Just kidding, emigration won’t fix this problem. Recently, out of Iceland, came news of an amyloid precursor protein variant that protected a lucky 1 percent of the islanders from Alzheimer’s disease. Alas, far fewer Americans stand to inherit such good fortune, according to results of a multicenter study published in the February 1 JAMA Neurology. The authors found the allegedly protective alanine-673-threonine allele in just three DNA samples from nearly 20,000 American Caucasians.

“This variant is extremely rare and does not have a discernible impact on AD risk in the U.S. population,” concluded the authors, led by Gerard Schellenberg of the University of Pennsylvania School of Medicine in Philadelphia.

The mutation sits next to APP’s cleavage site for BACE1 and suppresses Aβ production. Even in Iceland, the A673T substitution is rare, but the original study authors reported it was five times more prevalent in elderly people without dementia than in those with AD. Those researchers also detected the variant in nearly one in 100 people in Scandinavian countries, but only one in 5,000 North Americans (see Jul 2012 news). In a different study of North Americans, the variant was a no-show in more than 4,000 people (Bamne et al., 2014). 

In the new work, Schellenberg and colleagues picked up the variant in two of 10,480 cognitively normal Americans—one of whom hailed from Iceland—and one of 8,943 people with AD. That person was 89 when AD symptoms began, which is consistent with the allele being protective. The authors also examined DNA from 1,569 Swedes, and found three instances of the variant, all in controls. This is similar to the frequency reported earlier in that population.

The present cohort was big enough to determine that A673T occurs only rarely in Americans, commented Rita Guerreiro of University College London, who was not involved in the work (see full comment below). However, given just how rarely A673T turns up, she believes the study was still too small to confirm or rule out that the variant indeed protects against dementia.

What about other populations? A community study of 515 citizens of Vantaa, Finland, captured just one instance of A673T, in a woman who died at the age of 104 with no signs of AD (see Mar 2013 news). Two studies encompassing more than 11,000 Chinese people failed to find a single A673T allele (Ting et al., 2013Liu et al., 2014). “This variant may be primarily restricted to Icelandic and Scandinavian populations,” wrote Schellenberg and colleagues. Philippe Amouyel of the Institute Pasteur de Lille in France, who is also investigating A673T in European samples, told Alzforum in an email that his data also indicate the mutation may be limited to certain populations.—Amber Dance

Comments

  1. The study is large enough to conclude that this is a rare variant in this population. However, because the variant is so rare, the authors would have needed a much larger sample size to confirm or refute the initial observation that the variant is protective.

    In my opinion, the real value of these rare variants lies with the functional understanding they provide and not exactly with the number of people that carry them. The authors have a good discussion on functional value loosely framed by the amyloid cascade hypothesis.

    Rare variants are expected to have different allelic frequencies in different populations, so the only way to fully understand disease genetics will be to study very large numbers of cases and controls from different populations. Having said that, the original study hasn’t been independently replicated yet. Most probably this will need an independent large cohort from Northern Europe.

    View all comments by Rita Guerreiro
  2. APP*A673Ta rare Nordic mutation with a message to tell 

    Mutations causing early onset familial Alzheimer’s disease (AD) have been known for almost a quarter of a century, and functional analyses of these mutations have provided important clues to disease pathogenesis and pathways for therapy. Mutations conferring disease protection are less commonly found, but such mutations may provide even more straightforward links to therapy. Such an experiment of nature was reported in 2012 in the journal Nature (Jonsson et al., 2012). A rare mutation (APP*A673T, rs63750847) appeared to protect against AD. The frequency of this mutation was very low in Icelandic AD patients (0.13 percent) as compared to the general population (0.45 percent) and elderly population without cognitive decline (0.79 percent). The odds ratios for protection were very high, at 4.2 and 7.5. The genetic associations need to be confirmed, but recent data indicate that this one example is hard to confirm outside the Nordic countries/populations.

    Here, Li-San Wang et al. report a very large analysis of this mutation in the U.S. Caucasian population. They studied 8,943 AD cases and 10,480 cognitively normal controls. A smaller set of 862 Swedish AD cases and 707 Swedish cognitively normal controls was analyzed, too. Only one U.S. AD patient (with an age-of-onset of 89 years) and two of the elderly controls had the APP*A673T variant (carrier frequencies were 0.011 percent in cases and 0.019 percent in controls). All carriers had ancestors in Northern Europe. In the Swedes, this variant was found in three controls (0.42 percent), while none of the AD patients carried it. It is clear that such small numbers do not allow any conclusions to be made about the association of this mutation with protection from AD. Previous studies found no mutation carriers among several thousand Asian subjects, or among 1,674 late-onset AD cases and 2,644 elderly controls, all U.S. Caucasians (Ting et al., 2013; Liu et al., 2014; Bamne et al., 2014). All of these studies indicate that the APP*A673T mutation is very rare outside Nordic countries.

    Jonsson et al. (2012) already reported preliminary allele frequencies in the populations of Iceland (0.45 percent), Norway (0.21 percent), Sweden (0.42 percent), and Finland (0.51 percent). The Exome Aggregation Consortium database reports the following carrier frequencies (March 20, 2015): 18/3,307 (0.54 percent, or 1 in 184) in Finns, 36/33,369 (0.11 percent, or 1 in 927) in other Europeans, and 0/23,574 samples from African, East Asian, Latino, and South Asian populations. In a Finnish population-based autopsy study, the mutation was found in 1 out of 515 (0.2 percent) very elderly subjects (age ≥85 years). This single case lived until almost 105 and had virtually no Aβ deposition in brain parenchyma (Kero et al., 2013), which is quite an exceptional finding at this age. However, a single exceptional case is not a replication, although it fits with the idea of protection.

    Albeit rare, this experiment of nature is very illuminating and it shines very brightly on β-secretase. The A673T mutation is situated within the β-secretase recognition sequence (Maloney et al., 2014) at position two of the Aβ peptide sequence. Intriguingly, Jonsson et al. (2012) showed that this mutation changed the equilibrium between the two principal secretory pathways of APP (α vs. β). It decreased β-secretase and increased α-secretase cleavage of APP.

    The β-secretase pathway generates a specific secreted form of APP (termed sAPPβ) and (after a second γ-secretase cleavage) the Aβ-peptide, while α-secretase pathway generates sAPPα and precludes the formation of Aβ (via cleavage within the Aβ). These two pathways are central in regulating AD risk, and too much β-secretase activity has been considered detrimental. The findings from Iceland seem to reinforce this concept: β is bad. More recently Maloney et al. (2014) confirmed that the APP*A673T mutation reduces β-secretase cleavage products, but in addition, renders the Aβ1-42 peptide (but not Aβ1-40) less prone to aggregation. Hence both β-secretase inhibition and Aβ aggregation properties may operate.

    An overactive β-secretase pathway may be bad on at least two levels. First (Aβ level), by fostering the generation of Aβ peptides; the more these peptides are generated, the more they tend to form oligomers and other neurotoxic aggregates. Note that Aβ derived from APP*A673T carries an amino acid change and appears less aggregatory (Maloney et al., 2014). Second (APP-signaling level), by regulating homeostatic processes of the cell. The physiological function of APP is not yet fully clarified, but it was recently shown that sAPPα and sAPPβ have opposing signaling effects on cholesterol homeostasis in astroglia, hepatocytes, and fibroblasts; sAPPα increased cholesterol biosynthesis, while sAPPβ decreased it (Wang et al., 2014). Interestingly, the two famous proteins in AD, APP and APOE, both seem to be connected to cholesterol homeostasis. This is probably just one homeostatic difference in α- and β-secretase pathways; there may be other critical signaling events yet to be found. 

    The downstream mechanisms (after β-secretase cleavage) may be complex and multifactorial, but the good news is that there are already plenty of known modulators of the balance between α- and β-secretase pathways. For instance, many behavioral and lifestyle factors, e.g., sleep and nutrition (Kang et al., 2009; Hartmann et al., 2014), many old pharmacological agents (Fassbender et al., 2001; Endres et al., 2014), as well as novel β-secretase inhibitors (Yan and Vassar 2014), can modulate this balance. AD can be considered a homeostatic disease. The APP*A673T is an example that tilts the balance of one molecule slightly—and probably in a beneficial way.

    References:

    . Molecular mechanisms of Alzheimer disease protection by the A673T allele of amyloid precursor protein. J Biol Chem. 2014 Nov 7;289(45):30990-1000. Epub 2014 Sep 24 PubMed.

    . Investigation of an amyloid precursor protein protective mutation (A673T) in a North American case-control sample of late-onset Alzheimer's disease. Neurobiol Aging. 2014 Jul;35(7):1779.e15-6. Epub 2014 Jan 23 PubMed.

    . Increased CSF APPs-α levels in patients with Alzheimer disease treated with acitretin. Neurology. 2014 Nov 18;83(21):1930-5. Epub 2014 Oct 24 PubMed.

    . Simvastatin strongly reduces levels of Alzheimer's disease beta -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci U S A. 2001 May 8;98(10):5856-61. PubMed.

    . Absence of A673T variant in APP gene indicates an alternative protective mechanism contributing to longevity in Chinese individuals. Neurobiol Aging. 2013 Oct 12; PubMed.

    . A nutritional approach to ameliorate altered phospholipid metabolism in Alzheimer's disease. J Alzheimers Dis. 2014;41(3):715-7. PubMed.

    . Absence of A673T amyloid-β precursor protein variant in Alzheimer's disease and other neurological diseases. Neurobiol Aging. 2013 Oct;34(10):2441.e7-8. PubMed.

    . A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature. 2012 Aug 2;488(7409):96-9. PubMed.

    . Amyloid precursor protein (APP) A673T mutation in the elderly Finnish population. Neurobiol Aging. 2013 May;34(5):1518.e1-3. PubMed.

    . Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science. 2009 Nov 13;326(5955):1005-7. PubMed.

    . Targeting the β secretase BACE1 for Alzheimer's disease therapy. Lancet Neurol. 2014 Mar;13(3):319-29. Epub 2014 Feb 17 PubMed.

    . Amyloid precursor protein α- and β-cleaved ectodomains exert opposing control of cholesterol homeostasis via SREBP2. FASEB J. 2014 Feb;28(2):849-60. Epub 2013 Nov 18 PubMed.

    View all comments by Pentti Tienari

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References

Mutations Citations

  1. APP A673T (Icelandic)

News Citations

  1. Protective APP Mutation Found—Supports Amyloid Hypothesis
  2. In Shout-Out for Community Studies, Vantaa Finds Protective Mutation

Paper Citations

  1. . Investigation of an amyloid precursor protein protective mutation (A673T) in a North American case-control sample of late-onset Alzheimer's disease. Neurobiol Aging. 2014 Jul;35(7):1779.e15-6. Epub 2014 Jan 23 PubMed.
  2. . Absence of A673T amyloid-β precursor protein variant in Alzheimer's disease and other neurological diseases. Neurobiol Aging. 2013 Oct;34(10):2441.e7-8. PubMed.
  3. . Absence of A673T variant in APP gene indicates an alternative protective mechanism contributing to longevity in Chinese individuals. Neurobiol Aging. 2013 Oct 12; PubMed.

Further Reading

Papers

  1. . Molecular mechanisms of Alzheimer disease protection by the A673T allele of amyloid precursor protein. J Biol Chem. 2014 Nov 7;289(45):30990-1000. Epub 2014 Sep 24 PubMed.
  2. . A mutation protective against Alzheimer's disease renders amyloid β precursor protein incapable of mediating neurotoxicity. J Neurochem. 2014 Jul;130(2):291-300. Epub 2014 Apr 10 PubMed.
  3. . Novel polymorphism in the A4 region of the amyloid precursor protein gene in a patient without Alzheimer's disease. Neurology. 1993 Jun;43(6):1254-6. PubMed.
  4. . Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families. PLoS One. 2012;7(2):e31039. PubMed.
  5. . The Alzheimer disease protective mutation A2T modulates kinetic and thermodynamic properties of amyloid-β (Aβ) aggregation. J Biol Chem. 2014 Nov 7;289(45):30977-89. Epub 2014 Sep 24 PubMed.

Primary Papers

  1. . Rarity of the Alzheimer disease-protective APP A673T variant in the United States. JAMA Neurol. 2015 Feb;72(2):209-16. PubMed.