Do Alzheimer’s GWAS Hits Speed Up Disease?

Carriers of the ApoE4 allele—the strongest genetic risk factor for late-onset Alzheimer’s—tend to get the disease at younger ages than the rest of the population (see Blacker et al., 1997). Do other AD-associated genetic loci hasten onset? To find out, scientists led by Margaret Pericak-Vance, University of Miami, tested whether 10 loci linked with disease risk changed the age at onset in a large cohort of Alzheimer’s patients (see Naj et al., 2011, and Hollingworth et al., 2011). As they report in the November 1 JAMA Neurology, BIN1, CCR1, and PICALM made the cut, however, their influence was small.

“Even together, the combined effect of these variants on the age at onset is weaker than that of the ApoE variant,” said first author Adam Naj, University of Pennsylvania Perelman School of Medicine, Philadelphia. The results contradict a previous estimation that other genetic risk factors would equal or exceed ApoE4’s influence (see Daw et al., 2000). 

Naj and colleagues looked at the medical records of 9,162 patients and controls. They checked to see if single-nucleotide polymorphisms (SNPs) in APOE, PICALM, CLU, CR1, BIN1, CD2AP, EPHA1, MS4A4A, CD33, and ABCA7 correlated with an earlier AD diagnosis. ApoE4 contributed the most, with each additional copy of the allele reducing the age at onset by 2.45 years. AD-associated SNPs in CR1, BIN1, and PICALM trimmed that age by three to six months more. While ApoE alone contributed to 3.7 percent of the variation in age at onset, all nine other risk alleles together accounted for only 2.2 percent. While the individual effects of these SNPs are not clinically relevant, when combined and added to genetic variants yet to be discovered, they could eventually draw down age at onset by a few years or more and signal the need for earlier treatment, said Naj.

In a replication dataset of almost 2,000 people with AD, SNPs in CR1, BIN1, and PICALM trended toward lowering the age at onset of disease, but none reached significance. Naj said he and colleagues next plan to examine these associations in a larger replication dataset of about 5,000 patients.—Gwyneth Dickey Zakaib

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References

Paper Citations

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Further Reading

Papers

  1. Li YJ, Oliveira SA, Xu P, Martin ER, Stenger JE, Scherzer CR, Hauser MA, Scott WK, Small GW, Nance MA, Watts RL, Hubble JP, Koller WC, Pahwa R, Stern MB, Hiner BC, Jankovic J, Goetz CG, Mastaglia F, Middleton LT, Roses AD, Saunders AM, Schmechel DE, Gullans SR, Haines JL, Gilbert JR, Vance JM, Pericak-Vance MA, Hulette C, Welsh-Bohmer KA. Glutathione S-transferase omega-1 modifies age-at-onset of Alzheimer disease and Parkinson disease. Hum Mol Genet. 2003 Dec 15;12(24):3259-67. PubMed.
  2. Khachaturian AS, Corcoran CD, Mayer LS, Zandi PP, Breitner JC, . Apolipoprotein E epsilon4 count affects age at onset of Alzheimer disease, but not lifetime susceptibility: The Cache County Study. Arch Gen Psychiatry. 2004 May;61(5):518-24. PubMed.

Primary Papers

  1. Naj AC, Jun G, Reitz C, Kunkle BW, Perry W, Park YS, Beecham GW, Rajbhandary RA, Hamilton-Nelson KL, Wang LS, Kauwe JS, Huentelman MJ, Myers AJ, Bird TD, Boeve BF, Baldwin CT, Jarvik GP, Crane PK, Rogaeva E, Barmada MM, Demirci FY, Cruchaga C, Kramer PL, Ertekin-Taner N, Hardy J, Graff-Radford NR, Green RC, Larson EB, St George-Hyslop PH, Buxbaum JD, Evans DA, Schneider JA, Lunetta KL, Kamboh MI, Saykin AJ, Reiman EM, De Jager PL, Bennett DA, Morris JC, Montine TJ, Goate AM, Blacker D, Tsuang DW, Hakonarson H, Kukull WA, Foroud TM, Martin ER, Haines JL, Mayeux RP, Farrer LA, Schellenberg GD, Pericak-Vance MA, Alzheimer Disease Genetics Consortium, Albert MS, Albin RL, Apostolova LG, Arnold SE, Barber R, Barnes LL, Beach TG, Becker JT, Beekly D, Bigio EH, Bowen JD, Boxer A, Burke JR, Cairns NJ, Cantwell LB, Cao C, Carlson CS, Carney RM, Carrasquillo MM, Carroll SL, Chui HC, Clark DG, Corneveaux J, Cribbs DH, Crocco EA, DeCarli C, DeKosky ST, Dick M, Dickson DW, Duara R, Faber KM, Fallon KB, Farlow MR, Ferris S, Frosch MP, Galasko DR, Ganguli M, Gearing M, Geschwind DH, Ghetti B, Gilbert JR, Glass JD, Growdon JH, Hamilton RL, Harrell LE, Head E, Honig LS, Hulette CM, Hyman BT, Jicha GA, Jin LW, Karydas A, Kaye JA, Kim R, Koo EH, Kowall NW, Kramer JH, LaFerla FM, Lah JJ, Leverenz JB, Levey AI, Li G, Lieberman AP, Lin CF, Lopez OL, Lyketsos CG, Mack WJ, Martiniuk F, Mash DC, Masliah E, McCormick WC, McCurry SM, McDavid AN, McKee AC, Mesulam M, Miller BL, Miller CA, Miller JW, Murrell JR, Olichney JM, Pankratz VS, Parisi JE, Paulson HL, Peskind E, Petersen RC, Pierce A, Poon WW, Potter H, Quinn JF, Raj A, Raskind M, Reisberg B, Ringman JM, Roberson ED, Rosen HJ, Rosenberg RN, Sano M, Schneider LS, Seeley WW, Smith AG, Sonnen JA, Spina S, Stern RA, Tanzi RE, Thornton-Wells TA, Trojanowski JQ, Troncoso JC, Valladares O, Van Deerlin VM, Van Eldik LJ, Vardarajan BN, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Williamson J, Wishnek S, Woltjer RL, Wright CB, Younkin SG, Yu CE, Yu L. Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study. JAMA Neurol. 2014 Nov;71(11):1394-404. PubMed.

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