2023 Alzheimer’s disease facts and figures. Alzheimers Dement 19, 1598–1695 (2023).
Campion D, et al. Early-onset autosomal dominant alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999;65:664–70.
Sherrington R, et al. Cloning of a gene bearing missense mutations in early-onset Familial alzheimer’s disease. Nature. 1995;375:754–60.
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. 1995;376:775–8.
Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of alzheimer’s disease. Trends Pharmacol Sci. 1991;12:383–8.
Lanoiselée HM et al. APP, PSEN1, and PSEN2 mutations in early-onset alzheimer disease: A genetic screening study of Familial and sporadic cases. PLoS Med 14, (2017).
Goldman JS, et al. Genetic counseling and testing for alzheimer disease: joint practice guidelines of the American college of medical genetics and the National society of genetic counselors. Genet Sci. 2011;13:597.
Pilotto A, Padovani A, Borroni B, Clinical. Biological, and Imaging Features of Monogenic Alzheimer’s Disease. Biomed Res Int 2013, (2013).
Schwarze K, Buchanan J, Taylor JC, Wordsworth S. Are whole-exome and whole-genome sequencing approaches cost-effective? A systematic review of the literature. Genetics in Medicine 2018 20:10 20, 1122–1130 (2018).
Carmona S, Hardy J, Guerreiro R. The genetic landscape of alzheimer disease. Handb Clin Neurol. 2018;148:395–408.
Bellenguez C, et al. New insights into the genetic etiology of alzheimer’s disease and related dementias. Nat Genet. 2022;2022:1–25. https://doi.org/10.1038/s41588-022-01024-z.
de Rojas I, et al. Common variants in alzheimer’s disease and risk stratification by polygenic risk scores. Nat Commun. 2021;12:3417.
Wightman DP, et al. A genome-wide association study with 1,126,563 individuals identifies new risk loci for alzheimer’s disease. Nat Genet. 2021;53:1276–82.
Escott-Price V, et al. Polygenic score prediction captures nearly all common genetic risk for alzheimer’s disease. Neurobiol Aging. 2016;0:3–1342.
Chaudhury S et al. Alzheimer’s disease polygenic risk score as a predictor of conversion from mild-cognitive impairment. Translational Psychiatry 2019 9:1 9, 1–7 (2019).
Martiskainen H, et al. Effects of alzheimer’s disease-Associated risk loci on cerebrospinal fluid biomarkers and disease progression: A polygenic risk score approach. J Alzheimer’s Disease. 2015;43:565–73.
Lewis CM, Vassos E. Polygenic risk scores: from research tools to clinical instruments. Genome Med. 2020;12:1–11.
Läll K, Mägi R, Morris A, Metspalu A, Fischer K. Personalized risk prediction for type 2 diabetes: the potential of genetic risk scores. Genet Med. 2017;19:322–9.
Tesi N, et al. Polygenic risk score of longevity predicts longer survival across an age continuum. Journals Gerontology: Ser A. 2021;76:750–9.
Fahed AC, Philippakis AA, Khera AV. The potential of polygenic scores to improve cost and efficiency of clinical trials. Nature Communications 2022 13:1 13, 1–4 (2022).
Guerreiro R, et al. TREM2 variants in alzheimer’s disease. N Engl J Med. 2013;368:117–27.
Jonsson T, et al. Variant of TREM2 associated with the risk of alzheimer’s disease. N Engl J Med. 2013;368:107–16.
Sims R et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in alzheimer’s disease. Nat Genet 49, (2017).
Holstege H, et al. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for alzheimer’s disease. Nat Genet. 2022;2022:1–9. https://doi.org/10.1038/s41588-022-01208-7.
Jin SC, et al. Coding variants in TREM2 increase risk for alzheimer’s disease. Hum Mol Genet. 2014;23:5838–46.
Jay TR, Saucken V, V. E., Landreth GE. TREM2 in Neurodegenerative Diseases. Molecular Neurodegeneration 2017 12:1 12, 1–33 (2017).
Corder E, Saunders A. Gene dose of Apolipoprotein E type 4 allele and the risk of alzheimer’s disease in late onset families. Sci (1979). 1993;8:41–3.
Corder EH, et al. Protective effect of Apolipoprotein E type 2 allele for late onset alzheimer disease. Nat Genet. 1994;7:180–4.
Rubin R. Studying how genomic variation affects human health. JAMA 326, (2021).
Chia R, et al. Genome sequencing analysis identifies new loci associated with lewy body dementia and provides insights into its genetic architecture. Nat Genet. 2021;53:294–303.
Perrone F, Cacace R, van der Zee J, Van Broeckhoven C. Emerging genetic complexity and rare genetic variants in neurodegenerative brain diseases. Genome Medicine 2021 13:1 13, 1–13 (2021).
Van Lee D. S. J. Prevalence of pathogenic variants and eligibility criteria for genetic testing in patients who visit a memory clinic. Neurology 104, (2025).
Van Der Flier WM, Scheltens P. Amsterdam dementia cohort: performing research to optimize care. J Alzheimer’s Disease. 2018;62:1091–111. (J Alzheimers Dis.
Van Der Flier WM et al. Optimizing patient care and research: the Amsterdam Dementia Cohort. 41, 313–327 (2014).
McKhann G, et al. Clinical diagnosis of alzheimer’s disease: report of the NINCDS-ADRDA work group⋆ under the auspices of department of health and human services task force on alzheimer’s disease. Neurology. 1984;34:939–44.
Dubois B, et al. Research criteria for the diagnosis of alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007;6:734–46.
Neary D, et al. Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester groups. J Neurol Neurosurg Psychiatry. 1994;57:416.
McKeith IG. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): Report of the Consortium on DLB International Workshop. Journal of Alzheimer’s Disease 9, 417–423 (2006).
McKeith IG, et al. Diagnosis and management of dementia with lewy bodies. Neurology. 2017;89:88–100.
Petersen RC, et al. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999;56:303–8.
Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med. 2004;256:183–94.
McKhann GM, 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. Alzheimer’s Dement. 2011;7:263–9.
Jack CR, et al. NIA-AA research framework: toward a biological definition of alzheimer’s disease. Alzheimer’s Dement. 2018;14:535–62.
Das S, et al. Next-generation genotype imputation service and methods. Nat Genet. 2016;48:1284–7.
Fuchsberger C, Abecasis GR, Hinds D. A. minimac2: faster genotype imputation. Bioinformatics. 2015;31:782–4.
Taliun D et al. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. Nature 2021 590:7845 590, 290–299 (2021).
Richards S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med. 2015;17:405–24.
Holm SA, Simple Sequentially. Rejective multiple test procedure. Scand J Stat. 1979. https://doi.org/10.2307/4615733.
Liu X, Li C, Mou C, Dong Y, Tu Y. DbNSFP v4: a comprehensive database of transcript-specific functional predictions and annotations for human nonsynonymous and splice-site SNVs. Genome Med. 2020;12:1–8.
Karczewski KJ et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 2020 581:7809 581, 434–443 (2020).
Schramm C et al. Penetrance Estimation of alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes. Genome Med 14, (2022).
Corder EH, et al. Gene dose of Apolipoprotein E type 4 allele and the risk of alzheimer’s disease in late onset families. Science. 1993;261:921–3.
Duncan L et al. Analysis of polygenic risk score usage and performance in diverse human populations. Nature Communications 2019 10:1 10, 1–9 (2019).
Wray NR, Goddard ME, Visscher PM. Prediction of individual genetic risk to disease from genome-wide association studies. Genome Res. 2007;17:1520–8.
International Schizophrenia Consortium. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460:748–52.
Kim DH, et al. Genetic markers for diagnosis and pathogenesis of alzheimer’s disease. Gene. 2014;545:185–93.
Escott-Price V, Schmidt KM. Probability of alzheimer’s disease based on common and rare genetic variants. Alzheimers Res Ther. 2021;13:1–9.
Guerreiro R, et al. Investigating the genetic architecture of dementia with lewy bodies: a two-stage genome-wide association study. Lancet Neurol. 2018;17:64–74.
Rongve A et al. GBA and APOE ε4 associate with sporadic dementia with lewy bodies in European genome wide association study. Sci Rep 9, (2019).
Pottier C, et al. Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD. Acta Neuropathol. 2019;137:879–99.
Pottier C, et al. Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal dementia and GRN mutations: a genome-wide association study. Lancet Neurol. 2018;17:548.
Katsumata Y, et al. Multiple gene variants linked to Alzheimer’s-type clinical dementia via GWAS are also associated with non-Alzheimer’s neuropathologic entities. Neurobiol Dis. 2022;174:105880.
Dugan AJ, et al. Analysis of genes (TMEM106B, GRN, ABCC9, KCNMB2, and APOE) implicated in risk for LATE-NC and hippocampal sclerosis provides pathogenetic insights: a retrospective genetic association study. Acta Neuropathol Commun. 2021;9:1–18.
Robinson JL, et al. Pathological combinations in neurodegenerative disease are heterogeneous and disease-associated. Brain. 2023;146:2557–69.
Nicolas G et al. Assessment of Mendelian and risk-factor genes in alzheimer disease: A prospective nationwide clinical utility study and recommendations for genetic screening. Genet Sci 26, (2024).
Jensen AMG et al. The SORL1 p.Y1816C variant causes impaired endosomal dimerization and autosomal dominant alzheimer’s disease. Proc Natl Acad Sci U S A 121, (2024).
Fazeli E, Fazeli E, Fojtík P, Holstege H, Andersen OM. Functional characterization of SORL1 variants in cell-based assays to investigate variant pathogenicity. Philosophical Trans Royal Soc B: Biol Sci 379, (2024).
Hung C et al. SORL1 deficiency in human excitatory neurons causes APP-dependent defects in the endolysosome-autophagy network. Cell Rep 35, (2021).
Fazeli E et al. A Familial missense variant in the alzheimer’s disease gene SORL1 impairs its maturation and endosomal sorting. Acta Neuropathol 147, (2024).
Nicolas A et al. Transferability of a European-derived Alzheimer’s Disease Genetic Risk Score across Multi-Ancestry Populations. medRxiv (2023).
Escott-Price V, et al. Common polygenic variation enhances risk prediction for alzheimer’s disease. Brain. 2015;138:3673–84.
Van Lee D. Genetics contributes to concomitant pathology and clinical presentation in dementia with lewy bodies. J Alzheimers Dis. 2021;83:269–79.
Sleegers K, et al. A 22-single nucleotide polymorphism alzheimer’s disease risk score correlates with family history, onset age, and cerebrospinal fluid Aβ 42. Alzheimer’s Dement. 2015;11:1452–60.
Chouraki V, et al. Evaluation of a genetic risk score to improve risk prediction for alzheimer’s disease. J Alzheimer’s Disease. 2016;53:921–32.
Rodríguez-Rodríguez E, et al. Genetic risk score predicting accelerated progression from mild cognitive impairment to alzheimer’s disease. J Neural Transm. 2013;120:807–12.
Klunk WE. Amyloid imaging as a biomarker for cerebral β-amyloidosis and risk-prediction for alzheimer dementia. Neurobiol Aging. 2011;32:S20.
Edison P, et al. Comparison of MRI based and PET template based approaches in the quantitative analysis of amyloid imaging with PIB-PET. NeuroImage. 2013;70:423–33.
Tomassen J et al. Abnormal cerebrospinal fluid levels of amyloid and Tau are associated with cognitive decline over time in cognitively normal older adults: A monozygotic twin study. Alzheimers Dement (N Y) 8, (2022).
Palmqvist S, et al. Detailed comparison of amyloid PET and CSF biomarkers for identifying early alzheimer disease. Neurology. 2015;85:1240.
Shaffer JL, et al. Predicting cognitive decline in subjects at risk for alzheimer disease by using combined cerebrospinal fluid, MR imaging, and PET biomarkers. Radiology. 2013;266:583–91.
Walsh T, et al. Outreach, screening, and randomization of APOE ε4 carriers into an alzheimer’s prevention trial: A global perspective from the API generation program. J Prev Alzheimers Dis. 2023;10:453.
ALZ-801 for Early Alzheimer’s in People With the APOE4/4 Genotype. (APOLLOE4). https://www.alzheimers.gov/clinical-trials/alz-801-early-alzheimers-people-apoe4-4-genotype-apolloe4
Jackson S et al. INVOKE-2 – A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of AL002 in Participants with Early Alzheimer’s Disease (P17-3.005). Neurology 98, (2022).
Study Details |. First in Human Study for Safety and Tolerability of AL003. | ClinicalTrials.gov. https://www.clinicaltrials.gov/study/NCT03822208?cond=Alzheimer Disease&term = AL003&rank = 1.