 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chhatwal, J. P. et al. Plasma N-terminal tau fragment levels predict future cognitive decline and neurodegeneration in healthy elderly individuals. Nat. Commun. 11, 6024 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sato, C. et al. Tau kinetics in neurons and the human central nervous system. Neuron 97, 1284–1298 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Barthélemy, N. R., Horie, K., Sato, C. & Bateman, R. J. Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer’s disease. J. Exp. Med. 217, e20200861 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Janelidze, S. et al. Head-to-head comparison of 10 plasma phospho-tau assays in prodromal Alzheimer’s disease. Brain 146, 1592–1601 (2022).

    Article 
    PubMed Central 

    Google Scholar
     

  • Aguillon, D. et al. Plasma p-tau217 predicts in vivo brain pathology and cognition in autosomal dominant Alzheimer’s disease. Alzheimers Dement. 19, 2585–2594 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Horie, K., Barthélemy, N. R., Sato, C. & Bateman, R. J. CSF tau microtubule binding region identifies tau tangle and clinical stages of Alzheimer’s disease. Brain 144, 515–527 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Blennow, K. et al. Cerebrospinal fluid tau fragment correlates with tau PET: a candidate biomarker for tangle pathology. Brain 143, 650–660 (2019).

    Article 
    PubMed Central 

    Google Scholar
     

  • Fitzpatrick, A. W. P. et al. Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 547, 185–190 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Simrén, J. et al. CSF tau368/total-tau ratio reflects cognitive performance and neocortical tau better compared to p-tau181 and p-tau217 in cognitively impaired individuals. Alzheimer’s Res. Ther. 14, 192 (2022).

    Article 

    Google Scholar
     

  • Fischer, I. & Baas, P. W. Resurrecting the mysteries of big tau. Trends Neurosci. 43, 493–504 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gonzalez-Ortiz, F. et al. Brain-derived tau: a novel blood-based biomarker for Alzheimer’s disease-type neurodegeneration. Brain 146, 1162–1165 (2022).


    Google Scholar
     

  • Chatterjee, P. et al. Plasma glial fibrillary acidic protein in autosomal dominant Alzheimer’s disease: associations with Aβ-PET, neurodegeneration, and cognition. Alzheimers Dement. https://doi.org/10.1002/alz.12879 (2022).

  • Pereira, J. B. et al. Plasma GFAP is an early marker of amyloid-β but not tau pathology in Alzheimer’s disease. Brain 144, 3505–3516 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Biel, D. et al. sTREM2 is associated with amyloid-related p-tau increases and glucose hypermetabolism in Alzheimer’s disease. EMBO Mol. Med. 15, e16987 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cao, M. et al. ABI3 is a novel early biomarker of Alzheimer’s disease. J. Alzheimer’s Dis. 87, 335–344 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Gate, D. et al. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature 577, 399–404 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Piehl, N. et al. Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment. Cell 185, 5028–5039 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Halbgebauer, S. et al. CSF levels of SNAP-25 are increased early in Creutzfeldt-Jakob and Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatry 93, 1059–1065 (2022).

    Article 

    Google Scholar
     

  • Galasko, D. et al. Synaptic biomarkers in CSF aid in diagnosis, correlate with cognition and predict progression in MCI and Alzheimer’s disease. Alzheimer’s Dement. 5, 871–882 (2019).

    Article 

    Google Scholar
     

  • Bacioglu, M. et al. Neurofilament light chain in blood and CSF as marker of disease progression in mouse models and in neurodegenerative diseases. Neuron 91, 494–496 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kaeser, S. A. et al. A neuronal blood marker is associated with mortality in old age. Nat. Aging 1, 218–225 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Ashton, N. J. et al. A multicentre validation study of the diagnostic value of plasma neurofilament light. Nat. Commun. 12, 3400 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gianattasio, K. Z. et al. Generalizability of findings from a clinical sample to a community-based sample: a comparison of ADNI and ARIC. Alzheimers Dement. 17, 1265–1276 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mielke, M. M. et al. Performance of plasma phosphorylated tau 181 and 217 in the community. Nat. Med. 28, 1398–1405 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wisch, J. K. et al. Proteomic clusters underlie heterogeneity in preclinical Alzheimer’s disease progression. Brain 146, 2944–2956 (2022).

    Article 

    Google Scholar
     

  • Yang, C. et al. Genomic atlas of the proteome from brain, CSF and plasma prioritizes proteins implicated in neurological disorders. Nat. Neurosci. 24, 1302–1312 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sevigny, J. et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 537, 50–56 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Budd Haeberlein, S. et al. Two randomized phase 3 studies of aducanumab in early Alzheimer’s disease. J. Prev. Alzheimers Dis. 9, 197–210 (2022).

    CAS 
    PubMed 

    Google Scholar
     

  • Egan, M. F. et al. Randomized trial of verubecestat for mild-to-moderate Alzheimer’s disease. N. Engl. J. Med. 378, 1691–1703 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Doody, R. S. et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N. Engl. J. Med. 369, 341–350 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Vassar, R. BACE1 inhibitor drugs in clinical trials for Alzheimer’s disease. Alzheimer’s Res. Ther. 6, 89 (2014).

    Article 

    Google Scholar
     

  • Hur, J.-Y. γ-Secretase in Alzheimer’s disease. Exp. Mol. Med 54, 433–446 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Doody, R. S. et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N. Engl. J. Med. 370, 311–321 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ostrowitzki, S. et al. Evaluating the safety and efficacy of crenezumab vs placebo in adults with early Alzheimer disease: two phase 3 randomized placebo-controlled trials. JAMA Neurol. 79, 1113–1121 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Reish, N. J. et al. Multiple cerebral hemorrhages in a patient receiving lecanemab and treated with t-PA for stroke. N. Engl. J. Med. 388, 478–479 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Filippi, M. et al. Amyloid-related imaging abnormalities and β-amyloid–targeting antibodies: a systematic review. JAMA Neurol. 79, 291–304 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Reyderman, L. et al. Modeled impact of APOE4 genotype on ARIA-E incidence in patients treated with lecanemab. Alzheimer’s Dement. 18, e069402 (2022).

    Article 

    Google Scholar
     

  • Antolini, L. et al. Spontaneous ARIA-like events in cerebral amyloid angiopathy–related Inflammation: a multicenter prospective longitudinal cohort study. Neurology 97, e1809–e1822 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Xiong, M. et al. APOE immunotherapy reduces cerebral amyloid angiopathy and amyloid plaques while improving cerebrovascular function. Sci. Transl. Med. 13, eabd7522 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Salloway, S. et al. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat. Med. 27, 1187–1196 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rafii, M. S. et al. The AHEAD 3-45 study: design of a prevention trial for Alzheimer’s disease. Alzheimer’s Dement. 19, 1227–1233 (2023).

    Article 
    CAS 

    Google Scholar
     

  • Joseph-Mathurin, N. et al. Amyloid-related imaging abnormalities in the DIAN-TU-001 trial of gantenerumab and solanezumab: lessons from a trial in dominantly inherited Alzheimer disease. Ann. Neurol. 92, 729–744 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • US Food and Drug Administration. FDA converts novel Alzheimer’s disease treatment to traditional approval. https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval (2023).

  • Rafii, M. S. et al. Safety, tolerability, and immunogenicity of the ACI-24 vaccine in adults with Down syndrome: a phase 1b randomized clinical trial. JAMA Neurol. 79, 565–574 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rynearson, K. D. et al. Preclinical validation of a potent γ-secretase modulator for Alzheimer’s disease prevention. J. Exp. Med. 218, e20202560 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Duong, M. T. et al. Dissociation of tau pathology and neuronal hypometabolism within the ATN framework of Alzheimer’s disease. Nat. Commun. 13, 1495 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Imbimbo, B. P., Ippati, S., Watling, M. & Balducci, C. A critical appraisal of tau-targeting therapies for primary and secondary tauopathies. Alzheimer’s Dement. 18, 1008–1037 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Teng, E. et al. Safety and efficacy of semorinemab in individuals with prodromal to mild Alzheimer disease: a randomized clinical trial. JAMA Neurol. 79, 758–767 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Florian, H. et al. Tilavonemab in early Alzheimer’s disease: results from a phase 2, randomized, double-blind study. Brain 146, 2275–2284 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Meisl, G. et al. In vivo rate-determining steps of tau seed accumulation in Alzheimer’s disease. Sci. Adv. 7, eabh1448 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bateman, R. J. et al. The DIAN-TU next generation Alzheimer’s prevention trial: adaptive design and disease progression model. Alzheimer’s Dement. 13, 8–19 (2017).

    Article 

    Google Scholar
     

  • DeVos, S. L. et al. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci. Transl. Med. 9, eaag0481 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mummery, C. J. et al. Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial. Nat. Med. 29, 1437–1447 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Biogen. New data presented at AD/PD 2023 show Biogen’s BIIB080 (MAPT ASO) substantially reduced tau protein levels in patients with early-stage Alzheimer’s disease. https://investors.biogen.com/news-releases/news-release-details/new-data-presented-adpdtm-2023-show-biogens-biib080-mapt-aso (2023).

  • Cummings, J. et al. Alzheimer’s disease drug development pipeline: 2022. Alzheimers Dement. 8, e12295 (2022).

    Article 

    Google Scholar
     

  • Zhou, Y. et al. Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease. Nat. Med. 26, 131–142 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zeng, H. et al. Integrative in situ mapping of single-cell transcriptional states and tissue histopathology in a mouse model of Alzheimer’s disease. Nat. Neurosci. https://doi.org/10.1038/s41593-022-01251-x (2023).

  • Chen, W.-T. et al. Spatial transcriptomics and in situ sequencing to study Alzheimer’s disease. Cell 182, 976–991 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wang, S. et al. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer’s disease model. J. Exp. Med. 217, e20200785 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Leyns, C. E. G. et al. TREM2 function impedes tau seeding in neuritic plaques. Nat. Neurosci. 22, 1217–1222 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gratuze, M. et al. Impact of TREM2R47H variant on tau pathology-induced gliosis and neurodegeneration. J. Clin. Invest. 130, 4954–4968 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Leyns, C. E. G. et al. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc. Natl Acad. Sci. USA 114, 11524–11529 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hou, J., Chen, Y., Grajales-Reyes, G. & Colonna, M. TREM2 dependent and independent functions of microglia in Alzheimer’s disease. Mol. Neurodegener. 17, 84 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jain, N., Lewis, C. A., Ulrich, J. D. & Holtzman, D. M. Chronic TREM2 activation exacerbates Aβ-associated tau seeding and spreading. J. Exp. Med. 220, e20220654 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Romero-Molina, C., Garretti, F., Andrews, S. J., Marcora, E. & Goate, A. M. Microglial efferocytosis: diving into the Alzheimer’s disease gene pool. Neuron 110, 3513–3533 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Morioka, S. et al. Chimeric efferocytic receptors improve apoptotic cell clearance and alleviate inflammation. Cell 185, 4887–4903 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gratuze, M. et al. TREM2-independent microgliosis promotes tau-mediated neurodegeneration in the presence of ApoE4. Neuron 111, 202–219 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • McAlpine, C. S. et al. Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease. Nature 595, 701–706 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, C. et al. Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia. Neuron 109, 1657–1674 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Koutsodendris, N. et al. Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits. Nat. Aging 3, 275–296 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Litvinchuk, A. et al. Apolipoprotein E4 reduction with antisense oligonucleotides decreases neurodegeneration in a tauopathy model. Ann. Neurol. 89, 952–966 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Huynh, T. -P. V. et al. Age-dependent effects of apoE reduction using antisense oligonucleotides in a model of β-amyloidosis. Neuron 96, 1013–1023 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Da Mesquita, S. et al. Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy. Nature 593, 255–260 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • De Schepper, S. et al. Perivascular cells induce microglial phagocytic states and synaptic engulfment via SPP1 in mouse models of Alzheimer’s disease. Nat. Neurosci. 26, 406–415 (2023).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Drieu, A. et al. Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid. Nature 611, 585–593 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, X. et al. Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy. Nature 615, 668–677 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chandra, S., Sisodia, S. S. & Vassar, R. J. The gut microbiome in Alzheimer’s disease: what we know and what remains to be explored. Mol. Neurodegener. 18, 9 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Minter, M. R. et al. Antibiotic-induced perturbations in microbial diversity during post-natal development alters amyloid pathology in an aged APPSWE/PS1ΔE9 murine model of Alzheimer’s disease. Sci. Rep. 7, 10411 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Harach, T. et al. Reduction of Aβ amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci. Rep. 7, 41802 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Seo, D. et al. ApoE isoform– and microbiota-dependent progression of neurodegeneration in a mouse model of tauopathy. Science 379, eadd1236 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Cannistraro, R. J. et al. CNS small vessel disease: a clinical review. Neurology 92, 1146–1156 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wagner, J. et al. Medin co-aggregates with vascular amyloid-β in Alzheimer’s disease. Nature 612, 123–131 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ryu, J. K. et al. Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration. Nat. Immunol. 19, 1212–1223 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Verma, N. et al. Aβ efflux impairment and inflammation linked to cerebrovascular accumulation of amyloid-forming amylin secreted from pancreas. Commun. Biol. 6, 2 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Meneses, A. et al. TDP-43 pathology in Alzheimer’s disease. Mol. Neurodegener. 16, 84 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Schweighauser, M. et al. Age-dependent formation of TMEM106B amyloid filaments in human brains. Nature 605, 310–314 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bargar, C. et al. Streamlined alpha-synuclein RT-QuIC assay for various biospecimens in Parkinson’s disease and dementia with Lewy bodies. Acta Neuropathol. Commun. 9, 62 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Irwin, K. E. et al. A fluid biomarker reveals loss of TDP-43 splicing repression in pre-symptomatic ALS. Preprint at https://doi.org/10.1101/2023.01.23.525202 (2023).

  • Murdock, M. H. & Tsai, L.-H. Insights into Alzheimer’s disease from single-cell genomic approaches. Nat. Neurosci. 26, 181–195 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Small, S. A. & Petsko, G. A. Retromer in Alzheimer disease, Parkinson disease and other neurological disorders. Nat. Rev. Neurosci. 16, 126–132 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Morabito, S. et al. Single-nucleus chromatin accessibility and transcriptomic characterization of Alzheimer’s disease. Nat. Genet. 53, 1143–1155 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Anderson, A. G. et al. Single nucleus multiomics identifies ZEB1 and MAFB as candidate regulators of Alzheimer’s disease-specific cis-regulatory elements. Cell Genom. 3, 100263 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Blanchard, J. W. et al. APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes. Nature 611, 769–779 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • van Arendonk, J. et al. Diabetes and hypertension are related to amyloid-beta burden in the population-based Rotterdam Study. Brain 146, 337–348 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • De Miguel, Z. et al. Exercise plasma boosts memory and dampens brain inflammation via clusterin. Nature 600, 494–499 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Livingston, G. et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet 396, 413–446 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, C. & Holtzman, D. M. Bidirectional relationship between sleep and Alzheimer’s disease: role of amyloid, tau, and other factors. Neuropsychopharmacology 45, 104–120 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • ALZFORUM. Gantenerumab mystery: how did it lose potency in phase 3? https://www.alzforum.org/news/conference-coverage/gantenerumab-mystery-how-did-it-lose-potency-phase-3

  • Spangenberg, E. et al. Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model. Nat. Commun. 10, 3758 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kiani Shabestari, S. et al. Absence of microglia promotes diverse pathologies and early lethality in Alzheimer’s disease mice. Cell Rep. 39, 110961 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sosna, J. et al. Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer’s disease. Mol. Neurodegener. 13, 11 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yuan, P. et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 90, 724–739 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, Y. et al. TREM2 lipid sensing sustains microglia response in an Alzheimer’s disease model. Cell 160, 1061–1071 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gratuze, M. et al. Activated microglia mitigate Aβ-associated tau seeding and spreading. J. Exp. Med. 218, e20210542 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shi, Y. et al. Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J. Exp. Med. 216, 2546–2561 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mancuso, R. et al. CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice. Brain 142, 3243–3264 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rogers, J., Luber-Narod, J., Styren, S. D. & Civin, W. H. Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer’s disease. Neurobiol. Aging 9, 339–349 (1988).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Merlini, M. et al. Extravascular CD3+ T cells in brains of Alzheimer disease patients correlate with tau but not with amyloid pathology: an immunohistochemical study. Neurodegener. Dis. 18, 49–56 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Haass, C. et al. Amyloid β-peptide is produced by cultured cells during normal metabolism. Nature 359, 322–325 (1992).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rogaev, E. I. et al. Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 376, 775–778 (1995).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Levy-Lahad, E. et al. Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269, 973–977 (1995).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sherrington, R. et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375, 754–760 (1995).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Scheuner, D. et al. Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat. Med. 2, 864–870 (1996).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Nilsberth, C. et al. The ‘Arctic’ APP mutation (E693G) causes Alzheimer’s disease by enhanced Aβ protofibril formation. Nat. Neurosci. 4, 887–893 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Boerwinkle, A. H. et al. Comparison of amyloid burden in individuals with Down syndrome versus autosomal dominant Alzheimer’s disease: a cross-sectional study. Lancet Neurol. 22, 55–65 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jonsson, T. et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 488, 96–99 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mawuenyega, K. G. et al. Decreased clearance of CNS β-amyloid in Alzheimer’s disease. Science 330, 1774–1774 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Castellano, J. M. et al. Human apoE Isoforms differentially regulate brain Amyloid-β peptide clearance. Sci. Transl. Med. 3, 89ra57 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jansen, W. J. et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. J. Am. Med. Assoc. 313, 1924–1938 (2015).

    Article 

    Google Scholar
     

  • Radde, R. et al. Aβ42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep. 7, 940–946 (2006).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Saito, T. et al. Single App knock-in mouse models of Alzheimer’s disease. Nat. Neurosci. 17, 661–663 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Xia, D. et al. Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia. Mol. Neurodegener. 17, 41 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Musiek, E. S., McDade, E. & Holtzman, D. M. Lecanamab ushers in a new era of anti-amyloid therapy for Alzheimer’s disease. Ann. Neurol. 93, 877–880 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     



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