Generic placeholder image

Current Alzheimer Research


ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Research Article

Asymptomatic Carriers of Presenilin-1 E318G Variant Show no Cerebrospinal Fluid Biochemical Signs Suggestive of Alzheimer’s disease in a Family with Late-onset Dementia

Author(s): Vladimiro Artuso, Luisa Benussi, Roberta Ghidoni, Soraya Moradi-Bachiller, Federica Fusco, Stefano Curtolo, Ignazio Roiter, Gianluigi Forloni and Diego Albani*

Volume 16, Issue 1, 2019

Page: [1 - 7] Pages: 7

DOI: 10.2174/1567205015666181031150345

Price: $65


Background: Presenilin-1 (PSEN-1) is a component of the γ-secretase complex involved in β-amyloid Precursor Protein (AβPP) processing. Usually, Alzheimer’s disease (AD)-linked mutations in the PSEN-1 gene lead to the early onset and increase the production of the aggregation-prone peptide Aβ42. However, the PSEN-1 E318G variant has an unclear pathogenic role and is recently reported as a genetic risk factor for AD. In particular, E318G variant presence correlated with increased cerebrospinal fluid (CSF) levels of Total Tau (t-tau) and Phosphorylated Tau (p-tau).

Objective: We describe a large Italian family, which we followed from January 2003 to January 2018, with the late-onset AD and the E318G variant, with the aim of assessing E318G-associated CSF or plasma biochemical changes in biomarkers of dementia.

Method: CSF Aβ42, t-tau and p-tau, plasma Aβ42 and Aβ40 were assessed by ELISA tests, while CSF amyloid peptides profile was investigated by mass spectrometry.

Results: We did not find any changes in CSF biochemical markers (Aβ42, t-tau, p-tau and amyloid peptides) of asymptomatic E318G carriers in 2010 and 2012, but plasma Aβ40 was increased at the same times. From 2003 to 2018, no asymptomatic E318G carrier developed AD.

Conclusion: Our follow-up of this family may help elucidate E318G’s role in AD and globally points to a null effect of this variant.

Keywords: Alzheimer's disease, risk factor, familial dementia, amyloid-beta peptide, presenilin-1, E318G

Next »
Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349: 704-6. (1991)
Bergem AL, Engedal K, Kringlen E. The role of heredity in late-onset Alzheimer disease and vascular dementia. A twin study. Arch Gen Psychiatry 54: 264-70. (1997)
Brickell KL, Steinbart EJ, Rumbaugh M, Payami H, Schellenberg GD, Van Deerlin V, et al. Early-onset Alzheimer disease in families with late-onset Alzheimer disease: a potential important subtype of familial Alzheimer disease. Arch Neurol 63: 1307-11. (2006)
Louwersheimer E, Cohn-Hokke PE, Pijnenburg YA, Weiss MM, Sistermans EA, Rozemuller AJ, et al. Rare genetic variant in SORL1 may increase penetrance of Alzheimer’s Disease in a family with several generations of APOE-ɛ4 homozygosity. J Alzheimers Dis 56: 63-74. (2017)
Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, 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: 775-8. (1995)
Zhou R, Yang G, Shi Y. Dominant negative effect of the loss-of-function γ-secretase mutants on the wild-type enzyme through hetero oligomerization. Proc Natl Acad Sci USA 114: 12731-6. (2017)
Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA. Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet 13: 159-70. (2004)
Robinson M, Lee BY, Hanes FT. Recent progress in Alzheimer’s disease research, Part 2: Genetics and epidemiology. J Alzheimers Dis 61: 459. (2018)
Gantier R, Dumanchin C, Campion D, Loutelier C, Lange C, Gagnon J, et al. The L392V mutation of presenilin 1 associated with autosomal dominant early-onset Alzheimer’s disease alters the secondary structure of the hydrophilic loop. Neuroreport 29: 3071-4. (1999)
Aldudo J, Bullido MJ, Frank A, Valdivieso F. Missense mutation E318G of the presenilin-1 gene appears to be a nonpathogenic polymorphism. Ann Neurol 44: 985-6. (1998)
Helisalmi S, Hiltunen M, Mannermaa A, Koivisto AM, Lehtovirta M, Alafuzoff I, et al. Is the presenilin-1 E318G missense mutation a risk factor for Alzheimer’s disease? Neurosci Lett 7: 65-8. (2000)
Arango D, Cruts M, Torres O, Backhovens H, Serrano ML, Villareal E, et al. Systematic genetic study of Alzheimer disease in Latin America: mutation frequencies of the amyloid beta precursor protein and presenilin genes in Colombia. Am J Med Genet 103: 138-43. (2001)
Zekanowski C, Pepłońska B, Styczyńska M, Religa D, Pfeffer A, Czyzewski K, et al. The E318G substitution in PSEN1 gene is not connected with Alzheimer’s disease in a large Polish cohort. Neurosci Lett 357: 167-70. (2004)
Dermaut B, Cruts M, Backhovens H, Lubke U, Van Everbroeck B, Sciot R. Familial Creutzfeldt-Jakob disease in a patient carrying both a presenilin 1 missense substitution and a prion protein gene insertion. J Neurol 247: 364-8. (2000)
Berezovska O, Lleo A, Herl LD, Frosch MP, Stern EA, Bacskai BJ, et al. Familial Alzheimer’s disease presenilin 1 mutations cause alterations in the conformation of presenilin and interactions with amyloid precursor protein. J Neurosci 16: 3009-17. (2005)
Benitez BA, Karch CM, Cai Y, Jin SC, Cooper B, Carrell D, et al. The PSEN1, p.E318G variant increases the risk of Alzheimer’s disease in APOE-ε4 carriers. PLoS Genet 9: e1003685. (2013)
Hippen AA, Ebbert MT, Norton MC, Tschanz JT, Munger RG, Corcoran CD, et al. Presenilin E318G variant and Alzheimer’s disease risk: the Cache County study. BMC Genomics 17(3): 438. (2016)
Albani D, Roiter I, Artuso V, Batelli S, Prato F, Pesaresi M, et al. Presenilin-1 mutation E318G and familial Alzheimer’s disease in the Italian population. Neurobiol Aging 28: 1682-8. (2007)
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. 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 34: 939-44. (1984)
Dubois B, Hampel H, Feldman HH, Scheltens P, Aisen P, Andrieu S, et al. Preclinical Alzheimer’s disease: Definition, natural history, and diagnostic criteria. Proceedings of the Meeting of the International Working Group (IWG) and the American Alzheimer’s Association on “The Preclinical State of AD”; July 23, 2015; Washington DC, USA. Alzheimers Dement 12: 292-323. (2016)
Cockrell JR, Folstein MF. Mini Mental State Examination (MMSE). Psychopharmacology 24: 689-92. (1988)
Crum RM, Anthony JC, Bassett SS, Folstein MF. Population-based norms for the mini-mental state examination by age and educational level. JAMA 18: 2386-91. (1993)
Albertini V, Bruno A, Paterlini A, Lista S, Benussi L, Cereda C, et al. Optimization protocol for amyloid-beta peptides detection in human cerebrospinal fluid using SELDI TOF MS. Proteomics Clin Appl 4: 352-7. (2010)
Catania M, Di Fede G, Tonoli E, Benussi L, Pasquali C, Giaccone G, et al. Mirror image of the amyloid-β species in cerebrospinal fluid and cerebral amyloid in Alzheimer’s disease. J Alzheimers Dis 47: 877-81. (2015)
Ghidoni R, Albertini V, Squitti R, Paterlini A, Bruno A, Bernardini S, et al. Novel T719P AbetaPP mutation unbalances the relative proportion of amyloid-beta peptides. J Alzheimers Dis 18: 295-303. (2009)
Portelius E, Andreasson U, Ringman JM, Buerger K, Daborg J, Buchhave P, et al. Distinct cerebrospinal fluid amyloid beta peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer’s disease. Mol Neurodegener 5: 2. (2010)
Portelius E, Fortea J, Molinuevo JL, Gustavsson MK, Andreasson U, Sanchez-Valle R. The amyloid-β isoform pattern in cerebrospinal fluid in familial PSEN1 M139T- and L286P-associated Alzheimer’s disease. Mol Med Rep 5: 1111-5. (2012)
Sala Frigerio C, De Strooper B. Alzheimer’s disease mechanisms and emerging roads to novel therapeutics. Annu Rev Neurosci 39: 57-79. (2016)
Laws SM, Clarnette RM, Taddei K, Martins G, Paton A, Almeida OP, et al. Association between the presenilin-1 mutation Glu318Gly and complaints of memory impairment. Neurobiol Aging 23: 55-8. (2002)

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy