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Wang LS, Naj AC, Graham RR, Crane PK, Kunkle BW, Cruchaga C, Murcia JD, Cannon-Albright L, Baldwin CT, Zetterberg H, Blennow K, Kukull WA, Faber KM, Schupf N, Norton MC, Tschanz JT, Munger RG, Corcoran CD, Rogaeva E, Alzheimer's Disease Genetics Consortium, Lin CF, Dombroski BA, Cantwell LB, Partch A, Valladares O, Hakonarson H, St George-Hyslop P, Green RC, Goate AM, Foroud TM, Carney RM, Larson EB, Behrens TW, Kauwe JS, Haines JL, Farrer LA, Pericak-Vance MA, Mayeux R, Schellenberg GD, National Institute on Aging-Late-Onset Alzheimer’s Disease (NIA-LOAD) Family Study, Albert MS, Albin RL, Apostolova LG, Arnold SE, Barber R, Barmada MM, Barnes LL, Beach TG, Becker JT, Beecham GW, Beekly D, Bennett DA, Bigio EH, Bird TD, Blacker D, Boeve BF, Bowen JD, Boxer A, Burke JR, Buxbaum JD, Cairns NJ, Cao C, Carlson CS, Carroll SL, Chui HC, Clark DG, Cribbs DH, Crocco EA, DeCarli C, DeKosky ST, Demirci FY, Dick M, Dickson DW, Duara R, Ertekin-Taner N, Fallon KB, Farlow MR, Ferris S, Frosch MP, Galasko DR, Ganguli M, Gearing M, Geschwind DH, Ghetti B, Gilbert JR, Glass JD, Graff-Radford NR, Growdon JH, Hamilton RL, Hamilton-Nelson KL, Harrell LE, Head E, Honig LS, Hulette CM, Hyman BT, Jarvik GP, Jicha GA, Jin LW, Jun G, Kamboh MI, Karydas A, Kaye JA, Kim R, Koo EH, Kowall NW, Kramer JH, Kramer P, LaFerla FM, Lah JJ, Leverenz JB, Levey AI, Li G, Lieberman AP, Lopez OL, Lunetta KL, Lyketsos CG, Mack WJ, Marson DC, Martin ER, Martiniuk F, Mash DC, Masliah E, McCormick WC, McCurry SM, McDavid AN, McKee AC, Mesulam MM, Miller BL, Miller CA, Miller JW, Montine TJ, Morris JC, Murrell JR, Olichney JM, Parisi JE, Perry W, Peskind E, Petersen RC, Pierce A, Poon WW, Potter H, Quinn JF, Raj A, Raskind M, Reiman EM, Reisberg B, Reitz C, Ringman JM, Roberson ED, Rosen HJ, Rosenberg RN, Sano M, Saykin AJ, Schneider JA, Schneider LS, Seeley WW, Smith AG, Sonnen JA, Spina S, Stern RA, Tanzi RE, Thornton-Wells TA, Trojanowski JQ, Troncoso JC, Tsuang DW, 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. Rarity of the Alzheimer disease-protective APP A673T variant in the United States. JAMA Neurol. 2015 Feb;72(2):209-16. PubMed.
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Van Andel Institute
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.
University of Helsinki
APP*A673T—a 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:
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