Bhaskar M¹, Patne A²* and Addepalli V³

¹Postdoctoral research fellow, National Institute of Neurodegenerative Diseases and Stroke, USA
²Masters in Pharmaceutical Nanotechnology student, Taneja College of Pharmacy, University of South Florida, Tampa, FL, USA
³Director, Research and Professor (Pharmacology), Dr. DY Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune, Maharashtra, India

*Corresponding Author: Patne A, Masters in Pharmaceutical Nanotechnology student, Taneja College of Pharmacy, University of South Florida, Tampa, FL, USA.

Received: June 12, 2024; Published: June 25, 2024

Abstract

Neurodegenerative diseases are characterized by progressive neuronal loss and protein level changes in the brain, with gene defects playing a major role in their pathogenesis. Gene defects play a major role in the pathogenesis of degenerative disorders of the nervous system. In fact, it has been the very knowledge gained from genetic studies that has allowed the elucidation of the molecular mechanisms underlying the etiology and pathogenesis of many neurodegenerative disorders. To identify and rectify the deflects of neurodegenerative disease, advance technology such as gene mapping can be harnessed. Gene mapping is a method which is used to identify the locus of the gene and the distances between the genes. This technology serves as a map for researchers trying to discover the common genetic variation associated with complex disease as well as variations responsible for differences in drug and therapeutic response. With advancements in gene mapping techniques, researchers are gaining deeper insights into the genetic underpinnings of neurodegenerative diseases. In this review, we specifically focus on the status of genetic epidemiology in Alzheimer's disease, the most common form of neurodegeneration.

Keywords: Alzheimer's Disease (AD); Gene Mapping; Neurodegenerative Disorders; Genetic Epidemiology; β-amyloid Precursor Protein (APP); Presenilin (PSEN); Genome-Wide Association Studies (GWAS); Next-generation Sequencing; Genetic Variation; Therapeutic Targets

References

1. Lars Bertram and Rudolph E Tanzi. “The genetic epidemiology of neurodegenerative disease”. Journal of Clinical Investigation 115 (2005): 1449-1457.
2. Jonischkies K., et al. “The NDR family of kinases: essential regulators of aging”.
3. Arendt T. “Synaptic plasticity and cell cycle activation in neurons are alternative effector pathways: the ‘Dr. Jekyll and Mr. Hyde concept’ of Alzheimer’s disease or the yin and yang of neuroplasticity”. Progress in Neurobiology 71 (2003): 83-248.
4. Ray M., et al. “Variations in the transcriptome of Alzheimer’s disease reveal molecular networks involved in cardiovascular diseases”. Genome Biology 9: R148 (2008).
5. Labrecque M., et al. “Estimated prevalence of Niemann-Pick type C disease in Quebec”. Scientific reports1 (2021): 22621.
6. Goldstein DB., et al. “Sequencing studies in human genetics: design and interpretation”. Nature reviews Genetics 14 (2013): 460-470.
7. AM Bertoli Avella., et al. “Chasing genes in Alzheimer’s disease and Parkinson’s disease”. Human Genetics5 (2004): 413-438.
8. St George-Hyslop PH., et al. “The genetic defect causing familial Alzheimer’s disease maps on chromosome 21”. Science 235 (1987): 885-890.
9. Chartier-Harlin MC., et al. “Early-onset Alzheimer’s disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene”. Nature 353 (1991): 844-846.
10. Goate A., et al. “Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease”. Nature 349 (1991): 704-706.
11. Citron M., et al. “Mutation of the beta-amyloid precursor protein in familial Alzheimer’s disease increases beta-protein production”. Nature 360 (1992): 672-674.
12. Suzuki N., et al. “An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants”. Science 264 (1994): 1336-1340.
13. Schellenberg GD., et al. “Genetic linkage evidence for a familial Alzheimer’s disease locus on chromosome 14”. Science 258 (1992): 668-671.
14. St George-Hyslop P., et al. “Genetic evidence for a novel familial Alzheimer’s disease locus on chromosome 14”. Nature Genetics 2 (1992): 330-334.
15. Van Broeckhoven C., et al. “Mapping of a gene predisposing to earlyonset Alzheimer’s disease to chromosome 14q24.3”. Nature Genetics 2 (1992): 335-339.
16. Tanzi RE., et al. “Assessment of amyloid beta-protein precursor gene mutations in a large set of familial and sporadic Alzheimer disease cases”. American Journal of Human Genetics 51 (1992): 273-282.
17. Sherrington R., et al. “Cloning of a gene bearing missense mutations in earlyonset familial Alzheimer’s disease”. Nature 375 (1995): 754-760.
18. Ezquerra M., et al. “A novel presenilin 1 mutation (Leu166Arg) associated with early-onset Alzheimer disease”. Archives of Neurology 57 (2000): 485-488.
19. Janssen JC., et al. “Alzheimer’s disease due to an intronic presenilin-1 (PSEN1 intron 4) mutation: A clinicopathological study”. Brain 123 (2000): 894-907.
20. Takao M., et al. “Ectopic white matter neurons, a developmental abnormality that may be caused by the PSEN1 S169L mutation in a case of familial AD with myoclonus and seizures”. Journal of Neuropathology and Experimental Neurology 60 (2001): 1137-1152.
21. Bertoli Avella AM., et al. “A novel presenilin 1 mutation (L174 M) in a large Cuban family with early onset Alzheimer disease”. Neurogenetics 4 (2002): 97104.
22. Dermaut B., et al. “Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer’s disease due to a novel presenilin 1 mutation”. Brain 124 (2001): 2383-2392.
23. Levy-Lahad E., et al. “Candidate gene for the chromosome 1 familial Alzheimer’s disease locus”. Science 269 (1995): 973-977.
24. Rogaev EI., et al. “Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene”. Nature 376 (1995): 775-778.
25. Binetti G., et al. “Atypical dementia associated with a novel presenilin-2 mutation”. Annals of Neurology 54 (2003): 832-836.
26. Finckh U., et al. “Variable expression of familial Alzheimer disease associated with presenilin 2 mutation M239I”. Neurology 54 (2000): 2006-2008.
27. Tedde A., et al. “Identification of new presenilin gene mutations in earlyonset familial Alzheimer disease”. Archives of Neurology 60 (2003): 1541-1544.
28. Citron M., et al. “Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice”. Nature Medicine 3 (1997): 67-72.
29. De Strooper B., et al. “Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein”. Nature 391 (1998): 387-390.
30. Chapman PF., et al. “Genes, models and Alzheimer’s disease”. Trends in Genetics 17 (2001): 254-261.
31. Richards JG., et al. “PS2APP transgenic mice, co-expressing hPS2mut and hAPPswe, show age-related cognitive deficits associated with discrete brain amyloid deposition and inflammation”. Journal of Neuroscience 23 (2003): 8989-9003.
32. Borchelt DR., et al. “Familial Alzheimer’s disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo”. Neuron 17 (1996): 1005-1013.
33. Tomita T., et al. “The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid beta protein ending at the 42nd (or 43rd) residue”. Proceedings of the National Academy of Sciences of the United States of America 94 (1997): 2025-2030.
34. Li T., et al. “Nicastrin is required for assembly of presenilin/gamma-secretase complexes to mediate Notch signaling and for processing and trafficking of beta-amyloid precursor protein in mammals”. Journal of Neuroscience 23 (2003): 3272-3277.
35. Kimberly WT., et al. “Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2”. Proceedings of the National Academy of Sciences of the United States of America 100 (2003): 6382-6387.
36. LaVoie MJ., et al. “Assembly of the {gamma}-Secretase Complex Involves Early Formation of an Intermediate Subcomplex of Aph-1 and Nicastrin”. Journal of Biological Chemistry 278 (2003): 37213-37222.
37. Takasugi N., et al. “The role of presenilin cofactors in the gamma-secretase complex”. Nature 422 (2003): 438-441.
38. Warwick Daw E., et al. “The number of trait loci in late-onset Alzheimer disease”. American Journal of Human Genetics 66 (2000): 196-204.
39. Fagan AM., et al. “Human and murine ApoE markedly alters A beta metabolism before and after plaque formation in a mouse model of Alzheimer’s disease”. Neurobiology Disease 9 (2002): 305-318.
40. Holtzman DM., et al. “Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease”. Proceedings of the National Academy of Sciences of the United States of America 97 (2000): 2892-2897.
41. Harris FM., et al. “Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer’s disease-like neurodegeneration and behavioral defi cits in transgenic mice”. Proceedings of the National Academy of Sciences of the United States of America 100 (2003): 10966-10971.
42. Huang Y., et al. “Apolipoprotein E fragments present in Alzheimer’s disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons”. Proceedings of the National Academy of Sciences of the United States of America 98 (2001): 8838-8843.
43. Pericak-Vance MA., et al. “Complete genomic screen in late-onset familial Alzheimer disease. Evidence for a new locus on chromosome 12”. Jama 278 (1997): 1237-1241.
44. Scott WK., et al. “Fine mapping of the chromosome 12 late-onset Alzheimer disease locus: potential genetic and phenotypic heterogeneity”. American Journal of Human Genetics 66 (2000): 922-932.
45. Narita M., et al. “Alpha2-macroglobulin complexes with and mediates the endocytosis of beta-amyloid peptide via cell surface low-density lipoprotein receptor-related protein”. Journal of Neurochemistry 69 (1997): 1904-1911.
46. Kehoe P., et al. “A full genome scan for late onset Alzheimer’s disease”. Human Molecular Genetics 8 (1999): 237-245.
47. Myers A., et al. “Full genome screen for Alzheimer disease: stage II analysis”. American Journal of Medical Genetics 114 (2002): 235-244.
48. Myers A., et al. “Full genome screen for Alzheimer disease: stage II analysis”. American Journal of Medical Genetics 114 (2002): 235-244.
49. Clark CM and Karlawish JH. “Alzheimer disease: current concepts and emerging diagnostic and therapeutic strategies”. Annals of Internal Medicine 138 (2003): 400-410.
50. Zubenko GS., et al. “A genome survey for novel Alzheimer disease risk loci: results at 10-cM resolution”. Genomics 50 (1998): 121-128.
51. Zubenko GS., et al. “D10S1423 identifi es a susceptibility locus for Alzheimer’s disease in a prospective, longitudinal, double-blind study of asymptomatic individuals”. Molecular Psychiatry 6 (2001): 413-419.
52. Hiltunen M., et al. “Genome-wide linkage disequilibrium mapping of late onset Alzheimer’s disease in Finland”. Neurology 57 (2001): 1663-1668.
53. Olson JM., et al. “A second locus for very-late-onset Alzheimer disease: a genome scan reveals linkage to 20p and epistasis between 20p and the amyloid precursor protein region”. American Journal of Human Genetics 71 (2002): 154-161.
54. Olson JM., et al. “The amyloid precursor protein locus and very-late-onset Alzheimer disease”. American Journal of Human Genetics 69 (2001): 895-899.
55. Scott WK., et al. “Ordered-subsets linkage analysis detects novel Alzheimer disease Loci on chromosomes 2q34 and 15q22”. American Journal of Human Genetics 73 (2003): 10411051.
56. Farrer LA., et al. “Identification of multiple loci for Alzheimer disease in a consanguineous Israeli-Arab community”. Human Molecular Genetics 12 (2003): 415-422.
57. Zheng Q and Wang X. “Alzheimer's disease: insights into pathology, molecular mechanisms, and therapy”. Protein & Cell, pwae 026 (2024).
58. De Jager PL., et al. “Alzheimer’s Disease Neuroimaging Initiative. A genome-wide scan for common variants affecting the rate of age-related cognitive decline”. Neurobiology Aging5 (2012): 1017, e1-e15.
59. Eising E., et al. “Genome-wide analyses of individual differences in quantitatively assessed reading-and language-related skills in up to 34,000 people”. Proceedings of the National Academy of Sciences35 (2022): e2202764119.
60. Bis JC., et al. “Enhancing Neuro Imaging Genetics through Meta-Analysis Consortium”. Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (2012).
61. Van der Meer D., et al. “Brain scans from 21,297 individuals reveal the genetic architecture of hippocampal subfield volumes”. Molecular psychiatry11 (2020): 3053-3065.
62. Lee S., et al. “Plasma Leptin and Alzheimer Protein Pathologies Among Older Adults”. JAMA Network Open5 (2024): e249539-e249539.
63. Yang W., et al. “Association of Cognitive Reserve Indicator with Cognitive Decline and Structural Brain Differences in Middle and Older Age: Findings from the UK Biobank”. The Journal of Prevention of Alzheimer's Disease (2024): 1-10.
64. Liao X., et al. “Identification of Alzheimer’s disease-associated rare coding variants in the ECE2 gene”. JCI insight4 (2020).
65. Keenan BT., et al. “Alzheimer’s Disease Neuroimaging Initiative. A coding variant in CR1 interacts with APOE-ε4 to influence cognitive decline”. Human Molecular Genetics10 (2012): 2377-2388.
66. Morris JC., et al. “Developing an international network for Alzheimer research: the Dominantly Inherited Alzheimer Network”. Clinical Investigation (Lond)10 (2012): 975984.
67. Valentin-Escalera J., et al. “High-Fat Diets in Animal Models of Alzheimer’s Disease: How Can Eating Too Much Fat Increase Alzheimer’s Disease Risk?”. Journal of Alzheimer's Disease, (Preprint) (2024): 1-29.

Citation

Citation: Patne A., et al. “Gene Mapping in Alzheimer's Disease: Unveiling Genetic Mechanisms and Therapeutic Insights".Acta Scientific Pharmaceutical Sciences 8.7 (2024): 112-122.

Copyright

Copyright: © 2024 Patne A., et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.