Genetic Associations with Age at Dementia Onset in the PSEN1 E280A Colombian Kindred

Introduction: Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations.

Methods: A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early-onset AD study and four late-onset AD studies.

Results: 13 variants had p<1×10 or p<1×10 with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14.

Discussion: Variants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role.

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References

Bellenguez C, Kucukali F, Jansen I, Kleineidam L, Moreno-Grau S, Amin N . New insights into the genetic etiology of Alzheimer's disease and related dementias. Nat Genet. 2022; 54(4):412-436. PMC: 9005347. DOI: 10.1038/s41588-022-01024-z. View

Snow A, Cummings J, Lake T . The Unifying Hypothesis of Alzheimer's Disease: Heparan Sulfate Proteoglycans/Glycosaminoglycans Are Key as First Hypothesized Over 30 Years Ago. Front Aging Neurosci. 2021; 13:710683. PMC: 8521200. DOI: 10.3389/fnagi.2021.710683. View

Ardila A, Lopera F, Rosselli M, Moreno S, Madrigal L, Arango-Lasprilla J . Neuropsychological profile of a large kindred with familial Alzheimer's disease caused by the E280A single presenilin-1 mutation. Arch Clin Neuropsychol. 2003; 15(6):515-28. View

Chang C, Chow C, Tellier L, Vattikuti S, Purcell S, Lee J . Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015; 4:7. PMC: 4342193. DOI: 10.1186/s13742-015-0047-8. View

Ryman D, Acosta-Baena N, Aisen P, Bird T, Danek A, Fox N . Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology. 2014; 83(3):253-60. PMC: 4117367. DOI: 10.1212/WNL.0000000000000596. View

Day G, Cruchaga C, Wingo T, Schindler S, Coble D, Morris J . Association of Acquired and Heritable Factors With Intergenerational Differences in Age at Symptomatic Onset of Alzheimer Disease Between Offspring and Parents With Dementia. JAMA Netw Open. 2019; 2(10):e1913491. PMC: 6806434. DOI: 10.1001/jamanetworkopen.2019.13491. View

Mooney J, Huber C, Service S, Sul J, Marsden C, Zhang Z . Understanding the Hidden Complexity of Latin American Population Isolates. Am J Hum Genet. 2018; 103(5):707-726. PMC: 6218714. DOI: 10.1016/j.ajhg.2018.09.013. View

Holmes B, DeVos S, Kfoury N, Li M, Jacks R, Yanamandra K . Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc Natl Acad Sci U S A. 2013; 110(33):E3138-47. PMC: 3746848. DOI: 10.1073/pnas.1301440110. View

Lendon C, Martinez A, Behrens I, Kosik K, Madrigal L, Norton J . E280A PS-1 mutation causes Alzheimer's disease but age of onset is not modified by ApoE alleles. Hum Mutat. 1997; 10(3):186-95. DOI: 10.1002/(SICI)1098-1004(1997)10:3<186::AID-HUMU2>3.0.CO;2-H. View

10.

Manichaikul A, Mychaleckyj J, Rich S, Daly K, Sale M, Chen W . Robust relationship inference in genome-wide association studies. Bioinformatics. 2010; 26(22):2867-73. PMC: 3025716. DOI: 10.1093/bioinformatics/btq559. View

11.

Lambert J, Ibrahim-Verbaas C, Harold D, Naj A, Sims R, Bellenguez C . Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013; 45(12):1452-8. PMC: 3896259. DOI: 10.1038/ng.2802. View

12.

Velez J, Lopera F, Sepulveda-Falla D, Patel H, Johar A, Chuah A . APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer's disease. Mol Psychiatry. 2015; 21(7):916-24. PMC: 5414071. DOI: 10.1038/mp.2015.177. View

13.

Anderson A, Rogers B, Loupe J, Rodriguez-Nunez I, Roberts S, White L . Single nucleus multiomics identifies ZEB1 and MAFB as candidate regulators of Alzheimer's disease-specific -regulatory elements. Cell Genom. 2023; 3(3):100263. PMC: 10025452. DOI: 10.1016/j.xgen.2023.100263. View

14.

Lalli M, Garcia G, Madrigal L, Arcos-Burgos M, Arcila M, Kosik K . Exploratory data from complete genomes of familial alzheimer disease age-at-onset outliers. Hum Mutat. 2012; 33(12):1630-4. PMC: 3496074. DOI: 10.1002/humu.22167. View

15.

Zhou X, Chen Y, Mok K, Zhao Q, Chen K, Chen Y . Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer's disease pathogenesis. Proc Natl Acad Sci U S A. 2018; 115(8):1697-1706. PMC: 5828602. DOI: 10.1073/pnas.1715554115. View

16.

Ibanez A, Yokoyama J, Possin K, Matallana D, Lopera F, Nitrini R . The Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat): Driving Multicentric Research and Implementation Science. Front Neurol. 2021; 12:631722. PMC: 7992978. DOI: 10.3389/fneur.2021.631722. View

17.

Pastor P, Roe C, Villegas A, Bedoya G, Chakraverty S, Garcia G . Apolipoprotein Eepsilon4 modifies Alzheimer's disease onset in an E280A PS1 kindred. Ann Neurol. 2003; 54(2):163-9. DOI: 10.1002/ana.10636. View

18.

Marioni R, Harris S, Zhang Q, McRae A, Hagenaars S, Hill W . GWAS on family history of Alzheimer's disease. Transl Psychiatry. 2018; 8(1):99. PMC: 5959890. DOI: 10.1038/s41398-018-0150-6. View

19.

Nelson P, Estus S, Abner E, Parikh I, Malik M, Neltner J . ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology. Acta Neuropathol. 2014; 127(6):825-43. PMC: 4113197. DOI: 10.1007/s00401-014-1282-2. View

20.

Zhou X, Stephens M . Genome-wide efficient mixed-model analysis for association studies. Nat Genet. 2012; 44(7):821-4. PMC: 3386377. DOI: 10.1038/ng.2310. View