A comprehensive review and meta-analysis on Alzheimer’s genetics: Exploring the genetic architecture and its application in future genomic medicine
Paper Details
A comprehensive review and meta-analysis on Alzheimer’s genetics: Exploring the genetic architecture and its application in future genomic medicine
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder with 58–79% heritability, yet known variants explain only a fraction of this risk. This meta-analysis synthesizes 60 studies (2015–2025) on GWAS, neuroimaging-genetics integration, and molecular therapeutics. A systematic PubMed search identified studies with >1,000 samples, validated genetic findings, and relevance to AD pathology. Statistical analyses included meta-regression and pooled effect size calculations. Meta-analysis of 74 risk loci confirmed APOE, PSEN1, PSEN2, TREM2, CLU, and SORL1 as key contributors. APOE ε4 strongly correlated with amyloid burden (r = 0.62, p<0.001). Novel loci (e.g., RBFOX1) and population-specific variants were identified. Amyloid immunotherapies (lecanemab, donanemab) reduced plaques but had modest cognitive benefits. Gene silencing (BIIB080) and CRISPR/Cas9 showed therapeutic potential. Integrating genomics with neuroimaging enhances risk prediction. Gene-based interventions and precision medicine offer future promise, but further research is needed to address missing heritability.
Aguzzoli Heberle B, Fox KL, Lobraico Libermann L, Ronchetti Martins Xavier S, Tarnowski Dallarosa G, Carolina Santos R, Fardo DW, Wendt Viola T, Ebbert MT. 2025. Systematic review and meta-analysis of bulk RNAseq studies in human Alzheimer’s disease brain tissue. Alzheimer’s & Dementia 21(3), e70025.
Alhadidy M. 2024. Uncommonly studied post-translational modifications as potential regulators of tau function and pathobiology. Michigan State University (Doctoral dissertation).
Ali M, Archer DB, Gorijala P, Western D, Timsina J, Fernández MV, Wang TC, Satizabal CL, Yang Q, Beiser AS, Wang R. 2023. Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease. Acta Neuropathologica Communications 11(1), 68.
Angelopoulou E, Paudel YN, Papageorgiou SG, Piperi C. 2021. APOE genotype and Alzheimer’s disease: The influence of lifestyle and environmental factors. ACS Chemical Neuroscience 12(15), 2749–2764.
Anil AA, Krishnan AL, Chandra P, Unnikrishnan MK. 2025. Lecanemab: The advent of biologicals in Alzheimer’s disease, affordability, and clinical relevance. Journal of Applied Pharmaceutical Science 15(3), 030–038.
Beiter RM, Raghavan TP, Suchocki O, Ennerfelt HE, Rivet-Noor CR, Merchak AR, Phillips JL, Bathe T, Lukens JR, Prokop S, Dupree JL. 2025. Clusterin induced by OPC phagocytosis blocks IL-9 secretion to inhibit myelination in a model of Alzheimer’s disease. Heliyon 11(1).
Bissar N, Kassir R, Salami A, El Shamieh S. 2024. Association of immunity-related gene SNPs with Alzheimer’s disease. Experimental Biology and Medicine 249, 10303.
Bobbins A, Davies M, Lynn E, Roy D, Yeomans A, Shakir SA. 2025. Safety and effectiveness of the anti-amyloid monoclonal antibody lecanemab for early Alzheimer’s disease: The pharmacovigilance perspective. British Journal of Clinical Pharmacology.
Chaudhuri I, Das S. 2025. Heterogeneous treatment effects of BCG vaccine on Alzheimer’s disease risk. Journal of Alzheimer’s Disease Reports 9, 25424823251317955.
Chen XQ. 2025. APP gene-based strategies to combat Alzheimer’s disease in Down syndrome. Current Genomics.
Cummings JL, Osse AM, Kinney JW. 2023. Alzheimer’s disease: Novel targets and investigational drugs for disease modification. Drugs 83(15), 1387–1408.
De Deyn L, Sleegers K. 2025. The impact of rare genetic variants on Alzheimer disease. Nature Reviews Neurology.
Dias D, Socodato R. 2025. Beyond amyloid and tau: The critical role of microglia in Alzheimer’s disease therapeutics. Biomedicines 13(2), 279.
Dijkstra JI, Vermunt L, Venkatraghavan V, Ozhegov G, Coomans EM, Ossenkoppele R, van de Giessen E, Hulsman M, de Geus CM, van der Flier WM, Sikkes SA. 2025. TREM2 risk variants and associated endophenotypes in Alzheimer’s disease. Alzheimer’s Research & Therapy 17, 57.
Ferrari RR, Fantini V, Garofalo M, Di Gerlando R, Dragoni F, Rizzo B, Spina E, Rossi M, Calatozzolo C, Profka X, Ceroni M. 2024. A map of transcriptomic signatures of different brain areas in Alzheimer’s disease. International Journal of Molecular Sciences 25(20), 11117.
Ferrer I. 2022. Alzheimer’s disease is an inherent, natural part of human brain aging: An integrated perspective. Free Neuropathology 3, 3–17.
Frisoni GB, Altomare D, Thal DR, Ribaldi F, van der Kant R, Ossenkoppele R, Blennow K, Cummings J, van Duijn C, Nilsson PM, Dietrich PY. 2022. The probabilistic model of Alzheimer disease: The amyloid hypothesis revised. Nature Reviews Neuroscience 23(1), 53–66.
Gleason CE, Zuelsdorff M, Gooding DC, Kind AJ, Johnson AL, James TT, Lambrou NH, Wyman MF, Ketchum FB, Gee A, Johnson SC. 2022. Alzheimer’s disease biomarkers in Black and non-Hispanic White cohorts: A contextualized review. Alzheimer’s & Dementia 18(8), 1545–1564.
Granov R, Vedad S, Wang SH, Durham A, Shah D, Pasinetti GM. 2025. The neural exposome as a novel strategy to identify and mitigate health inequities in Alzheimer’s disease. Molecular Neurobiology 62(1), 1205–1224.
Guzman-Martinez L, Calfío C, Farias GA, Vilches C, Prieto R, Maccioni RB. 2021. New frontiers in the prevention, diagnosis, and treatment of Alzheimer’s disease. Journal of Alzheimer’s Disease 82(s1), S51–S63.
Hey JA, Yu JY, Abushakra S, Schaefer JF, Power A, Kesslak P, Paul J, Tolar M. 2025. Clinical pharmacokinetics of oral ALZ-801/valiltramiprosate in APOE4 carriers with early Alzheimer’s disease. Clinical Pharmacokinetics.
Hodges AK, Piers TM, Collier D, Cousins O, Pocock JM. 2021. Pathways linking Alzheimer’s disease risk genes expressed highly in microglia. Neuroimmunology and Neuroinflammation 8, 245–268.
Hosseini AM, Khaleghzadeh-Ahangar H, Rahimi A. 2025. The immunomodulatory effects of psychedelics in Alzheimer’s disease-related dementia. Neuroscience 564, 271–280.
Jung ES, Choi H, Mook-Jung I. 2025. Decoding microglial immunometabolism in Alzheimer’s disease. Molecular Neurodegeneration 20(1), 37.
Kamble SM, Patil KR, Upaganlawar AB. 2024. Etiology and pathogenesis of Alzheimer’s disease and the amyloid beta hypothesis. In Alzheimer’s disease and advanced drug delivery strategies. Academic Press, 1–11.
Kang C. 2024. Donanemab: First approval. Drugs 84(10), 1313–1318.
Karagas N, Young JE, Blue EE, Jayadev S. 2025. The spectrum of genetic risk in Alzheimer disease. Neurology: Genetics 11(1), e200224.
Khaled M, Al-Jamal H, Matar D, Ibrahim A, Tajer L, Issa N, El-Mir R, Hantour J. 2025. APOE ε4, environmental factors, and Alzheimer’s disease in North Lebanon: A case-control study. Journal of Alzheimer’s Disease 103(3), 889–904.
Khani M, Gibbons E, Bras J, Guerreiro R. 2022. Rare genetic variants in Alzheimer’s disease. Molecular Neurodegeneration 17, 1–5.
Kim Y, Ha TY, Lee MS, Chang KA. 2025. Regulatory mechanisms and therapeutic implications of lysosomal dysfunction in Alzheimer’s disease. International Journal of Biological Sciences 21(3), 1014.
Kjaergaard D, Simonsen AH, Waldemar G, Nielsen TR. 2025. Ethnic and racial influences on blood biomarkers for Alzheimer’s disease: A systematic review. Journal of Alzheimer’s Disease 103(1), 81–91.
Kshirsagar S, Reddy AP, Reddy PH. 2025. Mitophagy enhancers protect against amyloid beta-induced mitochondrial and synaptic toxicity in Alzheimer’s disease. Mitochondrion 83, 102038.
Li P, Abuloha S, Alshehri A, Alkhuzam K, Jaffee M, Ospina NS, Shao H. 2025. Glycemic control, medications, and Alzheimer’s disease: A scoping review in mild cognitive impairment. Healthcare and Rehabilitation 1(1), 100008.
Lui M, Salamone S, Pollastro F, Mazzon E, Artimagnella O. 2025. Cannabinerol restores mRNA splicing defects induced by β-amyloid in vitro. International Journal of Molecular Sciences 26(7), 3113.
Ma YN, Xia Y, Karako K, Song P, Tang W, Hu X. 2025. Serum proteomics reveals early biomarkers of Alzheimer’s disease: The dual role of APOE-ε4. BioScience Trends.
Mittal P, Singh N, Chaturvedi S, Jyoti A, Mishra AK, Hazari PP. 2021. PET ligands for β-amyloid, tau, and neuroinflammation: Diagnostic perspectives. Clinical and Translational Imaging 9, 153–175.
Momkute L, Vilkeviciute A, Gedvilaite G, Dubinskaite G, Kriauciuniene L, Liutkeviciene R. 2022. APOE serum levels and APOE alleles in optic neuritis. Genes 13(7), 1188.
Narasimhan S, Holtzman DM, Apostolova LG, Cruchaga C, Masters CL, Hardy J, Villemagne VL, Bell J, Cho M, Hampel H. 2024. Apolipoprotein E in Alzheimer’s disease trajectories and clinical care pathways. Nature Neuroscience 27(7), 1236–1252.
Nasb M, Tao W, Chen N. 2024. Alzheimer’s disease pathogenesis hypotheses. Aging and Disease 15(1), 43.
Orenay-Boyacioglu S, Boyacioglu O, Dondu A. 2025. Epigenetics in Alzheimer’s disease. In Handbook of the biology and pathology of mental disorders. Springer Nature Switzerland, 1–28.
Panza F, Dibello V, Sardone R, Zupo R, Castellana F, Leccisotti I, Moretti MC, Altamura M, Bellomo A, Daniele A, Solfrizzi V. 2025. Advances in amyloid-β monoclonal antibodies for treating Alzheimer’s disease. Expert Opinion on Biological Therapy 25(3), 275–283.
Phatnani H, Hengst U. 2024. The broken Alzheimer’s disease genome. Cell Genomics 4(5), 100555.
Philippidis A. 2024. FDA approves Lilly’s amyloid-targeting Kisunla for early Alzheimer’s. GEN Edge 6(1), 608–611.
Poniah P, Abdul Rashed A, Abdul Jalil J, Ali EZ. 2025. Early-onset Alzheimer’s mutations in Asian and Western populations: A scoping review. Genes 16(3), 345.
Rathee S, Sen D, Pandey V, Jain SK. 2024. Innovative therapeutic strategies in Alzheimer’s disease. Current Drug Targets 25(11), 752–774.
Shahidehpour RK, Nelson PT, Katsumata Y, Bachstetter AD. 2025. Dystrophic microglia and the spread of Alzheimer’s pathology. Brain 148(1), 89–101.
Shaw LM, Korecka M, Lee EB, Cousins KA, Vanderstichele H, Schindler SE, Tosun D, DeMarco ML, Brylska M, Wan Y, Burnham S. 2025. ADNI biomarker core: Progress and future challenges. Alzheimer’s & Dementia 21(1), e14264.
Sree RR, Kalyan M, Anand N, Mani S, Gorantla VR, Sakharkar MK, Song BJ, Chidambaram SB. 2025. New therapeutic approaches in Alzheimer’s disease: A comprehensive review. ACS Omega 10(6), 5148.
Sturchio A, Dwivedi AK, Young CB, Malm T, Marsili L, Sharma JS, Mahajan A, Hill EJ, Andaloussi SE, Poston KL, Manfredsson FP. 2021. High cerebrospinal amyloid-β42 associated with normal cognition in brain amyloidosis. EClinicalMedicine 38.
Tartaglia MC, Ingelsson M. 2025. Molecular therapeutics in development to treat Alzheimer’s disease. Molecular Diagnosis & Therapy 29(1), 9–24.
Tenner AJ, Petrisko TJ. 2025. Strategic targeting of complement in Alzheimer disease. Nature Reviews Neurology 21, 1073.
Timmins P. 2024. Latest developments in therapeutic delivery. Therapeutic Delivery 15(2), 77–94.
Vetere LM. 2024. Entorhinal-hippocampal desynchronization in Alzheimer’s disease pathology. Icahn School of Medicine at Mount Sinai (Doctoral dissertation).
Vogrinc D, Goričar K, Dolžan V. 2021. Genetic variability in molecular pathways implicated in Alzheimer’s disease: A comprehensive review. Frontiers in Aging Neuroscience 13, 646901.
Weiner MW, Kanoria S, Miller MJ, Aisen PS, Beckett LA, Conti C, Diaz A, Flenniken D, Green RC, Harvey DJ, Jack CR. 2025. Alzheimer’s Disease Neuroimaging Initiative: Overview and future trials. Alzheimer’s & Dementia 21(1), e14321.
Xue D, Blue EE, Sofer T, Hughes TM, Rotter JI, Fohner AE. 2025. Polygenic risk scores for incident dementia in a multi-ethnic cohort. medRxiv. DOI: 10.1101/2025.03.05.25323412.
Yang HS, Teng L, Kang D, Menon V, Ge T, Finucane HK, Schultz AP, Properzi M, Klein HU, Chibnik LB, Schneider JA. 2023. Cell-type-specific Alzheimer’s disease polygenic risk scores. Nature Communications 14(1), 7659.
Zhang H, Wei W, Zhao M, Ma L, Jiang X, Pei H, Cao Y, Li H. 2021. Interaction between Aβ and tau in Alzheimer’s disease pathogenesis. International Journal of Biological Sciences 17(9), 2181.
Shafee Ur Rehman, Shabeer Khan, Muhammad Usman, Sakarie Khadar Ibrahim, 2025. A comprehensive review and meta-analysis on Alzheimer’s genetics: Exploring the genetic architecture and its application in future genomic medicine. Int. J. Biosci., 27(5), 204-216.
Copyright © 2025 by the Authors. This article is an open access article and distributed under the terms and conditions of the Creative Commons Attribution 4.0 (CC BY 4.0) license.