JG created the mathematics from which the machine intelligence techniques utilized were derived, curated the data, led the vision, and carried out a good portion of the research along with MT, who contributed essential bioinformatics. BQ wrote the majority of the manuscript and carried out critical protein interaction work that allowed us to interpret the results provided by the machine intelligence. RA and AA were both primary readers of the manuscript, provided direction, criticism, and helped shape the overall flow of the research during the course of this work. All authors contributed to manuscript revision, read, and approved the submitted version.
Conflicts of interest
The author Joseph Geraci declares that he owns substantial shares in NetraMark Corp, which funded a major portion of this study.
This project was supported by NetraMark Corp., an AI company focused on advanced machine intelligence methods, and by graduate student support from Queen’s University for Bessi Qorri. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
WHO.Global action plan on the public health response to dementia 2017–2025. Geneva: World Health Organization; 2017.
2020 Alzheimer’s disease facts and figures. Alzheimer’s Dement. 2020;16:391–460. [DOI]
Prince M, Ali GC, Guerchet M, Prina AM, Albanese E, Wu YT.Recent global trends in the prevalence and incidence of dementia, and survival with dementia. Alzheimers Res Ther.2016;8:23. [DOI] [PubMed] [PMC]
Toro CA, Zhang L, Cao J, Cai D.Sex differences in Alzheimer’s disease: understanding the molecular impact. Brain Res.2019;1719:194–207. [DOI] [PubMed] [PMC]
Quan M, Zhao T, Tang Y, Luo P, Wang W, Qin Q, et al. Effects of gene mutation and disease progression on representative neural circuits in familial Alzheimer’s disease. Alzheimers Res Ther.2020;12:14. [DOI] [PubMed] [PMC]
Dorszewska J, Prendecki M, Oczkowska A, Dezor M, Kozubski W.Molecular basis of familial and sporadic Alzheimer’s disease. Curr Alzheimer Res.2016;13:952–63. [DOI] [PubMed]
Anand R, Gill KD, Mahdi AA.Therapeutics of Alzheimer’s disease: past, present and future. Neuropharmacology.2014;76:27–50. [DOI] [PubMed]
Eid A, Mhatre I, Richardson JR.Gene-environment interactions in Alzheimer’s disease: a potential path to precision medicine. Pharmacol Ther.2019;199:173–87. [DOI] [PubMed] [PMC]
Cummings J, Lee G, Ritter A, Zhong K.Alzheimer’s disease drug development pipeline: 2018. Alzheimers Dement (N Y).2018;4:195–214. [DOI] [PubMed] [PMC]
Cummings JL, Morstorf T, Zhong K.Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther.2014;6:37. [DOI] [PubMed] [PMC]
Wang X, Sun G, Feng T, Zhang J, Huang X, Wang T, et al. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Cell Res.2019;29:787–803. [DOI] [PubMed] [PMC]
Hampel H, O’Bryant SE, Castrillo JI, Ritchie C, Rojkova K, Broich K, et al. Precision medicine-the golden gate for detection, treatment and prevention of Alzheimer’s disease. J Prev Alzheimers Dis.2016;3:243–59. [DOI] [PubMed] [PMC]
Freudenberg-Hua Y, Li W, Davies P.The role of genetics in advancing precision medicine for Alzheimer’s disease-a narrative review. Front Med (Lausanne).2018;5:108. [DOI] [PubMed] [PMC]
Van Cauwenberghe C, Van Broeckhoven C, Sleegers K.The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet Med.2016;18:421–30. [DOI] [PubMed] [PMC]
Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet.2013;45:1452–8. [DOI] [PubMed] [PMC]
Tábuas-Pereira M, Santana I, Guerreiro R, Brás J.Alzheimer’s disease genetics: review of novel loci associated with disease. Curr Genet Med Rep.2020;8:1–16. [DOI]
Castrillo JI, Lista S, Hampel H, Ritchie CW.Systems biology methods for Alzheimer’s disease research toward molecular signatures, subtypes, and stages and precision medicine: application in cohort studies and trials. In: Perneczky R, editor. Biomarkers for Alzheimer’s Disease Drug Development. New York: Humana Press; 2018. p. 31–66. [DOI]
Zhang D, Wang Y, Zhou L, Yuan H, Shen D; Alzheimer’s Disease Neuroimaging Initiative. Multimodal classification of Alzheimer’s disease and mild cognitive impairment. Neuroimage.2011;55:856–67. [DOI] [PubMed] [PMC]
Wei R, Li C, Fogelson N, Li L.Prediction of conversion from mild cognitive impairment to alzheimer’s disease using MRI and structural network features. Front Aging Neurosci.2016;8:76. [DOI] [PubMed] [PMC]
Zhang D, Shen D; Alzheimer’s Disease Neuroimaging Initiative. Multimodal multi-task learning for joint prediction of multiple regression and classification variables in Alzheimer’s disease. Neuroimage.2012;59:895–907. [DOI] [PubMed] [PMC]
Zhang D, Shen D; Alzheimer’s Disease Neuroimaging Initiative. Predicting future clinical changes of MCI patients using longitudinal and multimodal biomarkers. PLoS One.2012;7:e33182. [DOI] [PubMed] [PMC]
Lo MT, Kauppi K, Fan CC, Sanyal N, Reas ET, Sundar VS, et al. Identification of genetic heterogeneity of Alzheimer’s disease across age. Neurobiol Aging.2019;84:243.e1–9. [DOI] [PubMed] [PMC]
Hong G, Zeng P, Li N, Cai H, Guo Y, Li X, et al. A qualitative analysis based on relative expression orderings identifies transcriptional subgroups for Alzheimer’s disease. Curr Alzheimer Res.2019;16:1175–82. [DOI] [PubMed]
Scheltens NM, Tijms BM, Koene T, Barkhof F, Teunissen CE, Wolfsgruber S, et al.; Alzheimer’s Disease Neuroimaging Initiative; German Dementia Competence Network; University of California San Francisco Memory and Aging Center; Amsterdam Dementia Cohort. Cognitive subtypes of probable Alzheimer’s disease robustly identified in four cohorts. Alzheimers Dement.2017;13:1226–36. [DOI] [PubMed] [PMC]
Scheltens NM, Galindo-Garre F, Pijnenburg YA, van der Vlies AE, Smits LL, Koene T, et al. The identification of cognitive subtypes in Alzheimer’s disease dementia using latent class analysis. J Neurol Neurosurg Psychiatry.2016;87:235–43. [DOI] [PubMed]
Crane PK, Trittschuh E, Mukherjee S, Saykin AJ, Sanders RE, Larson EB, et al.; Executive Prominent Alzheimer’s Disease: Genetics and Risk Factors (EPAD:GRF) Investigators. Incidence of cognitively defined late-onset Alzheimer’s dementia subgroups from a prospective cohort study. Alzheimers Dement.2017;13:1307–16. [DOI] [PubMed] [PMC]
Chasioti D, Yan J, Nho K, Saykin AJ.Progress in polygenic composite scores in Alzheimer’s and other complex diseases. Trends Genet.2019;35:371–82. [DOI] [PubMed] [PMC]
Gong CX, Liu F, Iqbal K.Multifactorial hypothesis and multi-targets for Alzheimer’s disease. J Alzheimers Dis2018;64:S107–17. [DOI] [PubMed]
Tsay M, Geraci J, Agrawal A.Next-gen AI for disease definition, patient stratification, and placebo effect. Version: 1. OSF Preprints [Preprint]. [posted 2020 Apr 6; revised 2020 Jul 22; cited 2020 Jun 18]: [9 p.]. Available from: https://osf.io/pc7ak
Silva GA.The effect of signaling latencies and node refractory states on the dynamics of networks. Neural Comput.2019;31:2492–522. [DOI] [PubMed]
Rokach L.Pattern classification using ensemble methods. Singapore: World Scientific; 2019.
Diaz-Papkovich A, Anderson-Trocmé L, Ben-Eghan C, Gravel S.UMAP reveals cryptic population structure and phenotype heterogeneity in large genomic cohorts. PLoS Genet.2019;15:e1008432. [DOI] [PubMed] [PMC]
Scheff SW.Nonparametric statistics. Fundamental statistical principles for the neurobiologist. Cambridge: Academic Press; 2016. p. 157–82.
Warde-Farley D, Donaldson SL, Comes O, Zuberi K, Badrawi R, Chao P, et al. The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res.2010;38:W214–20. [DOI] [PubMed] [PMC]
Burley K, Westbury SK, Mumford AD.TUBB1 variants and human platelet traits. Platelets.2018;29:209–11. [DOI] [PubMed]
de la Torre JC.Vascular basis of Alzheimer’s pathogenesis. Ann N Y Acad Sci.2002;977:196–215. [DOI] [PubMed]
de la Torre JC.Is Alzheimer’s disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics. Lancet Neurol.2004;3:184–90. [DOI] [PubMed]
Kim JA, Jayabalan AK, Kothandan VK, Mariappan R, Kee Y, Ohn T.Identification of Neuregulin-2 as a novel stress granule component. BMB Rep.2016;49:449–54. [DOI] [PubMed] [PMC]
Ledonne A, Mercuri NB.On the modulatory roles of Neuregulins/ErbB signaling on synaptic plasticity. Int J Mol Sci.2019;21:275. [DOI]
Islam T, Rahman R, Shahjaman, Zaman ST, Karim R, Quinn JMW, et al. Blood-based molecular biomarker signatures in Alzheimer’s disease: insights from systems biomedicine perspective. BioRxiv 481879 [Preprint]. 2018 [cited 2020 Oct 3]. Available from: https://www.biorxiv.org/content/10.1101/481879v4
Freude S, Hettich MM, Schumann C, Stöhr O, Koch L, Köhler C, et al. Neuronal IGF-1 resistance reduces Aβ accumulation and protects against premature death in a model of Alzheimer’s disease. FASEB J.2009;23:3315–24. [DOI] [PubMed]
Wu M, Fang K, Wang W, Lin W, Guo L, Wang J.Identification of key genes and pathways for Alzheimer’S disease via combined analysis of genome-wide expression profiling in the hippocampus. Biophys Rep.2019;5:98–109. [DOI]
Tipton AR, Wren JD, Daum JR, Siefert JC, Gorbsky GJ.GTSE1 regulates spindle microtubule dynamics to control Aurora B kinase and Kif4A chromokinesin on chromosome arms. J Cell Biol.2017;216:3117–32. [DOI] [PubMed] [PMC]
Puthiyedth N, Riveros C, Berretta R, Moscato P.Identification of differentially expressed genes through integrated study of Alzheimer’s disease affected brain regions. PLoS One.2016;11:e0152342. [DOI] [PubMed] [PMC]
Kessler T, Wobst J, Wolf B, Eckhold J, Vilne B, Hollstein R, et al. Functional characterization of the GUCY1A3 coronary artery disease risk locus. Circulation.2017;136:476–89. [DOI] [PubMed] [PMC]
Zhang X, Tan F, Brovkovych V, Zhang Y, Lowry JL, Skidgel RA.Carboxypeptidase M augments kinin B1 receptor signaling by conformational crosstalk and enhances endothelial nitric oxide output. Biol Chem.2013;394:335–45. [DOI] [PubMed] [PMC]
Lunnon K, Keohane A, Pidsley R, Newhouse S, Riddoch-Contreras J, Thubron EB, et al. Mitochondrial genes are altered in blood early in Alzheimer’s disease. Neurobiol Aging.2017;53:36–47. [DOI] [PubMed]
Arber CE, Li A, Houlden H, Wray S.Review: Insights into molecular mechanisms of disease in neurodegeneration with brain iron accumulation: unifying theories. Neuropathol Appl Neurobiol.2016;42:220–41. [DOI] [PubMed] [PMC]
Dagan H, Flashner-Abramson E, Vasudevan S, Jubran MR, Cohen E, Kravchenko-Balasha N.Exploring Alzheimer’s disease molecular variability via calculation of personalized transcriptional signatures. Biomolecules.2020;10:503. [DOI]
Huang X, Liu H, Li X, Guan L, Li J, Tellier LCAM, et al. Revealing Alzheimer’s disease genes spectrum in the whole-genome by machine learning. BMC Neurol.2018;18:5. [DOI] [PubMed] [PMC]
Kim JH, Franck J, Kang T, Heinsen H, Ravid R, Ferrer I, et al. Proteome-wide characterization of signalling interactions in the hippocampal CA4/DG subfield of patients with Alzheimer’s disease. Sci Rep.2015;5:11138. [DOI] [PubMed] [PMC]
Morello G, Cavallaro S.Transcriptional analysis reveals distinct subtypes in amyotrophic lateral sclerosis: implications for personalized therapy. Future Med Chem.2015;7:1335–59. [DOI] [PubMed]
Upadhyay A, Joshi V, Amanullah A, Mishra R, Arora N, Prasad A, et al. E3 ubiquitin ligases neurobiological mechanisms: development to degeneration. Front Mol Neurosci.2017;10:151. [DOI] [PubMed] [PMC]
Li JY, Chai B, Zhang W, Wu X, Zhang C, Fritze D, et al. Ankyrin repeat and SOCS box containing protein 4 (Asb-4) colocalizes with insulin receptor substrate 4 (IRS4) in the hypothalamic neurons and mediates IRS4 degradation. BMC Neurosci.2011;12:95. [DOI] [PubMed] [PMC]
Li JY, Kuick R, Thompson RC, Misek DE, Lai YM, Liu YQ, et al. Arcuate nucleus transcriptome profiling identifies ankyrin repeat and suppressor of cytokine signalling box-containing protein 4 as a gene regulated by fasting in central nervous system feeding circuits. J Neuroendocrinol.2005;17:394–404. [DOI] [PubMed]
Anasa VV, Ravanan P, Talwar P.Multifaceted roles of ASB proteins and its pathological significance. Front Biol.2018;13:376–88. [DOI]
Westwood AJ, Beiser A, DeCarli C, Harris TB, Chen TC, He XM, et al. Insulin-like growth factor-1 and risk of Alzheimer dementia and brain atrophy. Neurology.2014;82:1613–9. [DOI] [PubMed] [PMC]
Wu Y, Li Z, Huang YY, Wu D, Luo HB.Novel phosphodiesterase inhibitors for cognitive improvement in Alzheimer’s disease: miniperspective. J Med Chem.2018;61:5467–83. [DOI] [PubMed]
Zhou LY, Zhu Y, Jiang YR, Zhao XJ, Guo D.Design, synthesis and biological evaluation of dual acetylcholinesterase and phosphodiesterase 5A inhibitors in treatment for Alzheimer’s disease. Bioorg Med Chem Lett.2017;27:4180–4. [DOI] [PubMed]
García-Osta A, Cuadrado-Tejedor M, García-Barroso C, Oyarzabal J, Franco R.Phosphodiesterases as therapeutic targets for Alzheimer’s disease. ACS Chem Neurosci.2012;3:832–44. [DOI] [PubMed] [PMC]
Sanders O.Sildenafil for the treatment of Alzheimer’s disease: a systematic review. J Alzheimers Dis Rep.2020;4:91–106. [DOI] [PubMed] [PMC]
Liu L, Xu H, Ding S, Wang D, Song G, Huang X.Phosphodiesterase 5 inhibitors as novel agents for the treatment of Alzheimer’s disease. Brain Res Bull.2019;153:223–31. [DOI] [PubMed]
Hu X, Fan Q, Hou H, Yan R.Neurological dysfunctions associated with altered BACE 1-dependent Neuregulin-1 signaling. J Neurochem.2016;136:234–49. [DOI] [PubMed] [PMC]
Czarnek M, Bereta J.Proteolytic processing of Neuregulin 2. Mol Neurobiol.2019;57:1799–813. [DOI] [PubMed] [PMC]
Cespedes JC, Liu M, Harbuzariu A, Nti A, Onyekaba J, Cespedes HW, et al. Neuregulin in health and disease. Int J Brain Disord Treat.2018;4:024. [DOI] [PubMed] [PMC]
Wang KS, Xu N, Wang L, Aragon L, Ciubuc R, Arana TB, et al. NRG3 gene is associated with the risk and age at onset of Alzheimer disease. J Neural Transm (Vienna).2014;121:183–92. [DOI] [PubMed]
Naj AC, Schellenberg GD; Alzheimer’s Disease Genetics Consortium (ADGC). Genomic variants, genes, and pathways of Alzheimer’s disease: an overview. Am J Med Genet B Neuropsychiatr Genet.2017;174:5–26. [DOI] [PubMed] [PMC]
Escott-Price V, Bellenguez C, Wang LS, Choi SH, Harold D, Jones L, et al.; Cardiovascular Health Study (CHS). Gene-wide analysis detects two new susceptibility genes for Alzheimer’s disease. 2014;9:e94661. [DOI]
Warnatz HJ, Schmidt D, Manke T, Piccini I, Sultan M, Borodina T, et al. The BTB and CNC homology 1 (BACH1) target genes are involved in the oxidative stress response and in control of the cell cycle. J Biol Chem.2011;286:23521–32. [DOI] [PubMed] [PMC]
Moll L, Schubert M.The role of insulin and insulin-like growth factor-1/FoxO-mediated transcription for the pathogenesis of obesity-associated dementia. Curr Gerontol Geriatr Res.2012;2012:384094. [DOI] [PubMed] [PMC]
Ostrowski PP, Barszczyk A, Forstenpointner J, Zheng W, Feng ZP.Meta-analysis of serum insulin-like growth factor 1 in Alzheimer’s disease. PLoS One.2016;11:e0155733. [DOI] [PubMed] [PMC]
Gubbi S, Quipildor GF, Barzilai N, Huffman DM, Milman S.40 years of IGF1: IGF1: the Jekyll and Hyde of the aging brain. J Mol Endocrinol.2018;61:T171–85. [DOI] [PubMed] [PMC]
Freude S, Schilbach K, Schubert M.The role of IGF-1 receptor and insulin receptor signaling for the pathogenesis of Alzheimer’s disease: from model organisms to human disease. Curr Alzheimer Res.2009;6:213–23. [DOI] [PubMed]
George C, Gontier G, Lacube P, François JC, Holzenberger M, Aïd S.The Alzheimer’s disease transcriptome mimics the neuroprotective signature of IGF-1 receptor-deficient neurons. Brain.2017;140:2012–27. [DOI] [PubMed]
Galle SA, van der Spek A, Drent ML, Brugts MP, Scherder EJA, Janssen JAMJL, et al. Revisiting the role of insulin-like growth factor-I receptor stimulating activity and the apolipoprotein E in Alzheimer’s disease. Front Aging Neurosci.2019;11:20. [DOI] [PubMed] [PMC]
Jackson HM, Soto I, Graham LC, Carter GW, Howell GR.Clustering of transcriptional profiles identifies changes to insulin signaling as an early event in a mouse model of Alzheimer’s disease. BMC Genomics.2013;14:831. [DOI] [PubMed] [PMC]
Cesarini V, Martini M, Vitiani LR, Gravina GL, Di Agostino S, Graziani G, et al. Type 5 phosphodiesterase regulates glioblastoma multiforme aggressiveness and clinical outcome. Oncotarget.2017;8:13223–39. [DOI] [PubMed] [PMC]
Manso-Calderón R.Genetics in vascular dementia. Future Neurol.2019;14:FNL5. [DOI]
Wallace S, Guo DC, Regalado E, Mellor-Crummey L, Bamshad M, Nickerson DA, et al. Disrupted nitric oxide signaling due to GUCY1A3 mutations increases risk for moyamoya disease, achalasia and hypertension. Clin Genet.2016;90:351–60. [DOI] [PubMed] [PMC]
Palmieri O, Mazza T, Merla A, Fusilli C, Cuttitta A, Martino G, et al. Gene expression of muscular and neuronal pathways is cooperatively dysregulated in patients with idiopathic achalasia. Sci Rep.2016;6:31549. [DOI] [PubMed] [PMC]
Anderson KL, Ferreira A.α1 integrin activation: a link between β-amyloid deposition and neuronal death in aging hippocampal neurons. J Neurosci Res. 2004;75:688–97. [DOI] [PubMed]
Li H, Zeng J, Huang L, Wu D, Liu L, Liu Y, et al. Microarray analysis of gene expression changes in neuroplastin 65-Knockout mice: implications for abnormal cognition and emotional disorders. Neurosci Bull.2018;34:779–88. [DOI] [PubMed] [PMC]
Kalman J, Kitajka K, Pákáski M, Zvara A, Juhász A, Vincze G, et al. Gene expression profile analysis of lymphocytes from Alzheimer’s patients. Psychiatr Genet.2005;15:1–6. [DOI] [PubMed]
Tang X, Li Z, Zhang W, Yao Z.Nitric oxide might be an inducing factor in cognitive impairment in Alzheimer’s disease via downregulating the monocarboxylate transporter 1. Nitric Oxide.2019;91:35–41. [DOI] [PubMed]
Balez R, Ooi L.Getting to NO Alzheimer’s disease: neuroprotection versus neurotoxicity mediated by nitric oxide. Oxid Med Cell Longev.2016;2016:3806157. [DOI] [PubMed] [PMC]
Sarkar S, Korolchuk VI, Renna M, Imarisio S, Fleming A, Williams A, et al. Complex inhibitory effects of nitric oxide on autophagy. Mol Cell.2011;43:19–32. [DOI] [PubMed] [PMC]
Morris G, Berk M, Maes M, Puri BK.Could Alzheimer’s disease originate in the periphery and if so how so?Mol Neurobiol. 2019;56:406–34. [DOI] [PubMed] [PMC]
Uddin MS, Stachowiak A, Mamun AA, Tzvetkov NT, Takeda S, Atanasov AG, et al. Autophagy and Alzheimer’s disease: from molecular mechanisms to therapeutic implications. Front Aging Neurosci.2018;10:04. [DOI] [PubMed] [PMC]
Cheng Y, Cawley NX, Yanik T, Murthy SR, Liu C, Kasikci F, et al. A human carboxypeptidase E/NF-α1 gene mutation in an Alzheimer’s disease patient leads to dementia and depression in mice. Transl Psychiatry.2016;6:e973. [DOI] [PubMed] [PMC]
Puzzo D, Loreto C, Giunta S, Musumeci G, Frasca G, Podda MV, et al. Effect of phosphodiesterase-5 inhibition on apoptosis and beta amyloid load in aged mice. Neurobiol Aging.2014;35:520–31. [DOI] [PubMed]
Kelleher RJ 3rd, Shen J.Presenilin-1 mutations and Alzheimer’s disease. Proc Natl Acad Sci U S A.2017;114:629–31. [DOI] [PubMed] [PMC]
Paris D, Ait-Ghezala G, Bachmeier C, Laco G, Beaulieu-Abdelahad D, Lin Y, et al. The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation. J Biol Chem.2014;289:33927–44. [DOI] [PubMed] [PMC]
Schweig JE, Yao H, Beaulieu-Abdelahad D, Ait-Ghezala G, Mouzon B, Crawford F, et al. Alzheimer’s disease pathological lesions activate the spleen tyrosine kinase. Acta Neuropathol Commun.2017;5:69. [DOI] [PubMed] [PMC]
Lemire BD.Evolution, structure and membrane association of NDUFAF6, an assembly factor for NADH: ubiquinone oxidoreductase (Complex I). Mitochondrion.2017;35:13–22. [DOI] [PubMed]
Bagwe-Parab S, Kaur G.Molecular targets and therapeutic interventions for Iron induced neurodegeneration. Brain Res Bull.2019;156:1–9. [DOI] [PubMed]
Kong W, Mou X, Liu Q, Chen Z, Vanderburg CR, Rogers JT, et al. Independent component analysis of Alzheimer’s DNA microarray gene expression data. Mol Neurodegener.2009;4:5. [DOI] [PubMed] [PMC]
Kong W, Mou X, Hu X.Exploring matrix factorization techniques for significant genes identification of Alzheimer’s disease microarray gene expression data. BMC Bioinformatics.2011;12Suppl 5:S7. [DOI]
Peng Y, Shapiro SL, Banduseela VC, Dieterich IA, Hewitt KJ, Bresnick EH, et al. Increased transport of acetyl-CoA into the endoplasmic reticulum causes a progeria-like phenotype. Aging cell.2018;17:e12820. [DOI] [PubMed] [PMC]
Peng Y, Shapiro S, Hewitt K, Kong G, Bresnick E, Zhang J, et al. Systemic overexpression of AT-1/SLC33A1 causes a progeria-like phenotype. Innov Aging.2017;1:426–7. [DOI]
Huppke P, Brendel C, Kalscheuer V, Korenke GC, Marquardt I, Freisinger P, et al. Mutations in SLC33A1 cause a lethal autosomal-recessive disorder with congenital cataracts, hearing loss, and low serum copper and ceruloplasmin. The Am J Hum Genet.2012;90:61–8. [DOI] [PubMed] [PMC]
Wang L, Yin YL, Liu XZ, Shen P, Zheng YG, Lan XR, et al. Current understanding of metal ions in the pathogenesis of Alzheimer’s disease. Transl Neurodegener.2020;9:10. [DOI] [PubMed] [PMC]
Sun LL, Yang SL, Sun H, Li WD, Duan SR.Molecular differences in Alzheimer’s disease between male and female patients determined by integrative network analysis. J Cell Mol Med.2019;23:47–58. [DOI] [PubMed] [PMC]
Podcasy JL, Epperson CN.Considering sex and gender in Alzheimer disease and other dementias. Dialogues Clin Neurosci.2016;18:437–46. [DOI] [PubMed] [PMC]
Sinforiani E, Citterio A, Zucchella C, Bono G, Corbetta S, Merlo P, et al. Impact of gender differences on the outcome of Alzheimer’s disease. Dement Geriatr Cogn Disord.2010;30:147–54. [DOI] [PubMed]
Devi G, Scheltens P.Heterogeneity of Alzheimer’s disease: consequence for drug trials?Alzheimers Res Ther. 201810:122. [DOI] [PubMed] [PMC]
Au R, Piers RJ, Lancashire L.Back to the future: Alzheimer’s disease heterogeneity revisited. Alzheimers Dement (Amst).2015;1:368–70. [DOI] [PubMed] [PMC]
