Alzheimer’s disease: insights into pathology, molecular mechanisms, and therapy

Abstract

Alzheimer’s disease (AD), the leading cause of dementia, is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. This condition casts a significant shadow on global health due to its complex and multifactorial nature. In addition to genetic predispositions, the development of AD is influenced by a myriad of risk factors, including aging, systemic inflammation, chronic health conditions, lifestyle, and environmental exposures. Recent advancements in understanding the complex pathophysiology of AD are paving the way for enhanced diagnostic techniques, improved risk assessment, and potentially effective prevention strategies. These discoveries are crucial in the quest to unravel the complexities of AD, offering a beacon of hope for improved management and treatment options for the millions affected by this debilitating disease.

Keywords

Alzheimer’s disease / pathophysiology / risk factors / biomarkers / prevention

References

[1] Abelein A. Metal binding of Alzheimer’s amyloid-beta and its effect on peptide self-assembly. Acc Chem Res 2023;56:2653–2663.

[2] Adaikkan C, Middleton SJ, Marco A et al. Gamma entrainment binds higher-order brain regions and offers neuroprotection. Neuron 2019;102:929–943.e8.

[3] Ahmed Z, Cooper J, Murray TK et al. A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: the pattern of spread is determined by connectivity, not proximity. Acta Neuropathol 2014;127:667–683.

[4] Altmann A, Ng B, Landau SM et al. Alzheimer’s Disease Neuroimaging Initiative. Regional brain hypometabolism is unrelated to regional amyloid plaque burden. Brain 2015;138:3734–3746.

[5] Alzheimer’s Association. 2023 Alzheimer’s disease facts and figures. Alzheimers Dement 2023;19:1598–1695.

[6] Alzheimer A, Stelzmann RA, Schnitzlein HN et al. An English translation of Alzheimer’s 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”. Clin Anat 1995;8:429–431.

[7] Amelianchik A, Merkel J, Palanisamy P et al. The protective effect of early dietary fat consumption on Alzheimer’s disease-related pathology and cognitive function in mice. Alzheimers Dement (N Y) 2021;7:e12173.

[8] Anstey KJ, von Sanden C, Salim A et al. Smoking as a risk factor for dementia and cognitive decline: a meta-analysis of prospective studies. Am J Epidemiol 2007;166:367–378.

[9] Araque Caballero MA, Suarez-Calvet M, Duering M et al. White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer’s disease. Brain 2018;141:3065–3080.

[10] Arboleda-Velasquez JF, Lopera F, O’Hare M et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat Med 2019;25:1680–1683.

[11] Arnold CS, Johnson GV, Cole RN et al. The microtubule-associated protein tau is extensively modified with O-linked N-acetylglucosamine. J Biol Chem 1996;271:28741–28744.

[12] Arvanitakis Z, Capuano AW, Leurgans SE et al. Relation of cerebral vessel disease to Alzheimer’s disease dementia and cognitive function in elderly people: a cross-sectional study. Lancet Neurol 2016;15:934–943.

[13] Asai H, Ikezu S, Tsunoda S et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci 2015;18:1584–1593.

[14] Aschenbrenner AJ, Gordon BA, Benzinger TLS et al. Influence of tau PET, amyloid PET, and hippocampal volume on cognition in Alzheimer disease. Neurology 2018;91:e859–e866.

[15] Ashton NJ, Leuzy A, Karikari TK et al. The validation status of blood biomarkers of amyloid and phospho-tau assessed with the 5-phase development framework for AD biomarkers. Eur J Nucl Med Mol Imaging 2021;48:2140–2156.

[16] Ashton NJ, Brum WS, Di Molfetta G et al. Diagnostic accuracy of a plasma phosphorylated Tau 217 immunoassay for Alzheimer disease pathology. JAMA Neurol 2024;81:255–263.

[17] Atagi Y, Liu CC, Painter MM et al. Apolipoprotein E is a ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2). J Biol Chem 2015;290:26043–26050.

[18] Augustinack JC, Schneider A, Mandelkow EM et al. Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer’s disease. Acta Neuropathol 2002;103:26–35.

[19] Babu JR, Geetha T, Wooten MW. Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation. J Neurochem 2005;94:192–203.

[20] Bailey CC, DeVaux LB, Farzan M. The Triggering Receptor Expressed on Myeloid Cells 2 binds Apolipoprotein E. J Biol Chem 2015;290:26033–26042.

[21] Baker HF, Ridley RM, Duchen LW et al. Evidence for the experimental transmission of cerebral beta-amyloidosis to primates. Int J Exp Pathol 1993;74:441–454.

[22] Baker DJ, Wijshake T, Tchkonia T et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 2011;479:232–236.

[23] Balin BJ, Gerard HC, Arking EJ et al. Identification and localization of Chlamydia pneumoniae in the Alzheimer’s brain. Med Microbiol Immunol 1998;187:23–42.

[24] Balusu S, Horre K, Thrupp N et al. MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer’s disease. Science 2023;381:1176–1182.

[25] Bao J, Zheng L, Zhang Q et al. Deacetylation of TFEB promotes fibrillar Abeta degradation by upregulating lysosomal biogenesis in microglia. Protein Cell 2016;7:417–433.

[26] Bao WD, Pang P, Zhou XT et al. Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease. Cell Death Differ 2021;28:1548–1562.

[27] Barnes LL, Capuano AW, Aiello AE et al. Cytomegalovirus infection and risk of Alzheimer disease in older black and white individuals. J Infect Dis 2015;211:230–237.

[28] Barthelemy NR, Salvado G, Schindler SE et al. Highly accurate blood test for Alzheimer’s disease is similar or superior to clinical cerebrospinal fluid tests. Nat Med 2024;30:1085–1095.

[29] Bateman RJ, Aisen PS, De Strooper B et al. Autosomal-dominant Alzheimer’s disease: a review and proposal for the prevention of Alzheimer’s disease. Alzheimers Res Ther 2011;3:1.

[30] Beach TG, McGeer EG. Lamina-specific arrangement of astrocytic gliosis and senile plaques in Alzheimer’s disease visual cortex. Brain Res 1988;463:357–361.

[31] Becker E, Orellana Rios CL, Lahmann C et al. Anxiety as a risk factor of Alzheimer’s disease and vascular dementia. Br J Psychiatry 2018;213:654–660.

[32] Behrendt G, Baer K, Buffo A et al. Dynamic changes in myelin aberrations and oligodendrocyte generation in chronic amyloidosis in mice and men. Glia 2013;61:273–286.

[33] Behrendt A, Bichmann M, Ercan-Herbst E et al. Asparagine endopeptidase cleaves tau at N167 after uptake into microglia. Neurobiol Dis 2019;130:104518.

[34] Bemiller SM, McCray TJ, Allan K et al. TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy. Mol Neurodegener 2017;12:74.

[35] Benkert P, Meier S, Schaedelin S et al. NfL Reference Database in the Swiss Multiple Sclerosis Cohort Study Group. Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study. Lancet Neurol 2022;21:246–257.

[36] Bertram L, McQueen MB, Mullin K et al. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet 2007;39:17–23.

[37] Bertram L, Lill CM, Tanzi RE. The genetics of Alzheimer disease: back to the future. Neuron 2010;68:270–281.

[38] Bhat R, Crowe EP, Bitto A et al. Astrocyte senescence as a component of Alzheimer’s disease. PLoS One 2012;7:e45069.

[39] Bibl M, Mollenhauer B, Esselmann H et al. CSF amyloid-beta-peptides in Alzheimer’s disease, dementia with Lewy bodies and Parkinson’s disease dementia. Brain 2006;129:1177–1187.

[40] Bichmann M, Prat Oriol N, Ercan-Herbst E et al. SETD7-mediated monomethylation is enriched on soluble Tau in Alzheimer’s disease. Mol Neurodegener 2021;16:46.

[41] Bloom GS. Amyloid-beta and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol 2014;71:505–508.

[42] Boada M, Lopez OL, Olazaran J et al. AMBAR Trial Group. Neuropsychological, neuropsychiatric, and quality-of-life assessments in Alzheimer’s disease patients treated with plasma exchange with albumin replacement from the randomized AMBAR study. Alzheimers Dement 2022;18:1314–1324.

[43] Boluda S, Iba M, Zhang B et al. Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer’s disease or corticobasal degeneration brains. Acta Neuropathol 2015;129:221–237.

[44] Boza-Serrano A, Ruiz R, Sanchez-Varo R et al. Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer’s disease. Acta Neuropathol 2019;138:251–273.

[45] Braak H, Braak E. Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 1995;16:271–8;discussion 278.

[46] Braak H, Alafuzoff I, Arzberger T et al. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 2006;112:389–404.

[47] Brandebura AN, Paumier A, Onur TS et al. Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders. Nat Rev Neurosci 2023;24:23–39.

[48] Bu G. Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci 2009;10:333–344.

[49] Budd Haeberlein S, Aisen PS, Barkhof F et al. Two randomized phase 3 studies of Aducanumab in early Alzheimer’s disease. J Prev Alzheimers Dis 2022;9:197–210.

[50] Bussian TJ, Aziz A, Meyer CF et al. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 2018;562:578–582.

[51] Caccamo A, Branca C, Piras IS et al. Necroptosis activation in Alzheimer’s disease. Nat Neurosci 2017;20:1236–1246.

[52] Cairns DM, Rouleau N, Parker RN et al. A 3D human brain-like tissue model of herpes-induced Alzheimer’s disease. Sci Adv 2020;6:eaay8828.

[53] Calafate S, Flavin W, Verstreken P et al. Loss of BiN1 promotes the propagation of Tau pathology. Cell Rep 2016;17:931–940.

[54] Cardenas-Aguayo Mdel C, Gomez-Virgilio L, DeRosa S et al. The role of tau oligomers in the onset of Alzheimer’s disease neuropathology. ACS Chem Neurosci 2014;5:1178–1191.

[55] Carlomagno Y, Chung DC, Yue M et al. An acetylation-phosphorylation switch that regulates tau aggregation propensity and function. J Biol Chem 2017;292:15277–15286.

[56] Castellano JM, Kim J, Stewart FR et al. Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance. Sci Transl Med 2011;3:89ra57.

[57] Chapuis J, Hansmannel F, Gistelinck M et al. GERAD consortium. Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology. Mol Psychiatry 2013;18:1225–1234.

[58] Chen J, Zhou Y, Mueller-Steiner S et al. SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling. J Biol Chem 2005;280:40364–40374.

[59] Chen WT, Lu A, Craessaerts K et al. Spatial transcriptomics and in situ sequencing to study Alzheimer’s disease. Cell 2020;182:976–991.e19.

[60] Chen F, Swartzlander DB, Ghosh A et al. Clusterin secreted from astrocyte promotes excitatory synaptic transmission and ameliorates Alzheimer’s disease neuropathology. Mol Neurodegener 2021;16:5.

[61] Chen X, Firulyova M, Manis M et al. Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy. Nature 2023;615:668–677.

[62] Chen Y, Song S, Parhizkar S et al. APOE3ch alters microglial response and suppresses Abeta-induced tau seeding and spread. Cell 2024;187:428–445.e20.

[63] Chia S, Flagmeier P, Habchi J et al. Monomeric and fibrillar alpha-synuclein exert opposite effects on the catalytic cycle that promotes the proliferation of Abeta42 aggregates. Proc Natl Acad Sci U S A 2017;114:8005–8010.

[64] Chiang GC, Insel PS, Tosun D et al. Alzheimer’s Disease Neuroimaging Initiative.Hippocampal atrophy rates and CSF biomarkers in elderly APOE2 normal subjects. Neurology 2010;75:1976–1981.

[65] Choi BR, Johnson KR, Maric D et al. Monocyte-derived IL-6 programs microglia to rebuild damaged brain vasculature. Nat Immunol 2023;24:1110–1123.

[66] Christen Y. Oxidative stress and Alzheimer disease. Am J Clin Nutr 2000;71:621S–629S.

[67] Christensen DZ, Schneider-Axmann T, Lucassen PJ et al. Accumulation of intraneuronal Abeta correlates with ApoE4 genotype. Acta Neuropathol 2010;119:555–566.

[68] Christianson HC, Belting M. Heparan sulfate proteoglycan as a cell-surface endocytosis receptor. Matrix Biol 2014;35:51–55.

[69] Cicognola C, Janelidze S, Hertze J et al. Plasma glial fibrillary acidic protein detects Alzheimer pathology and predicts future conversion to Alzheimer dementia in patients with mild cognitive impairment. Alzheimers Res Ther 2021;13:68.

[70] Clavaguera F, Bolmont T, Crowther RA et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 2009;11:909–913.

[71] Clavaguera F, Akatsu H, Fraser G et al. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci U S A 2013;110:9535–9540.

[72] Clavaguera F, Hench J, Lavenir I et al. Peripheral administration of tau aggregates triggers intracerebral tauopathy in transgenic mice. Acta Neuropathol 2014;127:299–301.

[73] Cohen TJ, Guo JL, Hurtado DE et al. The acetylation of tau inhibits its function and promotes pathological tau aggregation. Nat Commun 2011;2:252.

[74] Condello C, Maxwell AM, Castillo E et al. Abeta and tau prions feature in the neuropathogenesis of Down syndrome. Proc Natl Acad Sci U S A 2022;119:e2212954119.

[75] Congdon EE, Sigurdsson EM. Tau-targeting therapies for Alzheimer disease. Nat Rev Neurol 2018;14:399–415.

[76] Congdon EE, Ji C, Tetlow AM et al. Tau-targeting therapies for Alzheimer disease: current status and future directions. Nat Rev Neurol 2023;19:715–736.

[77] Cook C, Stankowski JN, Carlomagno Y et al. Acetylation: a new key to unlock tau’s role in neurodegeneration. Alzheimers Res Ther 2014;6:29.

[78] Cope TE, Rittman T, Borchert RJ et al. Tau burden and the functional connectome in Alzheimer’s disease and progressive supranuclear palsy. Brain 2018;141:550–567.

[79] Corder EH, Saunders AM, Strittmatter WJ et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993;261:921–923.

[80] Crary JF, Trojanowski JQ, Schneider JA et al. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol 2014;128:755–766.

[81] Cresswell P, Ackerman AL, Giodini A et al. Mechanisms of MHC class I-restricted antigen processing and cross-presentation. Immunol Rev 2005;207:145–157.

[82] Crocker PR, Paulson JC, Varki A. Siglecs and their roles in the immune system. Nat Rev Immunol 2007;7:255–266.

[83] Crotti A, Sait HR, McAvoy KM et al. BIN1 favors the spreading of Tau via extracellular vesicles. Sci Rep 2019;9:9477.

[84] Cummings J, Zhou Y, Lee G et al. Alzheimer’s disease drug development pipeline:2023. Alzheimers Dement (N Y) 2023;9:e12385.

[85] Czirr E, Castello NA, Mosher KI et al. Microglial complement receptor 3 regulates brain Abeta levels through secreted proteolytic activity. J Exp Med 2017;214:1081–1092.

[86] D’Onofrio G, Sancarlo D, Panza F et al. Neuropsychiatric symptoms and functional status in Alzheimer’s disease and vascular dementia patients. Curr Alzheimer Res 2012;9:759–771.

[87] Da X, Hempel E, Ou Y et al. Noninvasive gamma sensory stimulation may reduce White matter and myelin loss in Alzheimer’s Disease. J Alzheimers Dis 2024;97:359–372.

[88] Dani M, Wood M, Mizoguchi R et al. Microglial activation correlates in vivo with both tau and amyloid in Alzheimer’s disease. Brain 2018;141:2740–2754.

[89] Dean DC 3rd, Hurley SA, Kecskemeti SR et al. Association of amyloid pathology with myelin alteration in preclinical Alzheimer disease. JAMA Neurol 2017;74:41–49.

[90] Deane R, Sagare A, Hamm K et al. apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J Clin Invest 2008;118:4002–4013.

[91] Deczkowska A, Weiner A, Amit I. The physiology, pathology, and potential therapeutic applications of the TREM2 Signaling Pathway. Cell 2020;181:1207–1217.

[92] DeMattos RB, O’Dell MA, Parsadanian M et al. Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 2002;99:10843–10848.

[93] Deming Y, Filipello F, Cignarella F et al. The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk. Sci Transl Med 2019;11:1–18.

[94] Depp C, Sun T, Sasmita AO et al. Myelin dysfunction drives amyloid-beta deposition in models of Alzheimer’s disease. Nature 2023;618:349–357.

[95] Desai MK, Sudol KL, Janelsins MC et al. Triple-transgenic Alzheimer’s disease mice exhibit region-specific abnormalities in brain myelination patterns prior to appearance of amyloid and tau pathology. Glia 2009;57:54–65.

[96] De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. Cell 2016;164:603–615.

[97] DeTure MA, Dickson DW. The neuropathological diagnosis of Alzheimer’s disease. Mol Neurodegener 2019;14:32.

[98] Dileep V, Boix CA, Mathys H et al. Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration. Cell 2023;186:4404–4421.e20.

[99] Doens D, Fernandez PL. Microglia receptors and their implications in the response to amyloid beta for Alzheimer’s disease pathogenesis. J Neuroinflammation 2014;11:48.

[100] Domert J, Rao SB, Agholme L et al. Spreading of amyloid-beta peptides via neuritic cell-to-cell transfer is dependent on insufficient cellular clearance. Neurobiol Dis 2014;65:82–92.

[101] Dominy SS, Lynch C, Ermini F et al. Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv 2019;5:eaau3333.

[102] Dubois B, Lopez-Arrieta J, Lipschitz S et al. AB09004 Study Group Investigators. Correction: Masitinib for mild-to-moderate Alzheimer’s disease: results from a randomized, placebo-controlled, phase 3, clinical trial. Alzheimers Res Ther 2023;15:85.

[103] Dyrks T, Weidemann A, Multhaup G et al. Identification, transmembrane orientation and biogenesis of the amyloid A4 precursor of Alzheimer’s disease. EMBO J 1988;7:949–957.

[104] Eide PK, Vinje V, Pripp AH et al. Sleep deprivation impairs molecular clearance from the human brain. Brain 2021;144:863–874.

[105] Eimer WA, Vijaya Kumar DK, Navalpur Shanmugam NK et al. Alzheimer’s disease-associated beta-amyloid is rapidly seeded by herpesviridae to protect against brain infection. Neuron 2018;99:56–63.e3.

[106] Eisele YS, Bolmont T, Heikenwalder M et al. Induction of cerebral beta-amyloidosis: intracerebral versus systemic Abeta inoculation. Proc Natl Acad Sci U S A 2009;106:12926–12931.

[107] Eisele YS, Obermuller U, Heilbronner G et al. Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis. Science 2010;330:980–982.

[108] Elshourbagy NA, Liao WS, Mahley RW et al. Apolipoprotein E mRNA is abundant in the brain and adrenals, as well as in the liver, and is present in other peripheral tissues of rats and marmosets. Proc Natl Acad Sci U S A 1985;82:203–207.

[109] Engelhart MJ, Geerlings MI, Ruitenberg A et al. Dietary intake of antioxidants and risk of Alzheimer disease. JAMA 2002;287:3223–3229.

[110] Esch FS, Keim PS, Beattie EC et al. Cleavage of amyloid beta peptide during constitutive processing of its precursor. Science 1990;248:1122–1124.

[111] Esiri MM, Biddolph SC, Morris CS. Prevalence of Alzheimer plaques in AIDS. J Neurol Neurosurg Psychiatry 1998;65:29–33.

[112] Eyting M, Xie M, Hess S et al. Causal evidence that herpes zoster vaccination prevents a proportion of dementia cases. medRxiv 2023.

[113] Falcon B, Zhang W, Murzin AG et al. Structures of filaments from Pick’s disease reveal a novel tau protein fold. Nature 2018a;561:137–140.

[114] Falcon B, Zhang W, Schweighauser M et al. Tau filaments from multiple cases of sporadic and inherited Alzheimer’s disease adopt a common fold. Acta Neuropathol 2018b;136:699–708.

[115] Falcon B, Zivanov J, Zhang W et al. Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Nature 2019;568:420–423.

[116] Faraco G, Brea D, Garcia-Bonilla L et al. Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response. Nat Neurosci 2018;21:240–249.

[117] Faraco G, Hochrainer K, Segarra SG et al. Dietary salt promotes cognitive impairment through tau phosphorylation. Nature 2019;574:686–690.

[118] Farrer LA, Cupples LA, Haines JL et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 1997;278:1349–1356.

[119] Feuerbach D, Schindler P, Barske C et al. ADAM17 is the main sheddase for the generation of human triggering receptor expressed in myeloid cells (hTREM2) ectodomain and cleaves TREM2 after Histidine 157. Neurosci Lett 2017;660:109–114.

[120] Fiandaca MS, Kapogiannis D, Mapstone M et al. Identification of preclinical Alzheimer’s disease by a profile of pathogenic proteins in neurally derived blood exosomes: a case-control study. Alzheimers Dement 2015;11:600–607 e601.

[121] Fitzpatrick AWP, Falcon B, He S et al. Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 2017;547:185–190.

[122] Flach K, Ramminger E, Hilbrich I et al. Axotrophin/MARCH7 acts as an E3 ubiquitin ligase and ubiquitinates tau protein in vitro impairing microtubule binding. Biochim Biophys Acta 2014;1842:1527–1538.

[123] Fleisher AS, Chen K, Quiroz YT et al. Florbetapir PET analysis of amyloid-beta deposition in the presenilin 1 E280A autosomal dominant Alzheimer’s disease kindred: a cross-sectional study. Lancet Neurol 2012;11:1057–1065.

[124] Fleminger S, Oliver DL, Lovestone S et al. Head injury as a risk factor for Alzheimer’s disease: the evidence 10 years on;a partial replication. J Neurol Neurosurg Psychiatry 2003;74:857–862.

[125] Franzmeier N, Rubinski A, Neitzel J et al. The BIN1 rs744373 SNP is associated with increased tau-PET levels and impaired memory. Nat Commun 2019;10:1766.

[126] Fricker M, Tolkovsky AM, Borutaite V et al. Neuronal cell death. Physiol Rev 2018;98:813–880.

[127] Fritschi SK, Langer F, Kaeser SA et al. Highly potent soluble amyloid-beta seeds in human Alzheimer brain but not cerebrospinal fluid. Brain 2014;137:2909–2915.

[128] Frost B, Jacks RL, Diamond MI. Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem 2009;284:12845–12852.

[129] Fu H, Liu B, Frost JL et al. Complement component C3 and complement receptor type 3 contribute to the phagocytosis and clearance of fibrillar Abeta by microglia. Glia 2012;60:993–1003.

[130] Funk KE, Thomas SN, Schafer KN et al. Lysine methylation is an endogenous post-translational modification of tau protein in human brain and a modulator of aggregation propensity. Biochem J 2014;462:77–88.

[131] Furukawa K, Sopher BL, Rydel RE et al. Increased activity-regulating and neuroprotective efficacy of alpha-secretase-derived secreted amyloid precursor protein conferred by a C-terminal heparin-binding domain. J Neurochem 1996;67:1882–1896.

[132] Gaikwad S, Puangmalai N, Bittar A et al. Tau oligomer induced HMGB1 release contributes to cellular senescence and neuropathology linked to Alzheimer’s disease and frontotemporal dementia. Cell Rep 2021;36:109419.

[133] Galasko D, Xiao M, Xu D et al. Synaptic biomarkers in CSF aid in diagnosis, correlate with cognition and predict progression in MCI and Alzheimer’s disease. Alzheimers Dement (N Y) 2019;5:871–882.

[134] Galvan V, Gorostiza OF, Banwait S et al. Reversal of Alzheimer’s-like pathology and behavior in human APP transgenic mice by mutation of Asp664. Proc Natl Acad Sci U S A 2006;103:7130–7135.

[135] Gamblin TC, Chen F, Zambrano A et al. Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer’s disease. Proc Natl Acad Sci U S A 2003;100:10032–10037.

[136] Gao Y, Hong Y, Huang L et al. beta2-microglobulin functions as an endogenous NMDAR antagonist to impair synaptic function. Cell 2023;186:1026–1038.e20.

[137] Garai K, Verghese PB, Baban B et al. The binding of apolipoprotein E to oligomers and fibrils of amyloid-beta alters the kinetics of amyloid aggregation. Biochemistry 2014;53:6323–6331.

[138] Gatz M, Reynolds CA, Fratiglioni L et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 2006;63:168–174.

[139] Gauthier S, Feldman HH, Schneider LS et al. Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer’s disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial. Lancet 2016;388:2873–2884.

[140] GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016;388:1545–1602.

[141] GBD 2016 Lifetime Risk of Stroke Collaborators, Feigin VL, Nguyen G et al Global, regional, and country-specific lifetime risks of stroke, 1990 and 2016. N Engl J Med 2018;379:2429–2437.

[142] GBD 2016 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol 2021;20:795–820.

[143] Geiss-Friedlander R, Melchior F. Concepts in sumoylation: a decade on. Nat Rev Mol Cell Biol 2007;8:947–956.

[144] Genin E, Hannequin D, Wallon D et al. APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol Psychiatry 2011;16:903–907.

[145] Gentleman SM, Greenberg BD, Savage MJ et al. A beta 42 is the predominant form of amyloid beta-protein in the brains of short-term survivors of head injury. Neuroreport 1997;8:1519–1522.

[146] Gerard HC, Dreses-Werringloer U, Wildt KS et al. Chlamydophila (Chlamydia) pneumoniae in the Alzheimer’s brain. FEMS Immunol Med Microbiol 2006;48:355–366.

[147] Gervais FG, Xu D, Robertson GS et al. Involvement of caspases in proteolytic cleavage of Alzheimer’s amyloid-beta precursor protein and amyloidogenic A beta peptide formation. Cell 1999;97:395–406.

[148] Giannakopoulos P, Herrmann FR, Bussiere T et al. Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology 2003;60:1495–1500.

[149] Gibbons GS, Banks RA, Kim B et al. GFP-mutant human Tau transgenic mice develop tauopathy following CNS injections of Alzheimer’s brain-derived pathological Tau or synthetic mutant human Tau Fibrils. J Neurosci 2017;37:11485–11494.

[150] Gibbons GS, Lee VMY, Trojanowski JQ. Mechanisms of cell-to-cell transmission of pathological Tau: a review. JAMA Neurol 2019;76:101–108.

[151] Ginhoux F, Greter M, Leboeuf M et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 2010;330:841–845.

[152] Glenner GG, Wong CW. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984;120:885–890.

[153] Goedert M, Spillantini MG, Jakes R et al. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 1989;3:519–526.

[154] Goel P, Chakrabarti S, Goel K et al. Neuronal cell death mechanisms in Alzheimer’s disease: an insight. Front Mol Neurosci 2022;15:937133.

[155] Gomez Perdiguero E, Klapproth K, Schulz C et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 2015;518:547–551.

[156] Gong CX, Singh TJ, Grundke-Iqbal I et al. Phosphoprotein phosphatase activities in Alzheimer disease brain. J Neurochem 1993;61:921–927.

[157] Gonzalez-Ortiz F, Turton M, Kac PR et al. Brain-derived tau: a novel blood-based biomarker for Alzheimer’s disease-type neurodegeneration. Brain 2023;146:1152–1165.

[158] Grande G, Ljungman PLS, Eneroth K et al. Association between cardiovascular disease and long-term exposure to air pollution with the risk of dementia. JAMA Neurol 2020;77:801–809.

[159] Gratuze M, Chen Y, Parhizkar S et al. Activated microglia mitigate Abeta-associated tau seeding and spreading. J Exp Med 2021;218:e20210542.

[160] Green RC, Cupples LA, Kurz A et al. Depression as a risk factor for Alzheimer disease: the MIRAGE Study. Arch Neurol 2003;60:753–759.

[161] Greenberg SM, Bacskai BJ, Hernandez-Guillamon M et al. Cerebral amyloid angiopathy and Alzheimer disease -one peptide, two pathways. Nat Rev Neurol 2020;16:30–42.

[162] Griciuc A, Serrano-Pozo A, Parrado AR et al. Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 2013;78:631–643.

[163] Griciuc A, Patel S, Federico AN et al. TREM2 acts down-stream of CD33 in modulating microglial pathology in Alzheimer’s disease. Neuron 2019;103:820–835.e7.

[164] Grothe MJ, Barthel H, Sepulcre J et al. In vivo staging of regional amyloid deposition. Neurology 2017a;89:2031–2038.

[165] Grothe MJ, Villeneuve S, Dyrba M et al. Multimodal characterization of older APOE2 carriers reveals selective reduction of amyloid load. Neurology 2017b;88:569–576.

[166] Gu D, Ou S, Liu G. Traumatic brain injury and risk of dementia and Alzheimer’s disease: a systematic review and meta-analysis. Neuroepidemiology 2022;56:4–16.

[167] Guerreiro R, Wojtas A, Bras J et al. TREM2 variants in Alzheimer’s disease. N Engl J Med 2013;368:117–127.

[168] Guerrero A, De Strooper B, Arancibia-Carcamo IL. Cellular senescence at the crossroads of inflammation and Alzheimer’s disease. Trends Neurosci 2021;44:714–727.

[169] Guo JP, Arai T, Miklossy J et al. Abeta and tau form soluble complexes that may promote self aggregation of both into the insoluble forms observed in Alzheimer’s disease. Proc Natl Acad Sci U S A 2006;103:1953–1958.

[170] Guo T, Noble W, Hanger DP. Roles of tau protein in health and disease. Acta Neuropathol 2017;133:665–704.

[171] Guo T, Zhang D, Zeng Y et al. Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease. Mol Neurodegener 2020;15:40.

[172] Haass C, Hung AY, Schlossmacher MG et al. beta-Amyloid peptide and a 3-kDa fragment are derived by distinct cellular mechanisms. J Biol Chem 1993;268:3021–3024.

[173] Habib N, McCabe C, Medina S et al. Disease-associated astrocytes in Alzheimer’s disease and aging. Nat Neurosci 2020;23:701–706.

[174] Hachinski V, Einhaupl K, Ganten D et al. Preventing dementia by preventing stroke: The Berlin Manifesto. Alzheimers Dement 2019;15:961–984.

[175] Hammond TR, Marsh SE, Stevens B. Immune signaling in neurodegeneration. Immunity 2019;50:955–974.

[176] Haney MS, Palovics R, Munson CN et al. APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia. Nature 2024;628:154–161.

[177] Hanger DP, Wray S. Tau cleavage and tau aggregation in neurodegenerative disease. Biochem Soc Trans 2010;38:1016–1020.

[178] Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science 1992;256:184–185.

[179] Harold D, Abraham R, Hollingworth P et al. Genomewide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 2009;41:1088–1093.

[180] Hashimoto T, Serrano-Pozo A, Hori Y et al. Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid beta peptide. J Neurosci 2012;32:15181–15192.

[181] Hayes A, Thaker U, Iwatsubo T et al. Pathological relation-ships between microglial cell activity and tau and amyloid beta protein in patients with Alzheimer’s disease. Neurosci Lett 2002;331:171–174.

[182] He Z, Guo JL, McBride JD et al. Amyloid-beta plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med 2018;24:29–38.

[183] Helboe L, Rosenqvist N, Volbracht C et al. Highly specific and sensitive target binding by the humanized pS396-Tau antibody hC10.2 across a wide spectrum of Alzheimer’s disease and primary tauopathy postmortem brains. J Alzheimers Dis 2022;88:207–228.

[184] Heneka MT, Kummer MP, Stutz A et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 2013;493:674–678.

[185] Heneka MT, Kummer MP, Latz E. Innate immune activation in neurodegenerative disease. Nat Rev Immunol 2014;14:463–477.

[186] Ho L, Qin W, Pompl PN et al. Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer’s disease. FASEB J 2004;18:902–904.

[187] Hollingworth P, Harold D, Sims R et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet 2011;43:429–435.

[188] Holmes BB, DeVos SL, Kfoury N et al. Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc Natl Acad Sci U S A 2013;110:E3138–E3147.

[189] Holth JK, Fritschi SK, Wang C et al. The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science 2019;363:880–884.

[190] Hong S, Beja-Glasser VF, Nfonoyim BM et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 2016;352:712–716.

[191] Horowitz PM, Patterson KR, Guillozet-Bongaarts AL et al. Early N-terminal changes and caspase-6 cleavage of tau in Alzheimer’s disease. J Neurosci 2004;24:7895–7902.

[192] Hu Y, Fryatt GL, Ghorbani M et al. Replicative senescence dictates the emergence of disease-associated microglia and contributes to Abeta pathology. Cell Rep 2021;35:109228.

[193] Huse JT, Pijak DS, Leslie GJ et al. Maturation and endosomal targeting of beta-site amyloid precursor protein-cleaving enzyme. The Alzheimer’s disease beta-secretase. J Biol Chem 2000;275:33729–33737.

[194] Huse JT, Liu K, Pijak DS et al. Beta-secretase processing in the trans-Golgi network preferentially generates truncated amyloid species that accumulate in Alzheimer’s disease brain. J Biol Chem 2002;277:16278–16284.

[195] Hussain I, Powell DJ, Howlett DR et al. ASP1 (BACe2) cleaves the amyloid precursor protein at the beta-secretase site. Mol Cell Neurosci 2000;16:609–619.

[196] Iaccarino HF, Singer AC, Martorell AJ et al. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature 2016;540:230–235.

[197] Iaccarino L, Sala A, Perani D; Alzheimer’s Disease Neuroimaging Initiative. Predicting long-term clinical stability in amyloid-positive subjects by FDG-PET. Ann Clin Transl Neurol 2019;6:1113–1120.

[198] Iannuzzi C, Irace G, Sirangelo I. The effect of glycosaminoglycans (GAGs) on amyloid aggregation and toxicity. Molecules 2015;20:2510–2528.

[199] Iliff JJ, Wang M, Liao Y et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med 2012;4:147ra–14111.

[200] Ising C, Venegas C, Zhang S et al. NLRP3 inflammasome activation drives tau pathology. Nature 2019;575:669–673.

[201] Itzhaki RF, Lin WR, Shang D et al. Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet 1997;349:241–244.

[202] Itzhaki RF, Golde TE, Heneka MT et al. Do infections have a role in the pathogenesis of Alzheimer disease? Nat Rev Neurol 2020;16:193–197.

[203] Iwashyna TJ, Ely EW, Smith DM et al. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 2010;304:1787–1794.

[204] Jack CR Jr, Knopman DS, Jagust WJ et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol 2010;9:119–128.

[205] Jack CR Jr, Bennett DA, Blennow K et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement 2018;14:535–562.

[206] James C, Harfouche M, Welton NJ et al. Herpes simplex virus: global infection prevalence and incidence estimates, 2016. Bull World Health Organ 2020;98:315–329.

[207] Jamieson GA, Maitland NJ, Wilcock GK et al. Latent herpes simplex virus type 1 in normal and Alzheimer’s disease brains. J Med Virol 1991;33:224–227.

[208] Janelidze S, Christian BT, Price J et al. Detection of brain Tau pathology in down syndrome using plasma biomarkers. JAMA Neurol 2022;79:797–807.

[209] Janelidze S, Bali D, Ashton NJ et al. Head-to-head comparison of 10 plasma phospho-tau assays in prodromal Alzheimer’s disease. Brain 2023;146:1592–1601.

[210] Jansen IE, Savage JE, Watanabe K et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat Genet 2019;51:404–413.

[211] Jia L, Qiu Q, Zhang H et al. Concordance between the assessment of Abeta42, T-tau, and P-T181-tau in peripheral blood neuronal-derived exosomes and cerebrospinal fluid. Alzheimers Dement 2019;15:1071–1080.

[212] Jiang Q, Lee CY, Mandrekar S et al. ApoE promotes the proteolytic degradation of Abeta. Neuron 2008;58:681–693.

[213] Jiang T, Tan L, Chen Q et al. A rare coding variant in TREM2 increases risk for Alzheimer’s disease in Han Chinese. Neurobiol Aging 2016;42:217.e1–217.e3.

[214] Jin SC, Benitez BA, Karch CM et al. Coding variants in TREM2 increase risk for Alzheimer’s disease. Hum Mol Genet 2014;23:5838–5846.

[215] Jiwaji Z, Tiwari SS, Aviles-Reyes RX et al. Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Ass pathology. Nat Commun 2022;13:135.

[216] Jones SE, Jomary C. Clusterin. Int J Biochem Cell Biol 2002;34:427–431.

[217] Jonsson T, Stefansson H, Steinberg S et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 2013;368:107–116.

[218] Ju YE, McLeland JS, Toedebusch CD et al. Sleep quality and preclinical Alzheimer disease. JAMA Neurol 2013;70:587–593.

[219] Ju YS, Ooms SJ, Sutphen C et al. Slow wave sleep disruption increases cerebrospinal fluid amyloid-beta levels. Brain 2017;140:2104–2111.

[220] Jucker M, Walker LC. Alzheimer’s disease: from immunotherapy to immunoprevention. Cell 2023;186:4260–4270.

[221] Jung Y, Damoiseaux JS. The potential of blood neurofilament light as a marker of neurodegeneration for Alzheimer’s disease. Brain 2024;147:12–25.

[222] Jurk D, Wang C, Miwa S et al. Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response. Aging Cell 2012;11:996–1004.

[223] Kadavath H, Cabrales Fontela Y, Jaremko M et al. The binding mode of a Tau peptide with tubulin. Angew Chem Int Ed Engl 2018;57:3246–3250.

[224] Kamah A, Huvent I, Cantrelle FX et al. Nuclear magnetic resonance analysis of the acetylation pattern of the neuronal Tau protein. Biochemistry 2014;53:3020–3032.

[225] Kang J, Lemaire HG, Unterbeck A et al. The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 1987;325:733–736.

[226] Kang JE, Lim MM, Bateman RJ et al. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science 2009;326:1005–1007.

[227] Kanmert D, Cantlon A, Muratore CR et al. C-terminally truncated forms of Tau, but not full-length Tau or its C-terminal fragments, are released from neurons independently of cell death. J Neurosci 2015;35:10851–10865.

[228] Karantali E, Kazis D, McKenna J et al. Neurofilament light chain in patients with a concussion or head impacts: a systematic review and meta-analysis. Eur J Trauma Emerg Surg 2022;48:1555–1567.

[229] Karch CM, Goate AM. Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry 2015;77:43–51.

[230] Karch CM, Jeng AT, Nowotny P et al. Expression of novel Alzheimer’s disease risk genes in control and Alzheimer’s disease brains. PLoS One 2012;7:e50976.

[231] Kenigsbuch M, Bost P, Halevi S et al. A shared disease-associated oligodendrocyte signature among multiple CNS pathologies. Nat Neurosci 2022;25:876–886.

[232] Keren-Shaul H, Spinrad A, Weiner A et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 2017;169:1276–1290.e17.

[233] Kidd M. Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature 1963;197:192–193.

[234] Kierdorf K, Erny D, Goldmann T et al. Microglia emerge from erythromyeloid precursors via Pu.1-and Irf8-dependent pathways. Nat Neurosci 2013;16:273–280.

[235] Kimberly WT, LaVoie MJ, Ostaszewski BL et al. Gammasecretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc Natl Acad Sci U S A 2003;100:6382–6387.

[236] Kimura T, Ono T, Takamatsu J et al. Sequential changes of tau-site-specific phosphorylation during development of paired helical filaments. Dementia 1996;7:177–181.

[237] Kisler K, Nelson AR, Montagne A et al. Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat Rev Neurosci 2017;18:419–434.

[238] Knight EM, Martins IV, Gumusgoz S et al. High-fat diet-induced memory impairment in triple-transgenic Alzheimer’s disease (3xTgAD) mice is independent of changes in amyloid and tau pathology. Neurobiol Aging 2014;35:1821–1832.

[239] Knopman DS, Jack CR Jr, Lundt ES et al. Evolution of neurodegeneration-imaging biomarkers from clinically normal to dementia in the Alzheimer disease spectrum. Neurobiol Aging 2016;46:32–42.

[240] Knopman DS, Amieva H, Petersen RC et al. Alzheimer disease. Nat Rev Dis Primers 2021;7:33.

[241] Koffie RM, Hashimoto T, Tai HC et al. Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-beta. Brain 2012;135:2155–2168.

[242] Kok E, Haikonen S, Luoto T et al. Apolipoprotein E-dependent accumulation of Alzheimer disease-related lesions begins in middle age. Ann Neurol 2009;65:650–657.

[243] Kole AJ, Annis RP, Deshmukh M. Mature neurons: equipped for survival. Cell Death Dis 2013;4:e689.

[244] Kountouras J, Tsolaki M, Gavalas E et al. Relationship between Helicobacter pylori infection and Alzheimer disease. Neurology 2006;66:938–940.

[245] Kraft AW, Hu X, Yoon H et al. Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice. FASEB J 2013;27:187–198.

[246] Kumari S, Dhapola R, Reddy DH. Apoptosis in Alzheimer’s disease: insight into the signaling pathways and therapeutic avenues. Apoptosis 2023;28:943–957.

[247] Kyalu Ngoie Zola N, Balty C, Pyr Dit Ruys S et al. Specific post-translational modifications of soluble tau protein distinguishes Alzheimer’s disease and primary tauopathies. Nat Commun 2023;14:3706.

[248] Laing KK, Simoes S, Baena-Caldas GP et al. Cerebrovascular disease promotes tau pathology in Alzheimer’s disease. Brain Commun 2020;2:fcaa132.

[249] Lambert JC, Heath S, Even G et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet 2009;41:1094–1099.

[250] Lambert JC, Ibrahim-Verbaas CA, Harold D et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 2013;45:1452–1458.

[251] Lee JH, Yang DS, Goulbourne CN et al. Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Abeta in neurons, yielding senile plaques. Nat Neurosci 2022;25:688–701.

[252] Le Guen Y, Belloy ME, Grenier-Boley B et al. Association of rare APOE missense variants V236E and R251G with risk of Alzheimer disease. JAMA Neurol 2022;79:652–663.

[253] Lei P, Ayton S, Finkelstein DI et al. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat Med 2012;18:291–295.

[254] Leng F, Edison P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat Rev Neurol 2021;17:157–172.

[255] Leng Y, Knutson K, Carnethon MR et al. Association between sleep quantity and quality in early adulthood with cognitive function in midlife. Neurology 2024;102:e208056.

[256] Leuzy A, Ashton NJ, Mattsson-Carlgren N et al. 2020 update on the clinical validity of cerebrospinal fluid amyloid, tau, and phospho-tau as biomarkers for Alzheimer’s disease in the context of a structured 5-phase development framework. Eur J Nucl Med Mol Imaging 2021;48:2121–2139.

[257] Leverenz JB, Raskind MA. Early amyloid deposition in the medial temporal lobe of young Down syndrome patients: a regional quantitative analysis. Exp Neurol 1998;150:296–304.

[258] Levy-Lahad E, Wasco W, Poorkaj P et al. Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 1995;269:973–977.

[259] Lewczuk P, Matzen A, Blennow K et al. Cerebrospinal fluid Abeta42/40 corresponds better than Abeta42 to amyloid PET in Alzheimer’s disease. J Alzheimers Dis 2017;55:813–822.

[260] Leyns CEG, Ulrich JD, Finn MB et al. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc Natl Acad Sci U S A 2017;114:11524–11529.

[261] Li Y, Schindler SE, Bollinger JG et al. Validation of plasma amyloid-beta 42/40 for detecting Alzheimer disease amyloid plaques. Neurology 2022;98:e688–e699.

[262] Liddelow SA, Guttenplan KA, Clarke LE et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 2017;541:481–487.

[263] Likeman M, Anderson VM, Stevens JM et al. Visual assessment of atrophy on magnetic resonance imaging in the diagnosis of pathologically confirmed young-onset dementias. Arch Neurol 2005;62:1410–1415.

[264] Lim YY, Mormino EC; Alzheimer’s Disease Neuroimaging Initiative. APOE genotype and early beta-amyloid accumulation in older adults without dementia. Neurology 2017;89:1028–1034.

[265] Lin X, Koelsch G, Wu S et al. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A 2000;97:1456–1460.

[266] Linard M, Letenneur L, Garrigue I et al. Interaction between APOE4 and herpes simplex virus type 1 in Alzheimer’s disease. Alzheimers Dement 2020;16:200–208.

[267] Litvinchuk A, Wan YW, Swartzlander DB et al. Complement C3aR inactivation attenuates Tau pathology and reverses an immune network deregulated in tauopathy models and Alzheimer’s disease. Neuron 2018;100:1337–1353.e5.

[268] Liu F, Zaidi T, Iqbal K et al. Role of glycosylation in hyperphosphorylation of tau in Alzheimer’s disease. FEBS Lett 2002;512:101–106.

[269] Liu F, Shi J, Tanimukai H et al. Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer’s disease. Brain 2009;132:1820–1832.

[270] Liu S, Liu Y, Hao W et al. TLR2 is a primary receptor for Alzheimer’s amyloid beta peptide to trigger neuroinflammatory activation. J Immunol 2012;188:1098–1107.

[271] Liu CC, Zhao N, Fu Y et al. ApoE4 accelerates early seeding of amyloid pathology. Neuron 2017;96:1024–1032.e3.

[272] Liu CC, Zhao J, Fu Y et al. Peripheral apoE4 enhances Alzheimer’s pathology and impairs cognition by compromising cerebrovascular function. Nat Neurosci 2022;25:1020–1033.

[273] Liu CC, Wang N, Chen Y et al. Cell-autonomous effects of APOE4 in restricting microglial response in brain homeostasis and Alzheimer’s disease. Nat Immunol 2023a;24:1854–1866.

[274] Liu W, Xing S, Wei F et al. Excessive dietary salt intake exacerbates cognitive impairment progression and increases dementia risk in older adults. J Am Med Dir Assoc 2023b;24:125–129.e4.

[275] Livingston G, Sommerlad A, Orgeta V et al. Dementia prevention, intervention, and care. Lancet 2017;390:2673–2734.

[276] Livingston G, Huntley J, Sommerlad A et al. Dementia prevention, intervention, and care:2020 report of the Lancet Commission. Lancet 2020;396:413–446.

[277] Lodato MA, Rodin RE, Bohrson CL et al. Aging and neurodegeneration are associated with increased mutations in single human neurons. Science 2018;359:555–559.

[278] Long JM, Holtzman DM. Alzheimer disease: an update on pathobiology and treatment strategies. Cell 2019;179:312–339.

[279] Lopatko Lindman K, Weidung B, Olsson J et al. A genetic signature including apolipoprotein EepsiloN4 potentiates the risk of herpes simplex-associated Alzheimer’s disease. Alzheimers Dement (N Y) 2019;5:697–704.

[280] Lopera F, Marino C, Chandrahas AS et al. Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man. Nat Med 2023;29:1243–1252.

[281] Losev Y, Paul A, Frenkel-Pinter M et al. Novel model of secreted human tau protein reveals the impact of the abnormal N-glycosylation of tau on its aggregation propensity. Sci Rep 2019;9:2254.

[282] Lott IT, Head E. Dementia in Down syndrome: unique insights for Alzheimer disease research. Nat Rev Neurol 2019;15:135–147.

[283] Lu DC, Soriano S, Bredesen DE et al. Caspase cleavage of the amyloid precursor protein modulates amyloid beta-protein toxicity. J Neurochem 2003;87:733–741.

[284] Lucassen PJ, Chung WC, Kamphorst W et al. DNA damage distribution in the human brain as shown by in situ end labeling; area-specific differences in aging and Alzheimer disease in the absence of apoptotic morphology. J Neuropathol Exp Neurol 1997;56:887–900.

[285] Lucey BP, Hicks TJ, McLeland JS et al. Effect of sleep on over-night cerebrospinal fluid amyloid beta kinetics. Ann Neurol 2018;83:197–204.

[286] Luchsinger JA, Tang MX, Shea S et al. Caloric intake and the risk of Alzheimer disease. Arch Neurol 2002;59:1258–1263.

[287] Luna-Munoz J, Chavez-Macias L, Garcia-Sierra F et al. Earliest stages of tau conformational changes are related to the appearance of a sequence of specific phospho-dependent tau epitopes in Alzheimer’s disease. J Alzheimers Dis 2007;12:365–375.

[288] Luo HB, Xia YY, Shu XJ et al. SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination. Proc Natl Acad Sci U S A 2014;111:16586–16591.

[289] Luo J, Thomassen JQ, Bellenguez C et al. Genetic associations between modifiable risk factors and Alzheimer disease. JAMA Netw Open 2023;6:e2313734.

[290] Mahmoudi E, Sadaghiyani S, Lin P et al. Diagnosis of Alzheimer’s disease and related dementia among people with multiple sclerosis: Large cohort study, USA. Mult Scler Relat Disord 2022;57:103351.

[291] Majumdar A, Capetillo-Zarate E, Cruz D et al. Degradation of Alzheimer’s amyloid fibrils by microglia requires delivery of ClC-7 to lysosomes. Mol Biol Cell 2011;22:1664–1676.

[292] Malaguarnera M, Bella R, Alagona G et al. Helicobacter pylori and Alzheimer’s disease: a possible link. Eur J Intern Med 2004;15:381–386.

[293] Marschallinger J, Iram T, Zardeneta M et al. Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat Neurosci 2020;23:194–208.

[294] Martini-Stoica H, Cole AL, Swartzlander DB et al. TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading. J Exp Med 2018;215:2355–2377.

[295] Martorell AJ, Paulson AL, Suk HJ et al. Multi-sensory gamma stimulation ameliorates Alzheimer’s-associated pathology and improves cognition. Cell 2019;177:256–271.e22.

[296] Masters CL, Simms G, Weinman NA et al. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A 1985;82:4245–4249.

[297] Mastorakos P, Mihelson N, Luby M et al. Temporally distinct myeloid cell responses mediate damage and repair after cerebrovascular injury. Nat Neurosci 2021;24:245–258.

[298] Mathys H, Davila-Velderrain J, Peng Z et al. Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 2019;570:332–337.

[299] Mathys H, Peng Z, Boix CA et al. Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer’s disease pathology. Cell 2023;186:4365–4385.e27.

[300] Mattsson N, Andreasson U, Zetterberg H et al. Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease. JAMA Neurol 2017;74:557–566.

[301] Mattsson N, Groot C, Jansen WJ et al. Prevalence of the apolipoprotein E epsilon4 allele in amyloid beta positive subjects across the spectrum of Alzheimer’s disease. Alzheimers Dement 2018;14:913–924.

[302] Mattsson N, Cullen NC, Andreasson U et al. Association between longitudinal plasma neurofilament light and neurodegeneration in patients With Alzheimer disease. JAMA Neurol 2019;76:791–799.

[303] McDowell I, Xi G, Lindsay J et al. Mapping the connections between education and dementia. J Clin Exp Neuropsychol 2007;29:127–141.

[304] McGeer PL, Itagaki S, Tago H et al. Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett 1987;79:195–200.

[305] McHutchison CA, Cvoro V, Makin S et al. Functional, cognitive and physical outcomes 3 years after minor lacunar or cortical ischaemic stroke. J Neurol Neurosurg Psychiatry 2019;90:436–443.

[306] McKee AC, Cantu RC, Nowinski CJ et al. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol 2009;68:709–735.

[307] McKhann GM, Knopman DS, Chertkow H et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011;7:263–269.

[308] Messier C, Awad N, Gagnon M. The relationships between atherosclerosis, heart disease, type 2 diabetes and dementia. Neurol Res 2004;26:567–572.

[309] Meyer-Luehmann M, Coomaraswamy J, Bolmont T et al. Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 2006;313:1781–1784.

[310] Middeldorp J, Lehallier B, Villeda SA et al. Preclinical assessment of young blood plasma for Alzheimer disease. JAMA Neurol 2016;73:1325–1333.

[311] Miklossy J. Bacterial amyloid and DNA are important constituents of senile plaques: further evidence of the spirochetal and biofilm nature of senile plaques. J Alzheimers Dis 2016;53:1459–1473.

[312] Miklossy J, Qing H, Radenovic A et al. Beta amyloid and hyperphosphorylated tau deposits in the pancreas in type 2 diabetes. Neurobiol Aging 2010;31:1503–1515.

[313] Miller MB, Huang AY, Kim J et al. Somatic genomic changes in single Alzheimer’s disease neurons. Nature 2022;604:714–722.

[314] Millet A, Ledo JH, Tavazoie SF. An exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer’s brains. Immunity 2024;57:153–170.e6.

[315] Min SW, Cho SH, Zhou Y et al. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron 2010;67:953–966.

[316] Mody PH, Marvin KN, Hynds DL et al. Cytomegalovirus infection induces Alzheimer’s disease-associated alterations in tau. J Neurovirol 2023;29:400–415.

[317] Mori H, Kondo J, Ihara Y. Ubiquitin is a component of paired helical filaments in Alzheimer’s disease. Science 1987;235:1641–1644.

[318] Morio B, Fardet A, Legrand P et al. Involvement of dietary saturated fats, from all sources or of dairy origin only, in insulin resistance and type 2 diabetes. Nutr Rev 2016;74:33–47.

[319] Morris MC, Evans DA, Bienias JL et al. Dietary fats and the risk of incident Alzheimer disease. Arch Neurol 2003;60:194–200.

[320] Morris JC, Roe CM, Xiong C et al. APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann Neurol 2010;67:122–131.

[321] Morris M, Knudsen GM, Maeda S et al. Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice. Nat Neurosci 2015;18:1183–1189.

[322] Moscoso A, Grothe MJ, Ashton NJ et al. Alzheimer’s Disease Neuroimaging Initiative. Longitudinal associations of blood phosphorylated Tau181 and neurofilament light chain with neurodegeneration in Alzheimer disease. JAMA Neurol 2021;78:396–406.

[323] Mothes T, Portal B, Konstantinidis E et al. Astrocytic uptake of neuronal corpses promotes cell-to-cell spreading of tau pathology. Acta Neuropathol Commun 2023;11:97.

[324] Mulcahy LA, Pink RC, Carter DR. Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles 2014;3:1–14.

[325] Mummery CJ, Borjesson-Hanson A, Blackburn DJ et al. Tautargeting antisense oligonucleotide MAPT(Rx) in mild Alzheimer’s disease: a phase 1b, randomized, placebocontrolled trial. Nat Med 2023;29:1437–1447.

[326] Murdock MH, Yang CY, Sun N et al. Multisensory gamma stimulation promotes glymphatic clearance of amyloid. Nature 2024;627:149–156.

[327] Musiek ES, Ju YS. Targeting sleep and circadian function in the prevention of Alzheimer disease. JAMA Neurol 2022;79:835–836.

[328] Musiek ES, Bhimasani M, Zangrilli MA et al. Circadian rest-activity pattern changes in aging and preclinical Alzheimer disease. JAMA Neurol 2018;75:582–590.

[329] Nacharaju P, Ko L, Yen SH. Characterization of in vitro glycation sites of tau. J Neurochem 1997;69:1709–1719.

[330] Naj AC, Jun G, Beecham GW et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet 2011;43:436–441.

[331] Narayan P, Orte A, Clarke RW et al. The extracellular chaper-one clusterin sequesters oligomeric forms of the amyloid-beta(1-40) peptide. Nat Struct Mol Biol 2011;19:79–83.

[332] Nath S, Agholme L, Kurudenkandy FR et al. Spreading of neurodegenerative pathology via neuron-to-neuron transmission of beta-amyloid. J Neurosci 2012;32:8767–8777.

[333] Nelson PT, Alafuzoff I, Bigio EH et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol 2012;71:362–381.

[334] Nelson MR, Liu P, Agrawal A et al. The APOE-R136S mutation protects against APOe4-driven Tau pathology, neurodegeneration and neuroinflammation. Nat Neurosci 2023;26:2104–2121.

[335] Nemetz PN, Leibson C, Naessens JM et al. Traumatic brain injury and time to onset of Alzheimer’s disease: a population-based study. Am J Epidemiol 1999;149:32–40.

[336] Neu SC, Pa J, Kukull W et al. Apolipoprotein E genotype and sex risk factors for Alzheimer disease: a meta-analysis. JAMA Neurol 2017;74:1178–1189.

[337] Nielsen HM, Chen K, Lee W et al. Peripheral apoE isoform levels in cognitively normal APOE epsilon3/epsilon4 individuals are associated with regional gray matter volume and cerebral glucose metabolism. Alzheimers Res Ther 2017;9:5.

[338] Nixon RA. Autophagy, amyloidogenesis and Alzheimer disease. J Cell Sci 2007;120:4081–4091.

[339] Norton S, Matthews FE, Barnes DE et al. Potential for primary prevention of Alzheimer’s disease: an analysis of population-based data. Lancet Neurol 2014;13:788–794.

[340] Nyamayaro P, Chibanda D, Robbins RN et al. Assessment of neurocognitive deficits in people living with HIV in Sub Saharan Africa: a systematic review. Clin Neuropsychol 2019;33:1–26.

[341] Oeckl P, Anderl-Straub S, Von Arnim CAF et al. Serum GFAP differentiates Alzheimer’s disease from frontotemporal dementia and predicts MCI-to-dementia conversion. J Neurol Neurosurg Psychiatry 2022;93:659–667.

[342] Olive C, Ibanez L, Farias FHG et al. Examination of the effect of rare variants in TREM2, ABI3, and PLCG2 in LOAD through multiple phenotypes. J Alzheimers Dis 2020;77:1469–1482.

[343] Olivera A, Lejbman N, Jeromin A et al. Peripheral total Tau in military personnel who sustain traumatic brain injuries during deployment. JAMA Neurol 2015;72:1109–1116.

[344] Ossenkoppele R, Schonhaut DR, Scholl M et al. Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer’s disease. Brain 2016;139:1551–1567.

[345] Ossenkoppele R, Rabinovici GD, Smith R et al. Discriminative accuracy of [18F]flortaucipir Positron emission tomography for Alzheimer disease vs other neurodegenerative disorders. JAMA 2018;320:1151–1162.

[346] Ost M, Nylen K, Csajbok L et al. Initial CSF total tau correlates with 1-year outcome in patients with traumatic brain injury. Neurology 2006;67:1600–1604.

[347] Palmqvist S, Janelidze S, Quiroz YT et al. Discriminative accuracy of plasma Phospho-tau217 for Alzheimer disease vs other neurodegenerative disorders. JAMA 2020;324:772–781.

[348] Pan Y, Li H, Wardlaw JM et al. A new dawn of preventing dementia by preventing cerebrovascular diseases. BMJ 2020;371:m3692.

[349] Pandey S, Shen K, Lee SH et al. Disease-associated oligodendrocyte responses across neurodegenerative diseases. Cell Rep 2022;40:111189.

[350] Parhizkar S, Arzberger T, Brendel M et al. Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat Neurosci 2019;22:191–204.

[351] Park SA, Shaked GM, Bredesen DE et al. Mechanism of cytotoxicity mediated by the C31 fragment of the amyloid precursor protein. Biochem Biophys Res Commun 2009;388:450–455.

[352] Park H, Cho B, Kim H et al. Single-cell RNA-sequencing identifies disease-associated oligodendrocytes in male APP NL-G-F and 5XFAD mice. Nat Commun 2023;14:802.

[353] Parra Bravo C, Giani AM, Perez JM et al. Human iPSC 4R tauopathy model uncovers modifiers of tau propagation. Cell 2024;187:2446–2464.

[354] Paudel B, Jeong SY, Martinez CP et al. Death Induced by Survival gene Elimination (DISE) correlates with neurotoxicity in Alzheimer’s disease and aging. Nat Commun 2024;15:264.

[355] Peacock ML, Warren JT Jr, Roses AD et al. Novel polymorphism in the A4 region of the amyloid precursor protein gene in a patient without Alzheimer’s disease. Neurology 1993;43:1254–1256.

[356] Pendlebury ST, Rothwell PM, Oxford Vascular S. Incidence and prevalence of dementia associated with transient ischaemic attack and stroke: analysis of the population-based Oxford Vascular Study. Lancet Neurol 2019;18:248–258.

[357] Peng Q, Malhotra S, Torchia JA et al. TREM2-and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1. Sci Signal 2010;3:ra38.

[358] Penninkilampi R, Casey AN, Singh MF et al. The association between social engagement, loneliness, and risk of dementia: a systematic review and meta-analysis. J Alzheimers Dis 2018;66:1619–1633.

[359] Perry G, Friedman R, Shaw G et al. Ubiquitin is detected in neurofibrillary tangles and senile plaque neurites of Alzheimer disease brains. Proc Natl Acad Sci U S A 1987;84:3033–3036.

[360] Perry G, Nunomura A, Lucassen P et al. Apoptosis and Alzheimer’s disease. Science 1998;282:1268–1269.

[361] Petrucelli L, Dickson D, Kehoe K et al. CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum Mol Genet 2004;13:703–714.

[362] Plescher M, Seifert G, Hansen JN et al. Plaque-dependent morphological and electrophysiological heterogeneity of microglia in an Alzheimer’s disease mouse model. Glia 2018;66:1464–1480.

[363] Poduslo JF, Curran GL, Berg CT. Macromolecular permeability across the blood-nerve and blood-brain barriers. Proc Natl Acad Sci U S A 1994;91:5705–5709.

[364] Polvikoski T, Sulkava R, Haltia M et al. Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein. N Engl J Med 1995;333:1242–1247.

[365] Povellato G, Tuxworth RI, Hanger DP et al. Modification of the Drosophila model of in vivo Tau toxicity reveals protective phosphorylation by GSK3beta. Biol Open 2014;3:1–11.

[366] Prifti E, Tsakiri EN, Vourkou E et al. The two cysteines of Tau protein are functionally distinct and contribute differentially to its pathogenicity in vivo. J Neurosci 2021;41:797–810.

[367] Profenno LA, Porsteinsson AP, Faraone SV. Meta-analysis of Alzheimer’s disease risk with obesity, diabetes, and related disorders. Biol Psychiatry 2010;67:505–512.

[368] Purro SA, Farrow MA, Linehan J et al. Transmission of amyloid-beta protein pathology from cadaveric pituitary growth hormone. Nature 2018;564:415–419.

[369] Qiu C, Winblad B, Marengoni A et al. Heart failure and risk of dementia and Alzheimer disease: a population-based cohort study. Arch Intern Med 2006;166:1003–1008.

[370] Rabin JS, Nichols E, La Joie R et al. Cerebral amyloid angiopathy interacts with neuritic amyloid plaques to promote tau and cognitive decline. Brain 2022;145:2823–2833.

[371] Rachmian N, Medina S, Cherqui U et al. Identification of senescent, TREM2-expressing microglia in aging and Alzheimer’s disease model mouse brain. Nat Neurosci 2024.

[372] Rannikmae K, Kalaria RN, Greenberg SM et al. APOE associations with severe CAA-associated vasculopathic changes: collaborative meta-analysis. J Neurol Neurosurg Psychiatry 2014;85:300–305.

[373] Rehm J, Hasan OSM, Black SE et al. Alcohol use and dementia: a systematic scoping review. Alzheimers Res Ther 2019;11:1.

[374] Reiman EM, Quiroz YT, Fleisher AS et al. Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer’s disease in the presenilin 1 E280A kindred: a case-control study. Lancet Neurol 2012;11:1048–1056.

[375] Rezai AR, D’Haese PF, Finomore V et al. Ultrasound blood-brain barrier opening and Aducanumab in Alzheimer’s disease. N Engl J Med 2024;390:55–62.

[376] Rhodius-Meester HFM, van Maurik IS, Koikkalainen J et al. Selection of memory clinic patients for CSF biomarker assessment can be restricted to a quarter of cases by using computerized decision support, without compromising diagnostic accuracy. PLoS One 2020;15:e0226784.

[377] Ring S, Weyer SW, Kilian SB et al. The secreted beta-amyloid precursor protein ectodomain APPs alpha is sufficient to rescue the anatomical, behavioral, and electrophysiological abnormalities of APP-deficient mice. J Neurosci 2007;27:7817–7826.

[378] Ringman JM, O’Neill J, Geschwind D et al. Diffusion tensor imaging in preclinical and presymptomatic carriers of familial Alzheimer’s disease mutations. Brain 2007;130:1767–1776.

[379] Rissman RA, Poon WW, Blurton-Jones M et al. Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology. J Clin Invest 2004;114:121–130.

[380] Rivera EJ, Goldin A, Fulmer N et al. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: link to brain reductions in acetylcholine. J Alzheimers Dis 2005;8:247–268.

[381] Roberts GW, Gentleman SM, Lynch A et al. beta A4 amyloid protein deposition in brain after head trauma. Lancet 1991;338:1422–1423.

[382] Roberts M, Sevastou I, Imaizumi Y et al. Pre-clinical characterisation of E2814, a high-affinity antibody targeting the microtubule-binding repeat domain of tau for passive immunotherapy in Alzheimer’s disease. Acta Neuropathol Commun 2020;8:13.

[383] Rohan de Silva HA, Jen A, Wickenden C et al. Cell-specific expression of beta-amyloid precursor protein isoform mRNAs and proteins in neurons and astrocytes. Brain Res Mol Brain Res 1997;47:147–156.

[384] Roher AE, Lowenson JD, Clarke S et al. beta-Amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease. Proc Natl Acad Sci U S A 1993;90:10836–10840.

[385] Roussos P, Katsel P, Fam P et al. The triggering receptor expressed on myeloid cells 2 (TREM2) is associated with enhanced inflammation, neuropathological lesions and increased risk for Alzheimer’s dementia. Alzheimers Dement 2015;11:1163–1170.

[386] Rusanen M, Kivipelto M, Quesenberry CP Jr et al. Heavy smoking in midlife and long-term risk of Alzheimer disease and vascular dementia. Arch Intern Med 2011;171:333–339.

[387] Ryan CM, Geckle MO. Circumscribed cognitive dysfunction in middle-aged adults with type 2 diabetes. Diabetes Care 2000;23:1486–1493.

[388] Ryman DC, Acosta-Baena N, Aisen PS et al. Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology 2014;83:253–260.

[389] Saab AS, Tzvetavona ID, Trevisiol A et al. Oligodendroglial NMDA receptors regulate glucose import and axonal energy metabolism. Neuron 2016;91:119–132.

[390] Sabia S, Fayosse A, Dumurgier J et al. Association of sleep duration in middle and old age with incidence of dementia. Nat Commun 2021;12:2289.

[391] Sadick JS, O’Dea MR, Hasel P et al. Astrocytes and oligodendrocytes undergo subtype-specific transcriptional changes in Alzheimer’s disease. Neuron 2022;110:1788–1805.e10.

[392] Saeed A, Lopez O, Cohen A et al. Cardiovascular disease and Alzheimer’s disease: the heart-brain axis. J Am Heart Assoc 2023;12:e030780.

[393] Salloway S, Chalkias S, Barkhof F et al. Amyloid-related imaging abnormalities in 2 phase 3 studies evaluating aducanumab in patients with early Alzheimer disease. JAMA Neurol 2022;79:13–21.

[394] Saman S, Kim W, Raya M et al. Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J Biol Chem 2012;287:3842–3849.

[395] Samieri C, Perier MC, Gaye B et al. Association of cardiovascular health level in older age with cognitive decline and incident dementia. JAMA 2018;320:657–664.

[396] Sando SB, Melquist S, Cannon A et al. Risk-reducing effect of education in Alzheimer’s disease. Int J Geriatr Psychiatry 2008;23:1156–1162.

[397] Saresella M, La Rosa F, Piancone F et al. The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer’s disease. Mol Neurodegener 2016;11:23.

[398] Sartori M, Mendes T, Desai S et al. BIN1 recovers tauopathy-induced long-term memory deficits in mice and interacts with Tau through Thr(348) phosphorylation. Acta Neuropathol 2019;138:631–652.

[399] Sastre M, Steiner H, Fuchs K et al. Presenilin-dependent gamma-secretase processing of beta-amyloid precursor protein at a site corresponding to the S3 cleavage of Notch. EMBO Rep 2001;2:835–841.

[400] Savastano A, Flores D, Kadavath H et al. Disease-associated Tau phosphorylation hinders tubulin assembly within Tau condensates. Angew Chem Int Ed Engl 2021;60:726–730.

[401] Sayed FA, Telpoukhovskaia M, Kodama L et al. Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy. Proc Natl Acad Sci U S A 2018;115:10172–10177.

[402] Scheltens P, De Strooper B, Kivipelto M et al. Alzheimer’s disease. Lancet 2021;397:1577–1590.

[403] Schlepckow K, Kleinberger G, Fukumori A et al. An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function. EMBO Mol Med 2017;9:1356–1365.

[404] Schmechel DE, Saunders AM, Strittmatter WJ et al. Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Natl Acad Sci U S A 1993;90:9649–9653.

[405] Schneider JA, Wilson RS, Bienias JL et al. Cerebral infarctions and the likelihood of dementia from Alzheimer disease pathology. Neurology 2004;62:1148–1155.

[406] Schneider JA, Boyle PA, Arvanitakis Z et al. Subcortical infarcts, Alzheimer’s disease pathology, and memory function in older persons. Ann Neurol 2007;62:59–66.

[407] Schrijvers EM, Koudstaal PJ, Hofman A et al. Plasma clusterin and the risk of Alzheimer disease. JAMA 2011;305:1322–1326.

[408] Self WK, Holtzman DM. Emerging diagnostics and therapeutics for Alzheimer disease. Nat Med 2023;29:2187–2199.

[409] Serrano-Pozo A, Frosch MP, Masliah E et al. Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med 2011;1:a006189.

[410] Seshadri S, Fitzpatrick AL, Ikram MA et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 2010;303:1832–1840.

[411] Sha SJ, Deutsch GK, Tian L et al. Safety, tolerability, and feasibility of young plasma infusion in the plasma for Alzheimer Symptom Amelioration Study: a randomized clinical trial. JAMA Neurol 2019;76:35–40.

[412] Shafiei SS, Guerrero-Munoz MJ, Castillo-Carranza DL. Tau oligomers: cytotoxicity, propagation, and mitochondrial damage. Front Aging Neurosci 2017;9:83.

[413] Shahidehpour RK, Higdon RE, Crawford NG et al. Dystrophic microglia are associated with neurodegenerative disease and not healthy aging in the human brain. Neurobiol Aging 2021;99:19–27.

[414] Shahim P, Tegner Y, Wilson DH et al. Blood biomarkers for brain injury in concussed professional ice hockey players. JAMA Neurol 2014;71:684–692.

[415] Sherrington R, Rogaev EI, Liang Y et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 1995;375:754–760.

[416] Shi Y, Yamada K, Liddelow SA et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 2017;549:523–527.

[417] Shi Y, Murzin AG, Falcon B et al. Cryo-EM structures of tau filaments from Alzheimer’s disease with PET ligand APN-1607. Acta Neuropathol 2021a;141:697–708.

[418] Shi Y, Zhang W, Yang Y et al. Structure-based classification of tauopathies. Nature 2021b;598:359–363.

[419] Shiells H, Schelter BO, Bentham P et al. Concentration-dependent activity of hydromethylthionine on clinical decline and brain atrophy in a randomized controlled trial in behavioral variant frontotemporal dementia. J Alzheimers Dis 2020;75:501–519.

[420] Shinohara M, Murray ME, Frank RD et al. Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer’s disease. Acta Neuropathol 2016;132:225–234.

[421] Shukla V, Skuntz S, Pant HC. Deregulated Cdk5 activity is involved in inducing Alzheimer’s disease. Arch Med Res 2012;43:655–662.

[422] Sims JR, Zimmer JA, Evans CD et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA 2023;330:512–527.

[423] Sinha S, Anderson JP, Barbour R et al. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 1999;402:537–540.

[424] Sisodia SS, Koo EH, Beyreuther K et al. Evidence that beta-amyloid protein in Alzheimer’s disease is not derived by normal processing. Science 1990;248:492–495.

[425] Skillback T, Farahmand BY, Rosen C et al. Cerebrospinal fluid tau and amyloid-beta1-42 in patients with dementia. Brain 2015;138:2716–2731.

[426] Smith DH, Chen XH, Iwata A et al. Amyloid beta accumulation in axons after traumatic brain injury in humans. J Neurosurg 2003;98:1072–1077.

[427] Sohn PD, Tracy TE, Son HI et al. Acetylated tau destabilizes the cytoskeleton in the axon initial segment and is mislocalized to the somatodendritic compartment. Mol Neurodegener 2016;11:47.

[428] Sommerlad A, Kivimaki M, Larson EB et al. Social participation and risk of developing dementia. Nat Aging 2023;3:532–545.

[429] Song HL, Shim S, Kim DH et al. beta-Amyloid is transmitted via neuronal connections along axonal membranes. Ann Neurol 2014;75:88–97.

[430] Song W, Hooli B, Mullin K et al. Alzheimer’s disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation. Alzheimers Dement 2017;13:381–387.

[431] Song WM, Joshita S, Zhou Y et al. Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism. J Exp Med 2018;215:745–760.

[432] Sontag E, Luangpirom A, Hladik C et al. Altered expression levels of the protein phosphatase 2A ABalphaC enzyme are associated with Alzheimer disease pathology. J Neuropathol Exp Neurol 2004;63:287–301.

[433] Soula M, Martin-Avila A, Zhang Y et al. Forty-hertz light stimulation does not entrain native gamma oscillations in Alzheimer’s disease model mice. Nat Neurosci 2023;26:570–578.

[434] Spangenberg E, Severson PL, Hohsfield LA et al. Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model. Nat Commun 2019;10:3758.

[435] Spillantini MG, Goedert M. Tau protein pathology in neuro-degenerative diseases. Trends Neurosci 1998;21:428–433.

[436] Stadelmann C, Bruck W, Bancher C et al. Alzheimer disease: DNA fragmentation indicates increased neuronal vulnerability, but not apoptosis. J Neuropathol Exp Neurol 1998;57:456–464.

[437] Steen E, Terry BM, Rivera EJ et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease–is this type 3 diabetes? J Alzheimers Dis 2005;7:63–80.

[438] Streit WJ, Braak H, Xue QS et al. Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathol 2009;118:475–485.

[439] Suarez-Calvet M, Karikari TK, Ashton NJ 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 Abeta pathology are detected. EMBO Mol Med 2020;12:e12921.

[440] Suelves N, Saleki S, Ibrahim T et al. Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-beta accumulation in a mouse model of amyloid pathology. Acta Neuropathol Commun 2023;11:82.

[441] Sugarman MA, Zetterberg H, Blennow K et al. A longitudinal examination of plasma neurofilament light and total tau for the clinical detection and monitoring of Alzheimer’s disease. Neurobiol Aging 2020;94:60–70.

[442] Suri S, Topiwala A, Chappell MA et al. Association of midlife cardiovascular risk profiles with cerebral perfusion at older ages. JAMA Netw Open 2019;2:e195776.

[443] Sveikata L, Charidimou A, Viswanathan A. Vessels sing their ARIAs: the role of vascular amyloid in the age of aducanumab. Stroke 2022;53:298–302.

[444] Takasugi N, Tomita T, Hayashi I et al. The role of presenilin cofactors in the gamma-secretase complex. Nature 2003;422:438–441.

[445] Tan JX, Finkel T. A phosphoinositide signalling pathway mediates rapid lysosomal repair. Nature 2022;609:815–821.

[446] Tan MS, Tan L, Jiang T et al. Amyloid-beta induces NLRP1-dependent neuronal pyroptosis in models of Alzheimer’s disease. Cell Death Dis 2014;5:e1382.

[447] Tao Q, Ang TFA, DeCarli C et al. Association of chronic low-grade inflammation with risk of Alzheimer disease in ApoE4 carriers. JAMA Netw Open 2018;1:e183597.

[448] Tarawneh R, Holtzman DM. The clinical problem of symptomatic Alzheimer disease and mild cognitive impairment. Cold Spring Harb Perspect Med 2012;2:a006148.

[449] Tcw J, Goate AM. Genetics of beta-amyloid precursor protein in Alzheimer’s disease. Cold Spring Harb Perspect Med 2017;7:a024539.

[450] Tell V, Hilgeroth A. Recent developments of protein kinase inhibitors as potential AD therapeutics. Front Cell Neurosci 2013;7:189.

[451] Terry RD. The fine structure of neurofibrillary tangles in Alzheimer’s disease. J Neuropathol Exp Neurol 1963;22:629–642.

[452] Teunissen CE, Verberk IMW, Thijssen EH et al. Blood-based biomarkers for Alzheimer’s disease: towards clinical implementation. Lancet Neurol 2022;21:66–77.

[453] Thal DR, Gawor K, Moonen S. Regulated cell death and its role in Alzheimer’s disease and amyotrophic lateral sclerosis. Acta Neuropathol 2024;147:69.

[454] Theofilas P, Piergies AMH, Oh I et al. Caspase-6-cleaved tau is relevant in Alzheimer’s disease and marginal in four-repeat tauopathies: Diagnostic and therapeutic implications. Neuropathol Appl Neurobiol 2022;48:e12819.

[455] Thomas SN, Funk KE, Wan Y et al. Dual modification of Alzheimer’s disease PHF-tau protein by lysine methylation and ubiquitylation: a mass spectrometry approach. Acta Neuropathol 2012;123:105–117.

[456] Thomson RS, Auduong P, Miller AT et al. Hearing loss as a risk factor for dementia: a systematic review. Laryngoscope Investig Otolaryngol 2017;2:69–79.

[457] Thornton P, Sevalle J, Deery MJ et al. TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the Alzheimer’s disease-associated H157Y variant. EMBO Mol Med 2017;9:1366–1378.

[458] Tiraboschi P, Hansen LA, Masliah E et al. Impact of APOE genotype on neuropathologic and neurochemical markers of Alzheimer disease. Neurology 2004;62:1977–1983.

[459] Tooyama I, Kimura H, Akiyama H et al. Reactive microglia express class I and class II major histocompatibility complex antigens in Alzheimer’s disease. Brain Res 1990;523:273–280.

[460] Tracy TE, Sohn PD, Minami SS et al. Acetylated Tau obstructs KIBRA-mediated signaling in synaptic plasticity and promotes tauopathy-related memory loss. Neuron 2016;90:245–260.

[461] Tuo QZ, Lei P, Jackman KA et al. Tau-mediated iron export prevents ferroptotic damage after ischemic stroke. Mol Psychiatry 2017;22:1520–1530.

[462] Turnquist C, Horikawa I, Foran E et al. p53 isoforms regulate astrocyte-mediated neuroprotection and neurodegeneration. Cell Death Differ 2016;23:1515–1528.

[463] Tzeng NS, Chung CH, Lin FH et al. Anti-herpetic medications and reduced risk of dementia in patients with herpes simplex virus infections-a nationwide, populationbased cohort study in Taiwan. Neurotherapeutics 2018;15:417–429.

[464] Vagelatos NT, Eslick GD. Type 2 diabetes as a risk factor for Alzheimer’s disease: the confounders, interactions, and neuropathology associated with this relationship. Epidemiol Rev 2013;35:152–160.

[465] Van Acker Z P, Perdok A, Bretou M et al. The microglial lysosomal system in Alzheimer’s disease: guardian against proteinopathy. Ageing Res Rev 2021;71:101444.

[466] van der Ende EL, Bron EE, Poos JM et al. A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementia. Brain 2022;145:1805–1817.

[467] van Dyck CH, Swanson CJ, Aisen P et al. Lecanemab in early Alzheimer’s disease. N Engl J Med 2023;388:9–21.

[468] Vassar R, Bennett BD, Babu-Khan S et al. Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999;286:735–741.

[469] Verghese PB, Castellano JM, Garai K et al. ApoE influences amyloid-beta (Abeta) clearance despite minimal apoE/Abeta association in physiological conditions. Proc Natl Acad Sci U S A 2013;110:E1807–E1816.

[470] Vershinin M, Carter BC, Razafsky DS et al. Multiple-motor based transport and its regulation by Tau. Proc Natl Acad Sci U S A 2007;104:87–92.

[471] Villain N, Planche V, Levy R. High-clearance anti-amyloid immunotherapies in Alzheimer’s disease. Part 1: Meta-analysis and review of efficacy and safety data, and medico-economical aspects. Rev Neurol (Paris) 2022;178:1011–1030.

[472] Vogelsberg-Ragaglia V, Schuck T, Trojanowski JQ et al. PP2A mRNA expression is quantitatively decreased in Alzheimer’s disease hippocampus. Exp Neurol 2001;168:402–412.

[473] Wakabayashi T, Yamaguchi K, Matsui K et al. Differential effects of diet- and genetically-induced brain insulin resistance on amyloid pathology in a mouse model of Alzheimer’s disease. Mol Neurodegener 2019;14:15.

[474] Walker LC, Jucker M. Neurodegenerative diseases: expanding the prion concept. Annu Rev Neurosci 2015;38:87–103.

[475] Walter J, Fluhrer R, Hartung B et al. Phosphorylation regulates intracellular trafficking of beta-secretase. J Biol Chem 2001;276:14634–14641.

[476] Wang Y, Mandelkow E. Tau in physiology and pathology. Nat Rev Neurosci 2016;17:5–21.

[477] Wang JZ, Grundke-Iqbal I, Iqbal K. Glycosylation of microtubule-associated protein tau: an abnormal post-translational modification in Alzheimer’s disease. Nat Med 1996;2:871–875.

[478] Wang Y, Cella M, Mallinson K et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 2015;160:1061–1071.

[479] Wang P, Joberty G, Buist A et al. Tau interactome mapping based identification of Otub1 as Tau deubiquitinase involved in accumulation of pathological Tau forms in vitro and in vivo. Acta Neuropathol 2017a;133:731–749.

[480] Wang Y, Balaji V, Kaniyappan S et al. The release and trans-synaptic transmission of Tau via exosomes. Mol Neurodegener 2017b;12:5.

[481] Wang S, Mustafa M, Yuede CM et al. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer’s disease model. J Exp Med 2020a;217:1–19.

[482] Wang Y, Liu M, Lu Q et al. Global prevalence and burden of HIV-associated neurocognitive disorder: a meta-analysis. Neurology 2020b;95:e2610–e2621.

[483] Wang C, Fan L, Khawaja RR et al. Microglial NF-kappaB drives tau spreading and toxicity in a mouse model of tauopathy. Nat Commun 2022;13:1969.

[484] Wang C, Nambiar A, Strickland MR et al. APOE-epsilon4 synergizes with sleep disruption to accelerate Abeta deposition and Abeta-associated tau seeding and spreading. J Clin Invest 2023;133:1–16.

[485] Wang B, Martini-Stoica H, Qi C et al. TFEB-vacuolar ATPase signaling regulates lysosomal function and microglial activation in tauopathy. Nat Neurosci 2024;27:48–62.

[486] Wardlaw JM, Smith C, Dichgans M. Small vessel disease: mechanisms and clinical implications. Lancet Neurol 2019;18:684–696.

[487] Wei J, Hou J, Su B et al. The prevalence of frascati-criteriabased HIV-Associated Neurocognitive Disorder (HAND) in HIV-infected adults: a systematic review and meta-analysis. Front Neurol 2020;11:581346.

[488] Weiner MW, Veitch DP, Hayes J et al. Effects of traumatic brain injury and posttraumatic stress disorder on Alzheimer’s disease in veterans, using the Alzheimer’s Disease Neuroimaging Initiative. Alzheimers Dement 2014;10:S226–S235.

[489] Weisgraber KH, Innerarity TL, Mahley RW. Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine-arginine interchange at a single site. J Biol Chem 1982;257:2518–2521.

[490] Wendeln AC, Degenhardt K, Kaurani L et al. Innate immune memory in the brain shapes neurological disease hall-marks. Nature 2018;556:332–338.

[491] Wesseling H, Mair W, Kumar M et al. Tau PTM profiles identify patient heterogeneity and stages of Alzheimer’s disease. Cell 2020;183:1699–1713.e13.

[492] Weston PSJ, Poole T, Ryan NS et al. Serum neurofilament light in familial Alzheimer disease: a marker of early neurodegeneration. Neurology 2017;89:2167–2175.

[493] Willem M, Tahirovic S, Busche MA et al. eta-Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature 2015;526:443–447.

[494] Winblad B, Amouyel P, Andrieu S et al. Defeating Alzheimer’s disease and other dementias: a priority for European science and society. Lancet Neurol 2016;15:455–532.

[495] Wisniewski KE, Dalton AJ, McLachlan C et al. Alzheimer’s disease in Down’s syndrome: clinicopathologic studies. Neurology 1985;35:957–961.

[496] Wissfeld J, Nozaki I, Mathews M et al. Deletion of Alzheimer’s disease-associated CD33 results in an inflammatory human microglia phenotype. Glia 2021;69:1393–1412.

[497] Wojtas AM, Kang SS, Olley BM et al. Loss of clusterin shifts amyloid deposition to the cerebrovasculature via disruption of perivascular drainage pathways. Proc Natl Acad Sci U S A 2017;114:E6962–E6971.

[498] Wu JW, Herman M, Liu L et al. Small misfolded Tau species are internalized via bulk endocytosis and anterogradely and retrogradely transported in neurons. J Biol Chem 2013;288:1856–1870.

[499] Wu Y, Wu H, Zeng J et al. Mild traumatic brain injury induces microvascular injury and accelerates Alzheimer-like pathogenesis in mice. Acta Neuropathol Commun 2021;9:74.

[500] Wu R, Sun F, Zhang W et al. Targeting aging and age-related diseases with vaccines. Nat Aging 2024;4:464–482.

[501] Xie L, Kang H, Xu Q et al. Sleep drives metabolite clearance from the adult brain. Science 2013;342:373–377.

[502] Xie M, Liu YU, Zhao S et al. TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration. Nat Neurosci 2022;25:26–38.

[503] Xiong X, James BT, Boix CA et al. Epigenomic dissection of Alzheimer’s disease pinpoints causal variants and reveals epigenome erosion. Cell 2023;186:4422–4437.e21.

[504] Xu Z, Xiao N, Chen Y et al. Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Abeta accumulation and memory deficits. Mol Neurodegener 2015;10:58.

[505] Yaffe K, Kanaya A, Lindquist K et al. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA 2004;292:2237–2242.

[506] Yaffe K, Laffan AM, Harrison SL et al. Sleep-disordered breathing, hypoxia, and risk of mild cognitive impairment and dementia in older women. JAMA 2011;306:613–619.

[507] Yagishita S, Itoh Y, Nan W et al. Reappraisal of the fine structure of Alzheimer’s neurofibrillary tangles. Acta Neuropathol 1981;54:239–246.

[508] Yamada M, Naiki H. Cerebral amyloid angiopathy. Prog Mol Biol Transl Sci 2012;107:41–78.

[509] Yamazaki Y, Zhao N, Caulfield TR et al. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol 2019;15:501–518.

[510] Yan R, Bienkowski MJ, Shuck ME et al. Membrane-anchored aspartyl protease with Alzheimer’s disease beta-secretase activity. Nature 1999;402:533–537.

[511] Yan HF, Zou T, Tuo QZ et al. Ferroptosis: mechanisms and links with diseases. Signal Transduct Target Ther 2021;6:49.

[512] Yan Y, Wang X, Chaput D et al. X-linked ubiquitin-specific peptidase 11 increases tauopathy vulnerability in women. Cell 2022;185:3913–3930.e19.

[513] Yang Y, Mufson EJ, Herrup K. Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer’s disease. J Neurosci 2003;23:2557–2563.

[514] Yang T, Li S, Xu H et al. Large soluble oligomers of amyloid beta-protein from Alzheimer brain are far less neuroactive than the smaller oligomers to which they dissociate. J Neurosci 2017;37:152–163.

[515] Yang Y, Arseni D, Zhang W et al. Cryo-EM structures of amyloid-beta 42 filaments from human brains. Science 2022;375:167–172.

[516] Yarza R, Vela S, Solas M et al. c-Jun N-terminal Kinase (JNK) signaling as a therapeutic target for Alzheimer’s disease. Front Pharmacol 2015;6:321.

[517] Ye L, Hamaguchi T, Fritschi SK et al. Progression of seed-induced abeta deposition within the limbic connectome. Brain Pathol 2015;25:743–752.

[518] Yeh FL, Wang Y, Tom I et al. TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia. Neuron 2016;91:328–340.

[519] Yin Z, Rosenzweig N, Kleemann KL et al. APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFbeta-mediated checkpoints. Nat Immunol 2023;24:1839–1853.

[520] Yuan P, Condello C, Keene CD et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 2016;90:724–739.

[521] Zhang YW, Thompson R, Zhang H et al. APP processing in Alzheimer’s disease. Mol Brain 2011;4:3.

[522] Zhang Z, Song M, Liu X et al. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease. Nat Med 2014;20:1254–1262.

[523] Zhang YH, Wang DW, Xu SF et al. alpha-Lipoic acid improves abnormal behavior by mitigation of oxidative stress, inflammation, ferroptosis, and tauopathy in P301S Tau transgenic mice. Redox Biol 2018;14:535–548.

[524] Zhang P, Kishimoto Y, Grammatikakis I et al. Senolytic therapy alleviates Abeta-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat Neurosci 2019;22:719–728.

[525] Zhang W, Tarutani A, Newell KL et al. Novel tau filament fold in corticobasal degeneration. Nature 2020;580:283–287.

[526] Zhang ZY, Harischandra DS, Wang R et al. TRIM11 protects against tauopathies and is down-regulated in Alzheimer’s disease. Science 2023;381:eadd6696.

[527] Zhao QF, Tan L, Wang HF et al. The prevalence of neuropsychiatric symptoms in Alzheimer’s disease: systematic review and meta-analysis. J Affect Disord 2016a;190:264–271.

[528] Zhao X, Kotilinek LA, Smith B et al. Caspase-2 cleavage of tau reversibly impairs memory. Nat Med 2016b;22:1268–1276.

[529] Zhao Y, Wu X, Li X et al. TREM2 is a receptor for beta-amyloid that mediates microglial function. Neuron 2018;97:1023–1031.e7.

[530] Zhao Y, Zheng Q, Hong Y et al. beta(2)-Microglobulin coaggregates with Abeta and contributes to amyloid pathology and cognitive deficits in Alzheimer’s disease model mice. Nat Neurosci 2023;26:1170–1184.

[531] Zheng Q, Li G, Wang S et al. Trisomy 21-induced dysregulation of microglial homeostasis in Alzheimer’s brains is mediated by USP25. Sci Adv 2021;7:eabe1340.

[532] Zheng Q, Song B, Li G et al. USP25 inhibition ameliorates Alzheimer’s pathology through the regulation of APP processing and Abeta generation. J Clin Invest 2022;132:e152170.

[533] Zhong L, Chen XF, Zhang ZL et al. DAP12 Stabilizes the C-terminal Fragment of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) and Protects against LPS-induced Pro-inflammatory Response. J Biol Chem 2015;290:15866–15877.

[534] Zhong L, Chen XF, Wang T et al. Soluble TREM2 induces inflammatory responses and enhances microglial survival. J Exp Med 2017;214:597–607.

[535] Zhong L, Wang Z, Wang D et al. Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2). Mol Neurodegener 2018;13:15.

[536] Zhong L, Xu Y, Zhuo R et al. Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer’s disease model. Nat Commun 2019;10:1365.

[537] Zhong L, Sheng X, Wang W et al. TREM2 receptor protects against complement-mediated synaptic loss by binding to complement C1q during neurodegeneration. Immunity 2023;56:1794–1808.e8.

[538] Zhou Y, Song WM, Andhey PS et al. Human and mouse ingle-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease. Nat Med 2020;26:131–142.

[539] Zivanovic M, Aracki Trenkic A, Milosevic V et al. The role of magnetic resonance imaging in the diagnosis and prognosis of dementia. Biomol Biomed 2023;23:209–224.

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