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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Paper Citations

  1. . ApoE-4 and age at onset of Alzheimer's disease: the NIMH genetics initiative. Neurology. 1997 Jan;48(1):139-47. PubMed.
  2. . Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet. 2011 May;43(5):436-41. Epub 2011 Apr 3 PubMed.
  3. . Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet. 2011 May;43(5):429-35. PubMed.
  4. . The number of trait loci in late-onset Alzheimer disease. Am J Hum Genet. 2000 Jan;66(1):196-204. PubMed.

Further Reading


  1. . 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. . 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. . 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.