THE COMPLEXITY OF ALZHEIEMER’S DISEASE - NEW FRONTIERS
Keywords:
subjective cognitive decline, mild cognitive imapirment, diagnostic criteria, genetics, fluid biomarkers, immunotherapy
Abstract
Alzheimer's disease (AD) represents one of the most significant challenges in the field of neurodegenerative diseases of our time, with its increasing prevalence and lack of curative treatments, which highlights the urgent need for innovative therapeutic strategies.
AD is a progressive disorder characterized by cognitive decline, impaired daily functioning and loss of independence. AD pathology is characterized by the accumulation of amyloid beta plaques and neurofibrillary tau protein tangles in the brain, accompanied by neuroinflammation and synaptic dysfunction. Genetic factors, such as mutations in the genes for APP, PSEN1 and PSEN2, directly cause familial forms, while the APOE e4 allele only contributes to an increased risk for the development of AD.
Advances in the identification and validation of reliable biomarkers from cerebrospinal fluid (CSF) and blood hold great promise for improving early diagnosis, monitoring disease progression, and assessing response to treatment not only in research but also in clinical practice in an effort to alleviate the burden of this devastating disease. Blood biomarkers in particular promise to significantly improve diagnostic accuracy and effectively simplify referral processes, and early diagnosis as well as timely access to treatment. Ongoing efforts shaping the integration of blood biomarkers in various clinical settings are paving the way toward precision medicine in AB. Research efforts are focused on the development of disease-modifying therapies that target the underlying pathological mechanisms of AD.
The current transformative period of knowledge about AD represents an important moment and promises significant changes in clinical conditions in the light of innovative immunotherapy that changes the course of the disease. Given the potential barriers that may impede access to AD therapy, and the need to expand treatment options beyond specialized centers, blood and CSF biomarkers provide an attractive option for screening and early detection of AD and monitoring treatment efficacy. This approach could be a testable scenario for how future clinical implementation could be designed, and how treatments proven to be successful in treating AD could be applied in daily clinical practice with widespread use of biomarkers.
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7.Nelson PT, Schneider JA, Jicha GA, Duong MT, Wolk DA. When Alzheimer’s is LATE: Why does it matter? Annals of Neurology. 2023; doi:10.1002/ana.26711
8. Nebel RA, Aggarwal NT, Barnes LL, Gallagher A, Goldstein JM, Kantarci K, et al. Understanding the impact of sex and gender in Alzheimer’s disease: A call to action. Alzheimer’s & Dementia. 2018;14(9):1171–83. doi:10.1016/j.jalz.2018.04.008
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10. Harada, CN, Natelson Love, MC, & Triebel, K. L. Normal cognitive aging. Clinics in geriatric medicine 2013; 29:737–752.
11. Nestor PJ, Scheltens P, Hodges JR. Advances in the early detection of Alzheimer’s disease. Nat Rev Neurosci. 2004; 5:S34-41.
12. Jessen F, Amariglio RE, Van Boxtel M, et al. A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer’s disease. Alzheimers Dement 2014; 10: 844–52.
13. Slot, R. E. R., Sikkes, S. A. M., Berkhof, J., Brodaty, H., Buckley, R., Cavedo, E et al. Subjective cognitive decline and rates of incident Alzheimer’s disease and non-Alzheimer’s disease dementia. Alzheimers Dement 2019; 15: 456–76.
14. Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med 2004; 256: 183–94.
15.Mitchell A, Beaumont H, Ferguson D, Yadegarfar M, Stubbs B. Risk of dementia and mild cognitive impairment in older people with subjective memory complaints: meta-analysis. Acta Psychiatr Scand 2014; 130: 439–51.
16. Jessen, F., Amariglio, R. E., Buckley, R. F., van der Flier, W. M., Han, Y., Molinuevo, J. et al. The characterisation of subjective cognitive decline. The Lancet Neurology, 2020; 19 : 271–278.
17. Petersen, R. C., Lopez, O., Armstrong, M. J., Getchius, T. S. D., Ganguli, M., Gloss, D.,et al. Practice guideline update summary: mild cognitive impairment: report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology. Neurology. 2018;90:126-135.
18. Dubois, B., Feldman, H. H., Jacova, C., Hampel, H., Molinuevo, J. L., Blennow, K., et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol 2014; 13: 614–29.
19. Dubois, B., Hampel, H., Feldman, H. H., Scheltens, P., Aisen, P., Andrieu, S., et al. Preclinical Alzheimer’s disease: definition, natural history, and diagnostic criteria. Alzheimers Dement 2016; 12: 292–323.
20. Crutch SJ, Lehmann M, Schott JM, Rabinovici GD, Rossor MN, Fox NC. Posterior cortical atrophy. Lancet Neurol 2012; 11: 170–178.
21. Crutch SJ, Schott JM, Rabinovici GD, Murray M, Snowden JS, van der Flier WM; Alzheimer’s Association ISTAART Atypical Alzheimer’s Disease and Associated Syndromes Professional Interest Area, et al. Consensus classification of posterior cortical atrophy. AlzheimersDement 13; 870–884, 2017. doi:10.1016/j.jalz.2017.01.014.
22.Villain N, Dubois B. Alzheimer’s disease including focal presentations. Semin Neurol 39: 213–226, 2019. doi:10.1055/s-0039- 1681041.
23. Black SE. Focal cortical atrophy syndromes. Brain Cogn 31; 188– 229, 1996. doi:10.1006/brcg.1996.0042.
24. Gorno-Tempini, M. L., Hillis, A. E., Weintraub, S., Kertesz, A., Mendez, M., Cappa, S. F., et al. Classification of primary progressive aphasia and its variants. Neurology 2011; 76: 1006–1014.
25. Ryan NS, Rossor MN. Correlating familial Alzheimer’s disease gene mutations with clinical phenotype. Biomark Med 2010; 4: 99–112.
26. Storandt M, Head D, Fagan AM, Holtzman DM, Morris JC. Toward a multifactorial model of Alzheimer disease. Neurobiol Aging 2012;33: 2262–2271,. doi:10.1016/j.neurobiolaging.2011.11.029.
27.Villain N, Dubois B. Alzheimer’s disease including focal presentations. Semin Neurol, 2019; 39: 213–226, doi:10.1055/s-0039- 1681041.
28. Vogel J. W., Young A. L., Oxtoby N. P., Smith R., Ossenkoppele R., Strandberg O. T., et al. Four distinct trajectories of tau deposition identified in Alzheimer’s disease. Nat. Med. 2021; 27, 871–881. doi: 10.1038/s41591-021-01309-6.
29. Knopman DS, Petersen RC, Jack CR Jr. A brief history of "Alzheimer disease": Multiple meanings separated by a common name. Neurology. 2019 May 28;92(22):1053-1059. doi: 10.1212/WNL.0000000000007583.
30. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al., Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):280-92. doi: 10.1016/j.jalz.2011.03.003.
31. Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al., Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol. 2004 Mar;55(3):306-19. doi: 10.1002/ana.20009.
32.Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al.. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018 Apr;14(4):535-562. doi: 10.1016/j.jalz.2018.02.018.
33. Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Feldman HH, Frisoni GB, Hampel H, Jagust WJ, Johnson KA, Knopman DS, Petersen RC, Scheltens P, Sperling RA, Dubois B. A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology. 2016 Aug 2;87(5):539-47. doi: 10.1212/WNL.0000000000002923.
34. Jack, CR, Jr, Andrews, SJ, Beach, TG, Buracchio, T, Dunn, B, Graf, A, et al. Revised criteria for the diagnosis and staging of Alzheimer's disease. Nature medicine, 2024; 30(8), 2121–2124.
35. Neuner SM, Tcw J, Goate AM. Genetic architecture of Alzheimer's disease. Neurobiol Dis. 2020 Sep;143:104976. doi: 10.1016/j.nbd.2020.104976.
36. Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Mortimer JA, Berg S, et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry. 2006 Feb;63(2):168-74. doi: 10.1001/archpsyc.63.2.168.
37. Chartier-Harlin MC, Crawford F, Houlden H, Warren A, Hughes D, Fidani L, Goate A, Rossor M, Roques P, Hardy J. Early-onset Alzheimer’s disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature, 1991; 353: 844–846. doi:10.1038/353844a0.
38.Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, et al. Cloning of a gene bearing missense mutations in early onset familial Alzheimer’s disease. Nature 375: 754–760, 1995. doi:10.1038/375754a0.
39. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K. Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science,1995; 269: 973–977. doi:10.1126/science.7638622.
39. Alzheimer's Association. Alzheimer’s disease facts and figures. Alzheimers Dement., 2020; 16:391–460. doi: 10.1002/ALZ.12068
40. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, 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. doi: 10.1126/science.8346443.
41. Andrews SJ, Renton AE, Fulton-Howard B, Podlesny-Drabiniok A, Marcora E, Goate AM. The complex genetic architecture of Alzheimer's disease: novel insights and future directions. EBioMedicine. 2023 Apr;90:104511. doi: 10.1016/j.ebiom.2023.104511.
42.Zetterberg H, Blennow K. Moving fluid biomarkers for Alzheimer's disease from research tools to routine clinical diagnostics. Mol Neurodegener. 2021 Feb 19;16(1):10. doi: 10.1186/s13024-021-00430-x. PMID: 33608044; PMCID: PMC7893769.
43.Dubois B, von Arnim CAF, Burnie N, Bozeat S, Cummings J. Biomarkers in Alzheimer's disease: role in early and differential diagnosis and recognition of atypical variants. Alzheimers Res Ther. 2023 Oct 13;15(1):175. doi: 10.1186/s13195-023-01314-6. PMID: 37833762.
44. Hunter TR, Santos LE, Tovar-Moll F, De Felice FG. Alzheimer's disease biomarkers and their current use in clinical research and practice. Mol Psychiatry. 2024 Sep 4. doi: 10.1038/s41380-024-02709.
45. Olsson B, Lautner R, Andreasson U, Öhrfelt A, Portelius E, Bjerke M, et al.. CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis. Lancet Neurol. 2016 Jun;15(7):673-684. doi: 10.1016/S1474-4422(16)00070-3.
44. Leitao MJ, Silva-Spinola A, Santana I, Olmedo V, Nadal A, Le Bastard N, et al. Clinical validation of the Lumipulse G cerebrospinal fluid assays for routine diagnosis of Alzheimer's disease. Alzheimers Res Ther. 2019;11:91.
45. Janelidze S, Barthélemy NR, Salvadó G, Schindler SE, Palmqvist S, Mattsson-Carlgren N, et al. Plasma Phosphorylated Tau 217 and Aβ42/40 to Predict Early Brain Aβ Accumulation in People Without Cognitive Impairment. JAMA Neurol. 2024 Sep 1;81(9):947-957. doi: 10.1001/jamaneurol.2024.2619.
46.Palmqvist S, Janelidze S, Stomrud E, Zetterberg H, Karl J, Zink K, et al. Performance of Fully Automated Plasma Assays as Screening Tests for Alzheimer Disease-Related beta-Amyloid Status. JAMA Neurol. 2019 Sep 1;76(9):1060-1069.
47.Palmqvist S, Janelidze S, Quiroz YT, Zetterberg H, Lopera F, Stomrud E et al. Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders. JAMA. 2020 Aug 25;324(8):772-781. doi: 10.1001/jama.2020.12134.
48. Guo Y, You J, Zhang Y, Liu WS, Huang YY, Zhang YR, et al. Plasma proteomic profiles predict future dementia in healthy adults. Nature aging, 2024; 4(2), 247–260.
49. Brookmeyer R, Abdalla N. Estimation of lifetime risks of Alzheimer's disease dementia using biomarkers for preclinical disease. Alzheimers Dement. 2018;14:981–8.
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