Mutations in amyloid precursor protein and presenilin can give rise to a late-onset, inherited version of Alzheimer’s disease, according to a paper in the February 1 PLoS One online. A consortium of researchers reports that rare variants in the genes for amyloid precursor protein (APP) and the presenilins (PSEN1 and PSEN2), as well as tau and progranulin (GRN), pop up in families where AD is common and occurs in old age, like the majority of sporadic Alzheimer’s cases. The work blurs the line between early and late onset, study authors said, and illustrates how difficult it is to distinguish AD from frontotemporal dementia (FTD), which is associated with tau and GRN mutations.

The distinction between early onset AD and late-onset disease is “probably artificial,” said Alison Goate of Washington University in St. Louis, Missouri, senior author on the paper. “I do not think that, mechanistically, there really is a difference,” although practically, an earlier onset is still more suggestive of a powerful genetic mutation. Given the wide range in age at onset, factors both genetic and environmental likely influence when disease arises, she said. “The terminology is really being rewritten here,” added Randall Bateman, who is also at Washington University but was not involved in the study. “It is not all late-onset versus early onset, or familial versus sporadic…the two diseases, even though they may have different causes, are far and away really the same disease.”

The ApoE4 allele is the biggest known risk factor for LOAD. While small studies have pointed before to associations between late-onset disease and mutations in PSEN1 and PSEN2 (ARF related news story on Kauwe et al., 2007; Larner et al., 2007; Tomaino et al., 2007), this is the first large screen for rare LOAD mutations, the authors wrote. Goate and first author Carlos Cruchaga, also at Washington University, penned the paper on behalf of the National Institute on Aging-Late Onset Alzheimer’s Disease National Cell Repository for Alzheimer’s Disease (NCRAD) Family Study Consortium. They sequenced the five genes in DNA from 439 families in which four or more members were afflicted with late-onset AD (LOAD).

As the price of DNA sequencing plummets, direct sequencing studies like this one are the latest trend in genetic investigations, said Adam Naj of the University of Miami, who was not involved in the work. Previously, genomewide association studies yielded common variants in AD genes (see ARF related news story; ARF news story; ARF related news story); however, common variants of APP, the presenilins, and tau are unlikely to affect LOAD risk very much (Gerrish et al., 2011). Direct sequencing, in contrast to GWAS, can pick up rare mutations, and studies in other diseases suggest that uncommon mutations, collectively, could actually account for a significant proportion of risk (Azzopardi et al., 2008; Masson et al., 2008; Ma et al., 2007). Goate intends to sequence the exomes (see ARF related news story) of the LOAD kindreds, but figured she would first eliminate the most likely candidate genes with this targeted sequencing of five genes known to be involved in familial AD and FTD, she told ARF.

“We expected to find mutations, but not that many,” Cruchaga said. A full 14 percent of the families carried a variant in one of the five genes. Among the sequences were five new and one known APP variant, one new and two known PSEN1 variants, three known PSEN2 variants, six new and one known tau variants, and six new and eight known GRN variants. It is too early to say which of the 33 mutations the researchers observed are pathogenic, which may be risk factors, or which are innocuous variants. In some families, carriers were not sick; that could be because of incomplete penetrance, because the healthy carriers were presymptomatic, or because the allele actually had nothing to do with disease. In other cases, a family had a mutation, but Alzheimer’s appeared in a person who was not a carrier—perhaps simply a sporadic case among the familial ones, or possibly evidence that the allele did not cause AD at all.

Examining their limited dataset, the researchers divided the mutations into eight that are likely or definitely pathogenic, 13 that appear not to cause disease, and 12 of unknown effect. The first group included two previously known familial AD mutations in PSEN1 and three FTD mutations in GRN, plus one new variant in each of APP, MAPT, and GRN. None of these three novel mutations were found in more than 1,000 unrelated elderly people without dementia. Other mutations that did not appear to directly cause disease occurred at higher-than-average frequency in the LOAD families, suggesting they might lower the age of onset or boost risk.

“You can find examples of early and late onset for all of the genes,” Goate said. For example, the A79V mutation in PSEN1 showed up in families with late-onset AD, kindreds with early onset AD (Rogaeva et al., 2001), and one person with apparently sporadic disease, she said. At least for AD linked to APP, ApoE, PSEN1, or PSEN2, onset can happen at any age, she said. “We always think about mutations as being early onset,” Bateman said. “We may have been missing half of the mutation carriers.”

To other scientists' minds, the early/late distinction still has merit. “The early onset probably still involves a small number of very highly penetrant mutations,” while late-onset mutations will put people at “higher risk, but not necessarily guaranteed to suffer from disease,” Naj said. Lars Bertram of the Max Planck Institute for Molecular Genetics in Berlin, Germany, who is a curator for the AlzGene database, also thinks early and late-onset remain discrete: “The genetic mechanism behind disease-causing (very rare) versus risk-increasing (common and rare) base changes are likely different,” he wrote in an e-mail to ARF.

Cruchaga and Goate were particularly surprised at 21 MAPT and GRN mutations among this cohort of people who were all diagnosed with Alzheimer’s. That suggests to the researchers that some cases of AD are actually misdiagnosed FTD. It will be “extremely important, once we have therapeutics, to make the right diagnosis,” Goate said, because doctors may want to treat AD and FTD differently. Even now, people with FTD generally do not respond to treatment with the currently approved AD drugs. Misdiagnosis could also confound clinical studies if researchers think their population is all people with AD but some actually have FTD, Naj noted.

People with a family history of Alzheimer’s, even if it was late onset, would be good candidates for genetic testing, Goate said. Naj cautioned that in order to provide informative genetic counseling, researchers need to find out more about the new variants so that identifying a mutation does not cause undue panic. However, Bateman added that families would likely want to know if they carry mutations, even if the science is incomplete.—Amber Dance


  1. Told you so (see reference).

    I missed from the discussion a mention of the stochastic nature of gene expression, and specifically of the age at onset, as an explanation of the incomplete "penetrance" of mutations with a late expression. Penetrance is a dirty word that explains nothing, as many carriers die from other causes before expression of the mutation.


    . Alzheimer's disease: a model from the quantitative study of a large kindred. J Geriatr Psychiatry Neurol. 1992 Jul-Sep;5(3):126-31. PubMed.

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News Citations

  1. The Value of Biomarkers—Diagnosis and Genetic Screens
  2. Paper Alert: GWAS Hits Clusterin, CR1, PICALM Formally Published
  3. LOADing Up—Largest GWAS to Date Confirms Two, Adds Two Risk Genes
  4. Large Genetic Analysis Pays Off With New AD Risk Genes
  5. Barcelona: What Lies Beyond Genomewide Association Studies?

Paper Citations

  1. . Extreme cerebrospinal fluid amyloid beta levels identify family with late-onset Alzheimer's disease presenilin 1 mutation. Ann Neurol. 2007 May;61(5):446-53. PubMed.
  2. . The R269H mutation in presenilin-1 presenting as late-onset autosomal dominant Alzheimer's disease. J Neurol Sci. 2007 Jan 31;252(2):173-6. Epub 2006 Dec 26 PubMed.
  3. . Presenilin 2 Ser130Leu mutation in a case of late-onset "sporadic" Alzheimer's disease. J Neurol. 2007 Mar;254(3):391-3. PubMed.
  4. . The Role of Variation at AβPP, PSEN1, PSEN2, and MAPT in Late Onset Alzheimer's Disease. J Alzheimers Dis. 2011 Oct 25; PubMed.
  5. . Multiple rare nonsynonymous variants in the adenomatous polyposis coli gene predispose to colorectal adenomas. Cancer Res. 2008 Jan 15;68(2):358-63. PubMed.
  6. . Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis. Hum Genet. 2008 Feb;123(1):83-91. PubMed.
  7. . Full-exon resequencing reveals toll-like receptor variants contribute to human susceptibility to tuberculosis disease. PLoS One. 2007;2(12):e1318. PubMed.
  8. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.

External Citations

  1. APP
  2. PSEN1
  3. PSEN2
  4. tau
  5. progranulin
  6. ApoE4
  7. National Cell Repository for Alzheimer’s Disease
  8. AlzGene

Further Reading


  1. . Alzheimer's disease phenotypes and genotypes associated with mutations in presenilin 2. Brain. 2010 Apr;133(Pt 4):1143-54. PubMed.
  2. . Genome scan of age-at-onset in the NIMH Alzheimer disease sample uncovers multiple loci, along with evidence of both genetic and sample heterogeneity. Am J Med Genet B Neuropsychiatr Genet. 2011 Dec;156B(7):785-98. PubMed.
  3. . Roles of the Tau Gene Short Tandem Repeats in Late-Onset Alzheimer's Disease. Int J Neurosci. 2012 Feb 6; PubMed.
  4. . Association of SORL1 alleles with late-onset Alzheimer's Disease. Findings from the GIGAS_LOAD study and mega-analysis. Curr Alzheimer Res. 2011 Oct 26; PubMed.
  5. . TOMM40 poly-T repeat lengths, age of onset and psychosis risk in Alzheimer disease. Neurobiol Aging. 2011 Dec;32(12):2328.e1-9. PubMed.

Primary Papers

  1. . Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families. PLoS One. 2012;7(2):e31039. Epub 2012 Feb 1 PubMed.