0
March 12, 1997, Vol 277, No. 10 >
ARTICLE | March 12, 1997

Exploring the Etiology of Alzheimer Disease Using Molecular Genetics FREE

Corinne L. Lendon, PhD; Frank Ashall, DPhil; Alison M. Goate, DPhil
[+] Author Affiliations

Reprints: Alison M. Goate, DPhil, Department of Psychiatry, Washington University School of Medicine, 4940 Children's PI, St Louis, MO 63110.


JAMA. 1997;277(10):825-831. doi:10.1001/jama.1997.03540340059034
Text Size: A A A
Published online
Article
References

Alzheimer disease (AD), the most common cause of dementia in the elderly, exists in both familial and sporadic forms. Genetic studies have led to the identification of 3 genes, β-amyloid precursor protein (APP), presenilin-1 (PS1), and presenilin-2 (PS2), which, when mutated, can cause familial forms of AD. Mutations in each of these genes result in elevated levels of Aβ42/43, a proteolytic processing fragment of APP that is deposited in brains of AD patients. Transgenic mice carrying AD-causing mutations in APP develop spontaneous agerelated β-amyloid (Aβ) deposition and memory impairment. Genetic linkage and association studies have also shown that the ϵ4 allele of the apolipoprotein E (APOE) gene increases risk for AD in a dose-dependent manner in both familial and sporadic forms of AD and may account for as much as 50% of the attributable risk. APOE genotyping may be useful both as an adjunct to diagnosis and in identifying patient groups for therapeutic intervention. While the biological basis for the association of APOEϵ4 with AD is not known, age of onset and Aβ deposition are positively correlated with ϵ4 allele dosage in some cases, suggesting that this risk may also be mediated directly or indirectly through Aβ. Because 50% of AD cases have no APOE ϵ4 alleles and families showing mendelian inheritance of AD exist in whom there are no mutations in any of the APP, PS1, or PS2genes, it is likely that there are additional AD risk factors, both genetic and environmental, still to be identified.

REFERENCES

1 +
McKhann G, Drachman D, Folstein M, et al.  Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease . Neurology . 1984;;34:939-944.
2 +
Glenner GG, Wong CW.  Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein . Biochem Biophys Res Commun . 1984;;120:885-890.
3 +
Goldgaber D, Lerman MI, McBride OW, Saffiotti U, Gajdusek DC.  Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease . Science . 1987;;235:877-880.
4 +
Kang J, Lemaire HG, Unterbeck A, et al.  The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor . Nature . 1987;;325:733-736.
5 +
Tanzi RE, Gusella JF, Watkins PC, et al.  Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus . Science . 1987;;235:880-884.
6 +
Robakis NK, Wisniewski HM, Jenkins EC, et al.  Chromosome 21q21 sublocalisation of gene encoding beta-amyloid peptide in cerebral vessels and neuritic (senile) plaques of people with Alzheimer disease and Down syndrome . Lancet . 1987;;1:384-385.
7 +
Lee VM-Y, Trojanowski JQ.  Tau proteins and their significance in the pathobiology of Alzheimer's disease . In: Goate A, Ashall F, eds. Pathobiology of Alzheimer's Disease . London, United Kingdom: Academic Press; 1995;:41-58.
8 +
Wang J-Z, Grundke-Iqbal I, Iqbal K.  Glycosylation of microtubule-associated protein tau: an abnormal posttranslational modification in Alzheimer's disease . Nat Med . 1996;;2:871-875.
9 +
David KL, Haroutunian V.  Strategies for the treatment of AD . Neurology . 1993;;43( (suppl 4) ):S52-S55.
10 +
Knapp MJ, Knopman DS, Solomon PR, Pendlebury WW, Davis CS, Gracon SI.  A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease . JAMA . 1994;;271:985-991.
11 +
Morris JC.  The neurology of aging: normal versus pathologic change . Geriatrics . 1991;;46:47-54.
12 +
Breteler M, Claus J, van Duijn C, Launer L, Hofman A.  Epidemiology of Alzheimer's disease . Epidemiol Rev . 1992;;14:59-82.
13 +
van Duijn C.  Epidemiology of the dementias: recent developments and new approaches . J Neurol Neurosurg Psychiatry . 1996;;60:478-488.
14 +
Bachman DL, Wolf PA, Linn R, et al.  Prevalence of dementia and probable senile dementia of the Alzheimer's type in the Framingham Study . Neurology . 1992;;42:1115-1140.
15 +
Stern Y, Gurland B, Tatemichi TK, et al.  Influence of education and occupation on the incidence of Alzheimer's disease . JAMA . 1994;;271:1004-1010.
16 +
Snowdon D, Kemper S, Mortimer J, et al.  Linguistic ability in early life and cognitive function and Alzheimer's disease in late life: findings from the Nun Study . JAMA . 1996;;275:528-532.
17 +
van Duijn C, Tanja T, Haaxma R, et al.  Head trauma and the risk of Alzheimer's disease . Am J Epidemiol . 1992;;135:775-782.
18 +
Nee LE, Polinsky RJ, Eldridge R, et al.  A family with histologically confirmed Alzheimer's disease . Arch Neurol . 1983;;40:203-208.
19 +
Haltia M, Viitanen M, Sulkava R, et al.  Chromosome 14-encoded Alzheimer's disease: genetic and clinicopathologic description . Neurology . 1994;;36:362-367.
20 +
Lampe TH, Bird TD, Nochlin D, et al.  Phenotype of chromosome 14-linked Alzheimer's disease: genetic and clinicopathological description . Ann Neurol . 1994;;34:368-378.
21 +
Mann DM, Yates PO, Marcyniuk B, Ravindra CR.  The topography of plaques and tangles in Down's syndrome patients of different ages . Neuropathol Appl Neurobiol . 1986;;12:447-457.
22 +
St George-Hyslop PH, Tanzi RE, Polinsky RJ, et al.  The genetic defect causing familial Alzheimer's disease maps on chromosome 21 . Science . 1987;;235:885-890.
23 +
Schellenberg GD, Bird TD, Wijsman EM, et al.  Absence of linkage of chromosome 21q21 markers to familial Alzheimer's disease . Science . 1988;;241:1507-1510.
24 +
Pericak-Vance MA, Yamaoka LH, Haynes CS, et al.  Genetic linkage studies in familial Alzheimer's disease . Exp Neurol . 1988;;102:271-279.
25 +
Goate AM, Haynes AR, Owen MJ, et al.  Predisposing locus for Alzheimer's disease on chromosome 21 . Lancet . 1989;;1:352-355.
26 +
St George-Hyslop PH, Haines JL, Farrer LA, et al.  Genetic linkage studies suggest that Alzheimer's disease is not a single homogeneous disorder . Nature . 1990;;347:194-197.
27 +
Goate A, Chartier-Harlin MC, Mullan M, et al.  Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease . Nature . 1991;;349:704-706.
28 +
Chartier-Harlin MC, Crawford F, Houlden H, et al.  Early onset Alzheimer's disease caused by mutations at codon 717 of the β-amyloid precursor protein gene . Nature . 1991;;353:844-846.
29 +
Hendriks L, van Duijn C, Cras P, et al.  Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the β-amyloid precursor protein gene . Nat Genet . 1992;;1:218-221.
30 +
Mullan M, Crawford F, Axelman K, et al.  A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of β-amyloid . Nat Genet . 1992;;1:345-347.
31 +
Murrell J, Farlow M, Ghetti B, Benson M.  A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease . Science . 1991;; 254:97-99.
32 +
Hardy J. Genetic analyses of the presenilins in Alzheimer's disease. Presented at the 1997 Keystone Symposia: Molecular Mechanisms in Alzheimer's Disease; February 2,1997; Tamarron, Colo.
33 +
Sorbi S, Nacmias B, Forleo P, et al.  Epistatic effect of APP717 mutation and apolipoprotein E genotype in familial Alzheimer's disease . Ann Neurol . 1995;;38:124-127.
34 +
Sorbi S, Nacmias B, Forleo P, et al.  Missense mutation of S182 gene in Italian families with earlyonset Alzheimer's disease . Lancet . 1995;;346:439.
35 +
Fidani L, Rooke K, Chartier-Harlin MC, et al.  Screening for mutations in the open reading frame and promoter of the β-amyloid precursor protein gene in familial Alzheimer's disease: identification of a further family with APP717 Val→Ile . Hum Mol Genet . 1992;;1:165-168.
36 +
Brooks W, Martins R, De Voecht J, et al.  A mutation in codon 717 of the amyloid precursor protein gene in an Australian family with Alzheimer's disease . Neurosci Lett . 1995;;199:183-186.
37 +
Campion D, Brice A, Hannequin D, et al.  No founder effect in three novel Alzheimer's disease families with APP717 Val→Ile mutation . J Med Genet . 1996;;33:661-664.
38 +
Karlinsky H, Vaula G, Haines JL, et al.  Molecular and prospective phenotypic characterization of a pedegree with familial Alzheimer's disease and a missense mutation in codon 717 of the β-amyloid precursor protein gene . Neurology . 1992;;42:1445-1453.
39 +
Naruse S, Igarashi S, Kobayashi H, et al.  Missense mutation Val→Ile in exon 17 of amyloid precursor protein gene in Japanese familial Alzheimer's disease . Lancet . 1991;;337:978-979.
40 +
Yoshioka K, Miki T, Katsuya T, Ogihara T, Sakaki Y.  The 717Val→Ile substitution in amyloid precursor protein is associated with familial Alzheimer's disease regardless of ethnic groups . Biochem Biophys Res Commun . 1991;;178:1141-1146.
41 +
Schellenberg GD, Anderson L, O'dahl S, et al.  APP717, APP693, and PRIP gene mutations are rare in Alzheimer's disease . Am J Hum Genet . 1991;;49:511-517.
42 +
Tanzi R, Vaula G, Romano D, et al.  Assessment of amyloid beta-protein pecursor gene mutations in a large set of familial and sporadic Alzheimer disease cases . Am J Hum Genet . 1992;;51:273-282.
43 +
Mullan M, Tsuji S, Mild T, et al.  Clinical comparison of Alzheimer's disease in pedigrees with codon 717 Val-Ile mutation in the amyloid precursor protein gene . Neurobiol Aging . 1993;;14:407-419.
44 +
Games D, Adams D, Alessandrini R, et al.  Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein . Nature . 1995;;373:523-527.
45 +
Hsiao K, Chapman P, Nilsen S, et al.  Correlative memory deficits, Aβ elevation and amyloid plaques in transgenic mice . Science . 1996;;274:99-102.
46 +
Schellenberg GD, Bird TD, Wijsman EM, et al.  Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14 . Science . 1992;;258:668-671.
47 +
Van Broeckhoven C, Backhovens H, Cruts M, et al.  Mapping of a gene predisposing to early-onset Alzheimer's disease to chromosome 14q24.3 . Nat Genet . 1992;;2:335-339.
48 +
St George-Hyslop P, Haines J, Rogaev E, et al.  Genetic evidence for a novel familial Alzheimer's dis.ease locus on chromosome 14 . Nat Genet . 1992;;2:330-334.
49 +
Mullan M, Houlden H, Windelspecht M, et al.  A locus for familial early-onset Alzheimer's disease on the long arm of chromosome 14, proximal to the α1-antichymotrypsin gene . Nat Genet . 1992;;2:340-342.
50 +
Sherrington R, Rogaev E, Liang Y, et al.  Cloning of a gene bearing mis-sense mutations in early-onset familial Alzheimer's disease . Nature . 1995;;375:754-760.
51 +
Van Broeckhoven C.  Presenilins in Alzheimer's disease . Nat Genet . 1995;;11:230-232.
52 +
Boteva K, Vitek M, Mitsuda H, et al.  Mutation analysis of presenilin 1 gene in Alzheimer's disease . Lancet . 1996;;347:130-131.
53 +
Campion D, Flaman J-M, Brice A, et al.  Mutations of the presenilin 1 gene in families with earlyonset Alzheimer's disease . Hum Mol Genet . 1995;;4:2373-2377.
54 +
Clark RF, Hutton M, Fuldner RA, et al.  The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families . Nat Genet . 1995;;11:219-222.
55 +
Cruts M, Backhovens H, Wang S-Y, et al.  Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3 . Hum Mol Genet . 1995;;4:2363-2371.
56 +
Hutton M, Busfield F, Wragg M, et al.  Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease . Neuroreport . 1996;;7:801-805.
57 +
Perez-Tur J, Froelich S, Prihar G, et al.  A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin-1 gene . Neuroreport . 1995;;7:297-301.
58 +
Pflieger-Bruss S, Hanf V, Behnisch P, Hagenmaier H, Rune G.  Familial Alzheimer's disease associated with S182 codon 286 mutation . Lancet . 1995;; 346:1040.
59 +
Wasco W, Pettingell WP, Jondro PD, et al.  Familial Alzheimer's chromosome 14 mutations . Nat Med . 1995;;1:848.
60 +
Tanahashi H, Mitsunaga Y, Takahashi K, et al.  Missense mutation of S182 gene in Japanese familial Alzheimer's disease . Lancet . 1995;;346:440.
61 +
Doan A, Thinakaran G, Borchelt D, et al.  Protein topology of presenilin . Neuron . 1996;;17:1023-1030.
62 +
Li X, Greenwald I.  Membrane topology of the C elegans SEL-12 presenilin . Neuron . 1996;;17:1015-1021.
63 +
Levy-Lahad E, Wijsman EM, Nemens E, et al.  A familial Alzheimer's disease locus on chromosome 1 . Science . 1995;;269:970-973.
64 +
Levy-Lahad E, Wasco W, Poorkaj P, et al.  Candidate gene for the chromosome 1 familial Alzheimer's disease locus . Science . 1995;;269:973-977.
65 +
Rogaev EI, Sherrington R, Rogaeva EA, et al.  Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene . Nature . 1995;; 376:775-778.
66 +
Sherrington R, Froelich S, Sorbi S, et al.  Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant . Hum Mol Genet . 1996;;5:985-988.
67 +
Prihar G, Fuldner RA, Perez-Tur J, et al.  Structure and alternate splicing of the presenilin 2 gene . Neuroreport . 1996;;7:1680-1684.
68 +
Tanzi RE, McClatchey AI, Lamberti ED, et al.  Protease inhibitor domain encoded by an amyloid precursor mRNA associated with Alzheimer's disease . Nature . 1988;;331:528-530.
69 +
Esch FS, Keim PS, Beattie EC, et al.  Cleavage of amyloid beta peptide during constitutive processing of its precursor . Science . 1990;;248:1122-1124.
70 +
Sisodia S, Koo E, Beyreuther K, Unterbeck A, Price D.  Evidence that beta-amyloid protein in Alzheimer's disease is not derived by normal processing . Science . 1990;;248:492-494.
71 +
Haass C, Schlossmacher M, Hung A, et al.  Amyloid β-peptide is produced by cultured cells during normal metabolism . Nature . 1992;;359:322-325.
72 +
Seubert P, Vigo-Pelfrey C, Esch F, et al.  Isolation and quantification of soluble Alzheimer's β-peptide from biological fluids . Nature . 1992;;359:325-327.
73 +
Anderson J, Chen Y, Kim K, Robakis N.  An alternative secretase cleavage produces soluble Alzheimer amyloid precursor protein containing a potentially amyloidogenic sequence . J Neurochem . 1992;; 59:2328-2331.
74 +
Smith RP, Higuchi DA, Broze GJJ.  Platelet coagulation factor XIa-inhibitor, a form of Alzheimer amyloid precursor protein . Science . 1990;;248:1126-1128.
75 +
Van Nostrand WE, Schmaier AH, Farrow JS, Cunningham DD.  Protease nexin-II (amyloid betaprotein precursor): a platelet alpha-granule protein . Science . 1990;;248:745-748.
76 +
Roch J, Shapiro P, Sundsmo M, et al.  Bacterial expression, purification, and functional mapping of the amyloid beta/A4 protein precursor . J Biol Chem . 1992;;267:2214-2221.
77 +
Schubert D, Jin L, Saitoh T, Cole G.  The regulation of amyloid beta protein precursor secretion and its modulatory role in cell adhesion . Neuron . 1989;;3:689-694.
78 +
Mattson M, Cheng B, Culwell A, et al.  Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the β-amyloid precursor protein . Neuron . 1993;;10:243-254.
79 +
Yankner BA, Duffy LK, Kirschner DA.  Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides . Science . 1990;;250:279-282.
80 +
Jarrett J, Berger E, Lansbury P.  The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease . Biochemistry . 1993;;32:4693-4697.
81 +
Dovey H, Suomesaari-Chrysler S, Lieberburg I, Sinha S, Kiem P.  Cells with a familial Alzheimer's disease mutation produce authentic β-peptide . Neuroreport . 1993;;4:1039-1042.
82 +
Scheuner D, Eckman C, Jensen M, et al.  Secreted amyloid-β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease . Nat Med . 1996;;2:864-870.
83 +
Duff K, Eckman C, Hutton M, et al.  Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1 . Nature . 1996;;383:710-713.
84 +
Borchelt D, Thinakaran G, Eckman C, et al.  Familial Alzheimer's disease-linked presenilin 1 variants elevate Aβ1-42/1-40 ratio in vitro and in vivo . Neuron . 1996;;17:1005-1013.
85 +
Citron M, Westaway D, Xia W, et al.  Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid βprotein in both transfected cells and transgenic mice . Nat Med . 1997;;3:67-72.
86 +
Iwatsubo T, Odaka A, Suzuki N, et al.  Visualization of Aβ42(43) and Aβ40 in senile plaques with end-specific Aβ monoclonals: evidence that an initially deposited species is Aβ42(43) . Neuron . 1994;; 13:45-53.
87 +
Lemere C, Lopera F, Kosik K, et al.  The E280A presenilin 1 Alzheimer mutation produces increased Aβ42 deposition and severe cerebellar pathology . Nat Med . 1996;;2:1146-1150.
88 +
Mann D, Iwatsubo T, Cairns N, et al.  Amyloid β protein (Aβ) deposition in chromosome 14-linked Alzheimer's disease: predominance of Aβ42(43) . Ann Neurol . 1996;;40:149-156.
89 +
Kovacs D, Fausett H, Page K, et al.  Alzheimerassociated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells . Nat Med . 1996;;2:224-229.
90 +
Thinakaran G, Borchelt D, Lee M, et al.  Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo . Neuron . 1996;;17:181-190.
91 +
Levitan D, Greenwald I.  Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene . Nature . 1995;; 377:351-354.
92 +
Levitan D, Doyle T, Brousseau D, et al.  Assessment of normal and mutant human presenilin function in Caenorhabditis elegans . Proc Nati Acad Sci USA . 1996;;93:14940-14944.
93 +
Vito P, Lacana E, D'adamio L.  Interfering with apoptosis: Ca2+-binding protein ALG-2 and Alzheimer's disease gene ALG3 . Science . 1996;;271:521-525.
94 +
Wolozin B, Iwasaki K, Vito P, et al.  Participation of presenilin 2 in apoptosis: enhanced basal activity conferred by an Alzheimer mutation . Science . 1996;; 274:1710-1712.
95 +
Strittmatter WJ, Saunders AM, Schmechel D, et al.  Apolipoprotein E: high-avidity binding to βamyloid and increased frequency of type 4 allele in lateonset familial Alzheimer's disease . Proc Natl Acad Sci U S A . 1993;;90:1977-1981.
96 +
van Duijn C, de Knijff P, Wehnert A, et al.  Apolipoprotein ϵ4 allele in a population-based study of early-onset Alzheimer's disease . Nat Genet . 1994;;7:74-77.
97 +
Corder E, Saunders A, Strittmatter W, et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families . Science . 1993;;261:921-923.
98 +
Poirier J, Davignon J, Kogan S, Bertrand P, Gauthier S.  Apolipoprotein E polymorphism and Alzheimer's disease . Lancet . 1993;;342:697-699.
99 +
Roses A.  Apolipoprotein E affects the rate of Alzheimer disease expression: βamyloid burden is a secondary consequence dependent on APOE genotype and duration of disease . J Neuropathol Exp Neurol . 1994;;53:429-437.
100 +
Osuntokun B, Sahota A, Ogunniyi A, et al.  Lack of an association between apolipoprotein E epsilon 4 and Alzheimer's disease in elderly Nigerians . Ann Neurol . 1995;;38:463-465.
101 +
Maestre G, Orman R, Stern Y, et al.  Apolipoprotein E and Alzheimer's disease: ethnic variation in genotypic risks . Ann Neurol . 1995;;37:254-259.
102 +
Hendrie H, Hall K, Hui S, et al.  Apolipoprotein E genotypes and Alzheimer's disease in a community study of elderly African Americans . Ann Neurol . 1995;;37:118-120.
103 +
Marder K, Maestre G, Cote L, et al.  The apolipoprotein epsilon 4 allele in Parkinson's disease with and without dementia . Neurology . 1994;;44:1330-1331.
104 +
Saunders A, Schmader K, Breitner J, et al.  Apolipoprotein E ϵ4 allele distributions in late onset Alzheimer's disease and in other amyloid forming diseases . Lancet . 1993;;342:710-711.
105 +
Kawamata J, Tanaka S, Shimohama S, Ueda K, Kimura J.  Apolipoprotein E polymorphism in Japanese patients with Alzheimer's disease or vascular dementia . J Neurol Neurosurg Psychiatry . 1994;;57:1414-1416.
106 +
Isoe K, Urakami K, Sato K, Takahashi K.  Apolipoprotein E in patients with dementia of the Alzheimer type and vascular dementia . Acta Neurol Scand . 1996;;93:133-137.
107 +
Lippa C, Smith T, Saunders A, et al.  Apolipo protein E genotype and Lewy body disease . Neurology . 1995;;45:97-103.
108 +
St Clair D, Norman J, Perry R, et al.  Apolipo protein E epsilon 4 allele frequency in patients with Lewy body disease . Neurosci Lett . 1994;;176:45-46.
109 +
Gearing M, Mori H, Mirra S.  Aβ-peptide length and apolipoprotein E genotype in Alzheimer's disease . Ann Neurol . 1996;;39:395-399.
110 +
Corder E, Saunders A, Risch N, et al.  Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease . Nat Genet . 1994;;7:180-183.
111 +
Chartier-Harlin M-C, Parfitt M, Legrain S, et al.  Apolipoprotein E ϵ4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer's disease: analysis of the 19q13.2 chromosomal region . Hum Mol Genet . 1994;;3:569-574.
112 +
Talbot C, Lendon C, Craddock N, et al.  Protection against Alzheimer's disease with ApoE ϵ2 . Lancet . 1994;;343:1432-1433.
113 +
van Duijn C, de Knijff P, Wehnert A, et al.  The apolipoprotein E ϵ2 allele is associated with increased risk of early onset Alzheimer's disease and a reduced survival . Ann Neurol . 1995;;37:605-610.
114 +
St George-Hyslop P, Crapper McLachlan D, Tuda T, et al.  Alzheimer's disease and possible gene interaction . Science . 1994;;263:537.
115 +
Hardy J, Houlden H, Collinge J, et al.  Apolipoprotein E genotype and Alzheimer's disease . Lancet . 1993;;342:737-738.
116 +
Van Broeckhoven C, Backhovens H, Cruts M, et al.  APOE genotype does not modulate age of onset in families with chromosome 14 encoded Alzheimer's disease . Neurosci Lett . 1994;;169:179-180.
117 +
Poirier J, Delisle M, Quirion R, et al.  Apolipoprotein ϵ4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer's disease . Proc Natl Acad Sci U S A . 1995;;92:12260-12264.
118 +
Mayeux R, Ottman R, Maestre G, et al.  Synergistic effects of traumatic head injury and apolipoprotein-epsilon 4 in patients with Alzheimer's disease . Neurology . 1995;;45:555-557.
119 +
Katzman R, Galasko D, Saitoh T, et al.  Apolipoprotein-ϵ4 and head trauma: synergistic or additive risks? Neurology . 1996;;46:889-891.
120 +
Nicoll J, Roberts GW, Graham D.  Apolipoprotein E 4 allele is associated with deposition of amyloid beta-protein following head injury . Nat Med . 1995;; 1:135-148.
121 +
Namba Y, Tomonaga M, Kawasaki H, Otomo E, Ikeda K.  Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease and kuru plaque amyloid in Creutzfeldt-Jakob disease . Brain Res . 1991;;541:163-166.
122 +
Zhou Z, Smith J, Greengard P, Gandy S.  Alzheimer amyloid-β peptide forms denaturant-resistant complex with type ϵ3 but not type ϵ4 isoform of native apolipoprotein E . Mol Med . 1996;;2:175-180.
123 +
Strittmatter W, Weisgraber K, Huang D, et al.  Binding of human apolipoprotein E to synthetic amyloid beta-peptide: isoform-specific effects and implications for late-onset Alzheimer disease . Proc Natl Acad Sci U S A . 1993;;90:8098-8102.
124 +
Ma J, Yee A, Brewer HB, Das S, Potter H.  Amyloid-associated proteins α1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer β-protein into filaments . Nature . 1994;;372:92-94.
125 +
LaDu M, Falduto M, Manelli A, et al.  Isoform-specific binding of apolipoprotein E to β-amyloid . J Biol Chem . 1994;;269:23403-23406.
126 +
Strittmatter W, Saunders A, Goedert M, et al.  Isoform-specific interactions of apolipoprotein E with microtubule associated protein tau: implications for Alzheimer's disease . Proc Natl Acad Sci U S A . 1994;;91:11183-11186.
127 +
Nathan B, Bellosta S, Sanan D, et al.  Differential effects of apolipoprotein E3 and E4 on neuronal growth in vitro . Science . 1994;;264:850-852.
128 +
Holtzman D, Pitas R, Kilbridge J, et al.  Low density lipoprotein receptor-related protein mediates apolipoprotein E-dependent neurite outgrowth in a central nervous system-derived neuronal cell line . Proc Natl Acad Sci U S A . 1995;;92:9480-9484.
129 +
Miyata M, Smith J.  Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and β-amyloid peptides . Nat Genet . 1996;;14:55-61.
130 +
LaDu M, Pederson T, Frail D, et al.  Purification of ApoE attenuates isoform-specific binding to β-amyloid . J Biol Chem . 1995;;270:9039-9042.

Figures

Tables

Interactive Graphics

Video

Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
McKhann G, Drachman D, Folstein M, et al.  Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease . Neurology . 1984;;34:939-944.
2 +
Glenner GG, Wong CW.  Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein . Biochem Biophys Res Commun . 1984;;120:885-890.
3 +
Goldgaber D, Lerman MI, McBride OW, Saffiotti U, Gajdusek DC.  Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease . Science . 1987;;235:877-880.
4 +
Kang J, Lemaire HG, Unterbeck A, et al.  The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor . Nature . 1987;;325:733-736.
5 +
Tanzi RE, Gusella JF, Watkins PC, et al.  Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus . Science . 1987;;235:880-884.
6 +
Robakis NK, Wisniewski HM, Jenkins EC, et al.  Chromosome 21q21 sublocalisation of gene encoding beta-amyloid peptide in cerebral vessels and neuritic (senile) plaques of people with Alzheimer disease and Down syndrome . Lancet . 1987;;1:384-385.
7 +
Lee VM-Y, Trojanowski JQ.  Tau proteins and their significance in the pathobiology of Alzheimer's disease . In: Goate A, Ashall F, eds. Pathobiology of Alzheimer's Disease . London, United Kingdom: Academic Press; 1995;:41-58.
8 +
Wang J-Z, Grundke-Iqbal I, Iqbal K.  Glycosylation of microtubule-associated protein tau: an abnormal posttranslational modification in Alzheimer's disease . Nat Med . 1996;;2:871-875.
9 +
David KL, Haroutunian V.  Strategies for the treatment of AD . Neurology . 1993;;43( (suppl 4) ):S52-S55.
10 +
Knapp MJ, Knopman DS, Solomon PR, Pendlebury WW, Davis CS, Gracon SI.  A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease . JAMA . 1994;;271:985-991.
11 +
Morris JC.  The neurology of aging: normal versus pathologic change . Geriatrics . 1991;;46:47-54.
12 +
Breteler M, Claus J, van Duijn C, Launer L, Hofman A.  Epidemiology of Alzheimer's disease . Epidemiol Rev . 1992;;14:59-82.
13 +
van Duijn C.  Epidemiology of the dementias: recent developments and new approaches . J Neurol Neurosurg Psychiatry . 1996;;60:478-488.
14 +
Bachman DL, Wolf PA, Linn R, et al.  Prevalence of dementia and probable senile dementia of the Alzheimer's type in the Framingham Study . Neurology . 1992;;42:1115-1140.
15 +
Stern Y, Gurland B, Tatemichi TK, et al.  Influence of education and occupation on the incidence of Alzheimer's disease . JAMA . 1994;;271:1004-1010.
16 +
Snowdon D, Kemper S, Mortimer J, et al.  Linguistic ability in early life and cognitive function and Alzheimer's disease in late life: findings from the Nun Study . JAMA . 1996;;275:528-532.
17 +
van Duijn C, Tanja T, Haaxma R, et al.  Head trauma and the risk of Alzheimer's disease . Am J Epidemiol . 1992;;135:775-782.
18 +
Nee LE, Polinsky RJ, Eldridge R, et al.  A family with histologically confirmed Alzheimer's disease . Arch Neurol . 1983;;40:203-208.
19 +
Haltia M, Viitanen M, Sulkava R, et al.  Chromosome 14-encoded Alzheimer's disease: genetic and clinicopathologic description . Neurology . 1994;;36:362-367.
20 +
Lampe TH, Bird TD, Nochlin D, et al.  Phenotype of chromosome 14-linked Alzheimer's disease: genetic and clinicopathological description . Ann Neurol . 1994;;34:368-378.
21 +
Mann DM, Yates PO, Marcyniuk B, Ravindra CR.  The topography of plaques and tangles in Down's syndrome patients of different ages . Neuropathol Appl Neurobiol . 1986;;12:447-457.
22 +
St George-Hyslop PH, Tanzi RE, Polinsky RJ, et al.  The genetic defect causing familial Alzheimer's disease maps on chromosome 21 . Science . 1987;;235:885-890.
23 +
Schellenberg GD, Bird TD, Wijsman EM, et al.  Absence of linkage of chromosome 21q21 markers to familial Alzheimer's disease . Science . 1988;;241:1507-1510.
24 +
Pericak-Vance MA, Yamaoka LH, Haynes CS, et al.  Genetic linkage studies in familial Alzheimer's disease . Exp Neurol . 1988;;102:271-279.
25 +
Goate AM, Haynes AR, Owen MJ, et al.  Predisposing locus for Alzheimer's disease on chromosome 21 . Lancet . 1989;;1:352-355.
26 +
St George-Hyslop PH, Haines JL, Farrer LA, et al.  Genetic linkage studies suggest that Alzheimer's disease is not a single homogeneous disorder . Nature . 1990;;347:194-197.
27 +
Goate A, Chartier-Harlin MC, Mullan M, et al.  Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease . Nature . 1991;;349:704-706.
28 +
Chartier-Harlin MC, Crawford F, Houlden H, et al.  Early onset Alzheimer's disease caused by mutations at codon 717 of the β-amyloid precursor protein gene . Nature . 1991;;353:844-846.
29 +
Hendriks L, van Duijn C, Cras P, et al.  Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the β-amyloid precursor protein gene . Nat Genet . 1992;;1:218-221.
30 +
Mullan M, Crawford F, Axelman K, et al.  A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of β-amyloid . Nat Genet . 1992;;1:345-347.
31 +
Murrell J, Farlow M, Ghetti B, Benson M.  A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease . Science . 1991;; 254:97-99.
32 +
Hardy J. Genetic analyses of the presenilins in Alzheimer's disease. Presented at the 1997 Keystone Symposia: Molecular Mechanisms in Alzheimer's Disease; February 2,1997; Tamarron, Colo.
33 +
Sorbi S, Nacmias B, Forleo P, et al.  Epistatic effect of APP717 mutation and apolipoprotein E genotype in familial Alzheimer's disease . Ann Neurol . 1995;;38:124-127.
34 +
Sorbi S, Nacmias B, Forleo P, et al.  Missense mutation of S182 gene in Italian families with earlyonset Alzheimer's disease . Lancet . 1995;;346:439.
35 +
Fidani L, Rooke K, Chartier-Harlin MC, et al.  Screening for mutations in the open reading frame and promoter of the β-amyloid precursor protein gene in familial Alzheimer's disease: identification of a further family with APP717 Val→Ile . Hum Mol Genet . 1992;;1:165-168.
36 +
Brooks W, Martins R, De Voecht J, et al.  A mutation in codon 717 of the amyloid precursor protein gene in an Australian family with Alzheimer's disease . Neurosci Lett . 1995;;199:183-186.
37 +
Campion D, Brice A, Hannequin D, et al.  No founder effect in three novel Alzheimer's disease families with APP717 Val→Ile mutation . J Med Genet . 1996;;33:661-664.
38 +
Karlinsky H, Vaula G, Haines JL, et al.  Molecular and prospective phenotypic characterization of a pedegree with familial Alzheimer's disease and a missense mutation in codon 717 of the β-amyloid precursor protein gene . Neurology . 1992;;42:1445-1453.
39 +
Naruse S, Igarashi S, Kobayashi H, et al.  Missense mutation Val→Ile in exon 17 of amyloid precursor protein gene in Japanese familial Alzheimer's disease . Lancet . 1991;;337:978-979.
40 +
Yoshioka K, Miki T, Katsuya T, Ogihara T, Sakaki Y.  The 717Val→Ile substitution in amyloid precursor protein is associated with familial Alzheimer's disease regardless of ethnic groups . Biochem Biophys Res Commun . 1991;;178:1141-1146.
41 +
Schellenberg GD, Anderson L, O'dahl S, et al.  APP717, APP693, and PRIP gene mutations are rare in Alzheimer's disease . Am J Hum Genet . 1991;;49:511-517.
42 +
Tanzi R, Vaula G, Romano D, et al.  Assessment of amyloid beta-protein pecursor gene mutations in a large set of familial and sporadic Alzheimer disease cases . Am J Hum Genet . 1992;;51:273-282.
43 +
Mullan M, Tsuji S, Mild T, et al.  Clinical comparison of Alzheimer's disease in pedigrees with codon 717 Val-Ile mutation in the amyloid precursor protein gene . Neurobiol Aging . 1993;;14:407-419.
44 +
Games D, Adams D, Alessandrini R, et al.  Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein . Nature . 1995;;373:523-527.
45 +
Hsiao K, Chapman P, Nilsen S, et al.  Correlative memory deficits, Aβ elevation and amyloid plaques in transgenic mice . Science . 1996;;274:99-102.
46 +
Schellenberg GD, Bird TD, Wijsman EM, et al.  Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14 . Science . 1992;;258:668-671.
47 +
Van Broeckhoven C, Backhovens H, Cruts M, et al.  Mapping of a gene predisposing to early-onset Alzheimer's disease to chromosome 14q24.3 . Nat Genet . 1992;;2:335-339.
48 +
St George-Hyslop P, Haines J, Rogaev E, et al.  Genetic evidence for a novel familial Alzheimer's dis.ease locus on chromosome 14 . Nat Genet . 1992;;2:330-334.
49 +
Mullan M, Houlden H, Windelspecht M, et al.  A locus for familial early-onset Alzheimer's disease on the long arm of chromosome 14, proximal to the α1-antichymotrypsin gene . Nat Genet . 1992;;2:340-342.
50 +
Sherrington R, Rogaev E, Liang Y, et al.  Cloning of a gene bearing mis-sense mutations in early-onset familial Alzheimer's disease . Nature . 1995;;375:754-760.
51 +
Van Broeckhoven C.  Presenilins in Alzheimer's disease . Nat Genet . 1995;;11:230-232.
52 +
Boteva K, Vitek M, Mitsuda H, et al.  Mutation analysis of presenilin 1 gene in Alzheimer's disease . Lancet . 1996;;347:130-131.
53 +
Campion D, Flaman J-M, Brice A, et al.  Mutations of the presenilin 1 gene in families with earlyonset Alzheimer's disease . Hum Mol Genet . 1995;;4:2373-2377.
54 +
Clark RF, Hutton M, Fuldner RA, et al.  The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families . Nat Genet . 1995;;11:219-222.
55 +
Cruts M, Backhovens H, Wang S-Y, et al.  Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3 . Hum Mol Genet . 1995;;4:2363-2371.
56 +
Hutton M, Busfield F, Wragg M, et al.  Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease . Neuroreport . 1996;;7:801-805.
57 +
Perez-Tur J, Froelich S, Prihar G, et al.  A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin-1 gene . Neuroreport . 1995;;7:297-301.
58 +
Pflieger-Bruss S, Hanf V, Behnisch P, Hagenmaier H, Rune G.  Familial Alzheimer's disease associated with S182 codon 286 mutation . Lancet . 1995;; 346:1040.
59 +
Wasco W, Pettingell WP, Jondro PD, et al.  Familial Alzheimer's chromosome 14 mutations . Nat Med . 1995;;1:848.
60 +
Tanahashi H, Mitsunaga Y, Takahashi K, et al.  Missense mutation of S182 gene in Japanese familial Alzheimer's disease . Lancet . 1995;;346:440.
61 +
Doan A, Thinakaran G, Borchelt D, et al.  Protein topology of presenilin . Neuron . 1996;;17:1023-1030.
62 +
Li X, Greenwald I.  Membrane topology of the C elegans SEL-12 presenilin . Neuron . 1996;;17:1015-1021.
63 +
Levy-Lahad E, Wijsman EM, Nemens E, et al.  A familial Alzheimer's disease locus on chromosome 1 . Science . 1995;;269:970-973.
64 +
Levy-Lahad E, Wasco W, Poorkaj P, et al.  Candidate gene for the chromosome 1 familial Alzheimer's disease locus . Science . 1995;;269:973-977.
65 +
Rogaev EI, Sherrington R, Rogaeva EA, et al.  Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene . Nature . 1995;; 376:775-778.
66 +
Sherrington R, Froelich S, Sorbi S, et al.  Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant . Hum Mol Genet . 1996;;5:985-988.
67 +
Prihar G, Fuldner RA, Perez-Tur J, et al.  Structure and alternate splicing of the presenilin 2 gene . Neuroreport . 1996;;7:1680-1684.
68 +
Tanzi RE, McClatchey AI, Lamberti ED, et al.  Protease inhibitor domain encoded by an amyloid precursor mRNA associated with Alzheimer's disease . Nature . 1988;;331:528-530.
69 +
Esch FS, Keim PS, Beattie EC, et al.  Cleavage of amyloid beta peptide during constitutive processing of its precursor . Science . 1990;;248:1122-1124.
70 +
Sisodia S, Koo E, Beyreuther K, Unterbeck A, Price D.  Evidence that beta-amyloid protein in Alzheimer's disease is not derived by normal processing . Science . 1990;;248:492-494.
71 +
Haass C, Schlossmacher M, Hung A, et al.  Amyloid β-peptide is produced by cultured cells during normal metabolism . Nature . 1992;;359:322-325.
72 +
Seubert P, Vigo-Pelfrey C, Esch F, et al.  Isolation and quantification of soluble Alzheimer's β-peptide from biological fluids . Nature . 1992;;359:325-327.
73 +
Anderson J, Chen Y, Kim K, Robakis N.  An alternative secretase cleavage produces soluble Alzheimer amyloid precursor protein containing a potentially amyloidogenic sequence . J Neurochem . 1992;; 59:2328-2331.
74 +
Smith RP, Higuchi DA, Broze GJJ.  Platelet coagulation factor XIa-inhibitor, a form of Alzheimer amyloid precursor protein . Science . 1990;;248:1126-1128.
75 +
Van Nostrand WE, Schmaier AH, Farrow JS, Cunningham DD.  Protease nexin-II (amyloid betaprotein precursor): a platelet alpha-granule protein . Science . 1990;;248:745-748.
76 +
Roch J, Shapiro P, Sundsmo M, et al.  Bacterial expression, purification, and functional mapping of the amyloid beta/A4 protein precursor . J Biol Chem . 1992;;267:2214-2221.
77 +
Schubert D, Jin L, Saitoh T, Cole G.  The regulation of amyloid beta protein precursor secretion and its modulatory role in cell adhesion . Neuron . 1989;;3:689-694.
78 +
Mattson M, Cheng B, Culwell A, et al.  Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the β-amyloid precursor protein . Neuron . 1993;;10:243-254.
79 +
Yankner BA, Duffy LK, Kirschner DA.  Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides . Science . 1990;;250:279-282.
80 +
Jarrett J, Berger E, Lansbury P.  The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease . Biochemistry . 1993;;32:4693-4697.
81 +
Dovey H, Suomesaari-Chrysler S, Lieberburg I, Sinha S, Kiem P.  Cells with a familial Alzheimer's disease mutation produce authentic β-peptide . Neuroreport . 1993;;4:1039-1042.
82 +
Scheuner D, Eckman C, Jensen M, et al.  Secreted amyloid-β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease . Nat Med . 1996;;2:864-870.
83 +
Duff K, Eckman C, Hutton M, et al.  Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1 . Nature . 1996;;383:710-713.
84 +
Borchelt D, Thinakaran G, Eckman C, et al.  Familial Alzheimer's disease-linked presenilin 1 variants elevate Aβ1-42/1-40 ratio in vitro and in vivo . Neuron . 1996;;17:1005-1013.
85 +
Citron M, Westaway D, Xia W, et al.  Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid βprotein in both transfected cells and transgenic mice . Nat Med . 1997;;3:67-72.
86 +
Iwatsubo T, Odaka A, Suzuki N, et al.  Visualization of Aβ42(43) and Aβ40 in senile plaques with end-specific Aβ monoclonals: evidence that an initially deposited species is Aβ42(43) . Neuron . 1994;; 13:45-53.
87 +
Lemere C, Lopera F, Kosik K, et al.  The E280A presenilin 1 Alzheimer mutation produces increased Aβ42 deposition and severe cerebellar pathology . Nat Med . 1996;;2:1146-1150.
88 +
Mann D, Iwatsubo T, Cairns N, et al.  Amyloid β protein (Aβ) deposition in chromosome 14-linked Alzheimer's disease: predominance of Aβ42(43) . Ann Neurol . 1996;;40:149-156.
89 +
Kovacs D, Fausett H, Page K, et al.  Alzheimerassociated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells . Nat Med . 1996;;2:224-229.
90 +
Thinakaran G, Borchelt D, Lee M, et al.  Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo . Neuron . 1996;;17:181-190.
91 +
Levitan D, Greenwald I.  Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene . Nature . 1995;; 377:351-354.
92 +
Levitan D, Doyle T, Brousseau D, et al.  Assessment of normal and mutant human presenilin function in Caenorhabditis elegans . Proc Nati Acad Sci USA . 1996;;93:14940-14944.
93 +
Vito P, Lacana E, D'adamio L.  Interfering with apoptosis: Ca2+-binding protein ALG-2 and Alzheimer's disease gene ALG3 . Science . 1996;;271:521-525.
94 +
Wolozin B, Iwasaki K, Vito P, et al.  Participation of presenilin 2 in apoptosis: enhanced basal activity conferred by an Alzheimer mutation . Science . 1996;; 274:1710-1712.
95 +
Strittmatter WJ, Saunders AM, Schmechel D, et al.  Apolipoprotein E: high-avidity binding to βamyloid and increased frequency of type 4 allele in lateonset familial Alzheimer's disease . Proc Natl Acad Sci U S A . 1993;;90:1977-1981.
96 +
van Duijn C, de Knijff P, Wehnert A, et al.  Apolipoprotein ϵ4 allele in a population-based study of early-onset Alzheimer's disease . Nat Genet . 1994;;7:74-77.
97 +
Corder E, Saunders A, Strittmatter W, et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families . Science . 1993;;261:921-923.
98 +
Poirier J, Davignon J, Kogan S, Bertrand P, Gauthier S.  Apolipoprotein E polymorphism and Alzheimer's disease . Lancet . 1993;;342:697-699.
99 +
Roses A.  Apolipoprotein E affects the rate of Alzheimer disease expression: βamyloid burden is a secondary consequence dependent on APOE genotype and duration of disease . J Neuropathol Exp Neurol . 1994;;53:429-437.
100 +
Osuntokun B, Sahota A, Ogunniyi A, et al.  Lack of an association between apolipoprotein E epsilon 4 and Alzheimer's disease in elderly Nigerians . Ann Neurol . 1995;;38:463-465.
101 +
Maestre G, Orman R, Stern Y, et al.  Apolipoprotein E and Alzheimer's disease: ethnic variation in genotypic risks . Ann Neurol . 1995;;37:254-259.
102 +
Hendrie H, Hall K, Hui S, et al.  Apolipoprotein E genotypes and Alzheimer's disease in a community study of elderly African Americans . Ann Neurol . 1995;;37:118-120.
103 +
Marder K, Maestre G, Cote L, et al.  The apolipoprotein epsilon 4 allele in Parkinson's disease with and without dementia . Neurology . 1994;;44:1330-1331.
104 +
Saunders A, Schmader K, Breitner J, et al.  Apolipoprotein E ϵ4 allele distributions in late onset Alzheimer's disease and in other amyloid forming diseases . Lancet . 1993;;342:710-711.
105 +
Kawamata J, Tanaka S, Shimohama S, Ueda K, Kimura J.  Apolipoprotein E polymorphism in Japanese patients with Alzheimer's disease or vascular dementia . J Neurol Neurosurg Psychiatry . 1994;;57:1414-1416.
106 +
Isoe K, Urakami K, Sato K, Takahashi K.  Apolipoprotein E in patients with dementia of the Alzheimer type and vascular dementia . Acta Neurol Scand . 1996;;93:133-137.
107 +
Lippa C, Smith T, Saunders A, et al.  Apolipo protein E genotype and Lewy body disease . Neurology . 1995;;45:97-103.
108 +
St Clair D, Norman J, Perry R, et al.  Apolipo protein E epsilon 4 allele frequency in patients with Lewy body disease . Neurosci Lett . 1994;;176:45-46.
109 +
Gearing M, Mori H, Mirra S.  Aβ-peptide length and apolipoprotein E genotype in Alzheimer's disease . Ann Neurol . 1996;;39:395-399.
110 +
Corder E, Saunders A, Risch N, et al.  Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease . Nat Genet . 1994;;7:180-183.
111 +
Chartier-Harlin M-C, Parfitt M, Legrain S, et al.  Apolipoprotein E ϵ4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer's disease: analysis of the 19q13.2 chromosomal region . Hum Mol Genet . 1994;;3:569-574.
112 +
Talbot C, Lendon C, Craddock N, et al.  Protection against Alzheimer's disease with ApoE ϵ2 . Lancet . 1994;;343:1432-1433.
113 +
van Duijn C, de Knijff P, Wehnert A, et al.  The apolipoprotein E ϵ2 allele is associated with increased risk of early onset Alzheimer's disease and a reduced survival . Ann Neurol . 1995;;37:605-610.
114 +
St George-Hyslop P, Crapper McLachlan D, Tuda T, et al.  Alzheimer's disease and possible gene interaction . Science . 1994;;263:537.
115 +
Hardy J, Houlden H, Collinge J, et al.  Apolipoprotein E genotype and Alzheimer's disease . Lancet . 1993;;342:737-738.
116 +
Van Broeckhoven C, Backhovens H, Cruts M, et al.  APOE genotype does not modulate age of onset in families with chromosome 14 encoded Alzheimer's disease . Neurosci Lett . 1994;;169:179-180.
117 +
Poirier J, Delisle M, Quirion R, et al.  Apolipoprotein ϵ4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer's disease . Proc Natl Acad Sci U S A . 1995;;92:12260-12264.
118 +
Mayeux R, Ottman R, Maestre G, et al.  Synergistic effects of traumatic head injury and apolipoprotein-epsilon 4 in patients with Alzheimer's disease . Neurology . 1995;;45:555-557.
119 +
Katzman R, Galasko D, Saitoh T, et al.  Apolipoprotein-ϵ4 and head trauma: synergistic or additive risks? Neurology . 1996;;46:889-891.
120 +
Nicoll J, Roberts GW, Graham D.  Apolipoprotein E 4 allele is associated with deposition of amyloid beta-protein following head injury . Nat Med . 1995;; 1:135-148.
121 +
Namba Y, Tomonaga M, Kawasaki H, Otomo E, Ikeda K.  Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease and kuru plaque amyloid in Creutzfeldt-Jakob disease . Brain Res . 1991;;541:163-166.
122 +
Zhou Z, Smith J, Greengard P, Gandy S.  Alzheimer amyloid-β peptide forms denaturant-resistant complex with type ϵ3 but not type ϵ4 isoform of native apolipoprotein E . Mol Med . 1996;;2:175-180.
123 +
Strittmatter W, Weisgraber K, Huang D, et al.  Binding of human apolipoprotein E to synthetic amyloid beta-peptide: isoform-specific effects and implications for late-onset Alzheimer disease . Proc Natl Acad Sci U S A . 1993;;90:8098-8102.
124 +
Ma J, Yee A, Brewer HB, Das S, Potter H.  Amyloid-associated proteins α1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer β-protein into filaments . Nature . 1994;;372:92-94.
125 +
LaDu M, Falduto M, Manelli A, et al.  Isoform-specific binding of apolipoprotein E to β-amyloid . J Biol Chem . 1994;;269:23403-23406.
126 +
Strittmatter W, Saunders A, Goedert M, et al.  Isoform-specific interactions of apolipoprotein E with microtubule associated protein tau: implications for Alzheimer's disease . Proc Natl Acad Sci U S A . 1994;;91:11183-11186.
127 +
Nathan B, Bellosta S, Sanan D, et al.  Differential effects of apolipoprotein E3 and E4 on neuronal growth in vitro . Science . 1994;;264:850-852.
128 +
Holtzman D, Pitas R, Kilbridge J, et al.  Low density lipoprotein receptor-related protein mediates apolipoprotein E-dependent neurite outgrowth in a central nervous system-derived neuronal cell line . Proc Natl Acad Sci U S A . 1995;;92:9480-9484.
129 +
Miyata M, Smith J.  Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and β-amyloid peptides . Nat Genet . 1996;;14:55-61.
130 +
LaDu M, Pederson T, Frail D, et al.  Purification of ApoE attenuates isoform-specific binding to β-amyloid . J Biol Chem . 1995;;270:9039-9042.

Letters

Submit a Letter
CME Course for:


You need to register in order to view this quiz.


To understand the clinical management of acute heart failure syndromes.
Accreditation Information The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
To view and print your certificate and access a summary of your CME courses go to My CME.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s “Cited By” API will populate this tab (http://www.crossref.org/citedby.html).
Compression-Only CPR: Pushing the Science Forward
Cone
AAM 2010;304:1493-1495.
All you need to read in the other general journals
BMJ 2010;341:c5893-c1494.
Submit a Response

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

© 2012 American Medical Association. All Rights Reserved.
Powered bySilverchair Information Systems