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

Clinical Features of Early-Onset Alzheimer Disease in a Large Kindred With an E280A Presenilin-1 Mutation FREE

Francisco Lopera, MD; Alfredo Ardilla, PhD; Alonso Martínez; Lucia Madrigal; Juan Carlos Arango-Viana, MD; Cynthia A. Lemere, PhD; Juan Carlos Arango-Lasprilla; Liliana Hincapié; Mauricio Arcos-Burgos, MD; Jorge E. Ossa, DVM, PhD; Isabella M. Behrens, MD; Joanne Norton; Corrine Lendon, PhD; Alison M. Goate, PhD; Andres Ruiz-Linares, MD; Monica Rosselli, PhD; Kenneth S. Kosik, MD
[+] Author Affiliations

Reprints: Kenneth S. Kosik, MD, Center for Neurologic Diseases, Brigham and Women's Hospital, 221 Longwood Ave Boston, MA 02115.


JAMA. 1997;277(10):793-799. doi:10.1001/jama.1997.03540340027028
Text Size: A A A
Published online
Article
References

Objectives.  —To characterize clinical features of a very large pedigree with early-onset Alzheimer disease (AD) in which all affected individuals carry the identical glutamic acid-to-alanine mutation at codon 280 in the presenilin-1 gene.

Design.  —Clinical histories were obtained by patient and family interviews and through medical or civil records. Using standard diagnostic criteria, a case series of 128 individuals was identified, of which 6 have definitive (autopsy-proven) early-onset AD, 93 have probable early-onset AD, and 29 have possible early-onset AD.

Setting.  —Community based in Antioquia, Colombia.

Patients.  —A population-based sample in which all members of 5 extended families (nearly 3000 individuals) were surveyed. Criteria for inclusion required obtaining sufficient information to categorize the individual as affected.

Main Outcome Measures.  —Age at onset, neuropsychological profile, neurologic history, and examination.

Results.  —The patients had a mean age at onset of 46.8 years (range, 34-62 years). The average interval until death was 8 years. Headache was noted in affected individuals significantly more frequently than in those not affected. The most frequent presentation was memory loss followed by behavior and personality changes and progressive loss of language ability. In the final stages, gait disturbances, seizures, and myoclonus were frequent.

Conclusions.  —Other than the early onset, this clinical phenotype is indistinguishable from sporadic AD except that affected individuals frequently complained of headache preceding and during the disease. Despite the uniform genetic basis for the disease, there was significant variability in the age at onset, suggesting an important role for environmental factors or genetic modifiers in determining the age at onset.

REFERENCES

1 +
Goate A, Chartier-Harlin M-C, 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.
2 +
Sherrington R, Rogaev EI, Liang Y, et al.  Cloning of a novel gene bearing missense mutations in early onset familial Alzheimer disease . Nature . 1995;; 375:754-760.
3 +
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.
4 +
Li J, Ma J, Potter H.  Identification and expression analysis of a potential familial Alzheimer disease gene on chromosome 1 related to AD3 . Proc Natl Acad Sci U S A . 1995;;92:12180-12184.
5 +
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.
6 +
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.
7 +
Van Broeckhoven C.  Presenilins and Alzheimer's disease . Nat Genet . 1995;;11:230-232.
8 +
Levy E, Carman MD, Fernandez-Madrid IJ, et al.  Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutchtype . Science . 1990;;248:1124-1126.
9 +
Hendriks L, van Duijn CM, 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.
10 +
Haltia M, Viitanen M, Sulkava R, et al.  Chromosome 14-encoded Alzheimer's disease: genetic and clinicopathological description . Ann Neurol . 1994;;36:362-367.
11 +
Lampe TH, Bird TD, Nochlin D, et al.  Phenotype of chromosome 14-linked familial Alzheimer's disease in a large kindred . Ann Neurol . 1994;;36:368-378.
12 +
Kennedy AM, Newman SK, Frackowiak RS, et al.  Chromosome 14 linked familial Alzheimer's disease: a clinico-pathological study of a single pedigree . Brain . 1995;;118:185-205.
13 +
Bird TD, Lampe TH, Nemens EJ, et al.  Characteristics of familial Alzheimer's disease in nine kindreds of Volga Germany ancestry . Prog Clin Biol Res . 1989;;317:229-234.
14 +
Campion D, Brice A, Hannequin D, et al.  A large pedigree with early-onset Alzheimer's disease: clinical, neuropathologic, and genetic characterization . Neurology . 1995;;45:80-85.
15 +
Cornejo W, Lopera F, Uribe CS, Salinas M.  Descripción de una familia con demencia presenil tipo Alzheimer . Acta Med Colombiana . 1987;;12:55-61.
16 +
Lopera F, Arcos M, Madrigal L, et al.  Demencia tipo Alzheimer con agregacion familiar en Antioquia, Colombia . Acta Neurol Colombiana . 1994;; 10:173-187.
17 +
Lendon CL, Martinez A, Behrens IM, et al. The E280A mutation causes Alzheimer's, but age of disease onset is not determined by ApoE alleles. Hum Mutat. In press.
18 +
McKhann G, Drachman D, Folstein M, Katzman R, Price DL, Stadlan EM.  Clinical diagnosis of Alzheimer's disease: a report of the NINCDSADRDA Work Group, Department of Health and Human Services Task Force on Alzheimer's Disease . Neurology . 1984;;34:939-944.
19 +
Khachaturian ZS.  Diagnosis of Alzheimer's disease . Arch Neurol . 1985;;42:1097-1105.
20 +
Rogers JD, Brogan D, Mirra SS.  The nucleus basalis of Meynert in neurological disease: a quantitative morphological study . Ann Neurol . 1985;;17:163-170.
21 +
Morris JC, Heyman A, Mohs RC, et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD), part I: clinical and neuropsychological assessment of Alzheimer's disease . Neurology . 1989;;39:1159-1165.
22 +
Folstein MF, Folstein SE, McHugh PR.  'Mini-Mental State': a practical method for grading the cognitive state of patients for the clinician . J Psychiatr Res . 1975;;12:189-198.
23 +
Reitan RM, Wolfson D. The Halsted-Reitan Neuropsychological Test Battery: Theory and Clinical Interpretation . Tucson, Ariz: Neuropsychology Press; 1993;.
24 +
Raven JC. Revised Manual for Raven's Progressive Matrices and Vocabulary Scale . Oxford, England: Oxford Psychologists Press Ltd; 1976;.
25 +
Wechsler D. Manual for the Wechsler Memory Scale-Revised . San Antonio, Tex: The Psychological Corp; 1987;.
26 +
Kaplan E, Goodglass H, Weintraub S. The Boston Naming Test . Philadelphia, Pa: Lea & Febiger; 1983;.
27 +
Goodglass H, Kaplan H. Evaluación de las Afasias y de Transtornos Similares . Buenos Aires, Argentina: Editorial Medica Panamericana; 1983;.
28 +
Taylor EM. The Appraisal of Children With Cerebral Deficits . Cambridge, Mass: Harvard University Press; 1959;.
29 +
Ardila A, Rosselli M, Puente A. Neuropsychological Evaluation of the Spanish Speaker . New York, NY: Plenum Press; 1994;.
30 +
Ardila A, Rosselli M.  Neuropsychological characteristics of normal aging . Dev Neuropsychol . 1989;; 5:307-320.
31 +
Ardila A, Rosselli M.  Development of language, memory and visuospatial abilities in 5- to 12-year-old children using a neuropsychological battery . Dev Neuropsychol . 1994;;10:97-120.
32 +
Rossselli M, Ardila A, Florez A, Castro C.  Normative data on the Boston Diagnostic Aphasia Examination in a Spanish-speaking population . J Clin Exp Neuropsychol . 1990;;12:313-322.
33 +
Rosselli M, Ardila A.  Effects of age, education and gender on the Rey-Osterrieth Complex Figure . Clin Neuropsychologist . 1991;;5:370-376.
34 +
Mirra SS, Heyman A, McKeel D, et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD), part II: standardization of the neuropathologic assessment of Alzheimer's disease . Neurology . 1991;;41:479-486.
35 +
Lemere CA, Lopera F, Kosik KS, et al.  The E280A presenilin 1 Alzheimer mutation produces increased Aβ42 deposition and severe cerebellar pathology . Nat Med . 1996;;2:1146-1148.
36 +
Schottyky J.  Uber prasenile verblodungen . Z Gesamte Neurol Psychiatr . 1932;;140:333-387.
37 +
Bird TD.  Familial Alzheimer's disease . Ann Neurol . 1994;;36:335-336.
38 +
Gomez JR, Bravo ML. Estudio de la Estructura Genetica de la Poblacion del Santuario Antioquia . Medellin, Colombia: Universidad de Antioquia; 1985;:93H.
39 +
Arcos OM. Epidemiologia Genetica de Hendidura Facial no Sindromatica en la Poblacion de Antioquia . Medellin, Colombia: Universidad de Antioquia; 1992;.
40 +
Mullan M, Tsuji S, Miki T, et al.  Clinical comparison of Alzheimer's disease in pedigrees with the codon 717 Val->Ile mutation in the amyloid precursor protein gene . Neurobiol Aging . 1993;;14:407-419.
41 +
Ardila A.  Directions of research in cross-cultural neuropsychology . J Clin Exp Neuropsychol . 1995;;17:143-150.
42 +
Ardila A, Rosselli M, Rosas P.  Neuropsychological assessment in illiterates: visuospatial and memory abilities . Brain Cogn . 1989;;11:147-166.
43 +
Rosselli M, Ardila A, Rosas P.  Neuropsychological assessment in illiterates, II: language and praxic abilities . Brain Cogn . 1990;;12:281-296.
44 +
Erkinjuntti T.  Differential diagnosis between Alzheimer's disease and vascular dementia: evaluation of common clinical methods . Acta Neurol Scand . 1987;;76:433-442.
45 +
Mendez MF, Catanzaro P, Doss RC, Arguello R, Frey WH.  Seizures in Alzheimer's disease: clinicopathologic study . J Geriatr Psychiatry Neurol . 1994;;7:230-233.
46 +
McAreavey MJ, Ballinger BR, Fenton GW.  Epileptic seizures in elderly patients with dementia . Epilepsia . 1992;;33:657-660.
47 +
Hauser WA, Morris ML, Heston LL, Anderson VE.  Seizures and myoclonus in patients with Alzheimer's disease . Neurology . 1986;;36:1226-1230.
48 +
Mega MS, Cummings JL, Fiorello T, Gornbein J.  The spectrum of behavioral changes in Alzheimer's disease . Neurology . 1996;;46:130-135.
49 +
Koss E, Edland S, Fillenbaum G, et al.  Clinical and neuropsychological differences between patients with earlier and later onset of Alzheimer's disease: a CERAD analysis, part XII . Neurology . 1996;;46:136-141.
50 +
Mann DM, Iwatsubo T, Cairns NJ, et al.  Amyloid beta protein (Aβ) deposition in chromosome 14—linked Alzheimer's disease: predominance of Aβ42 (43) . Ann Neurol . 1996;;40:149-156.
51 +
Corder EH, Saunders AM, Strittmatter WJ, 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.
52 +
Chen X, Xia Y, Alford M, et al.  The CYP2D6B allele is associated with a milder synaptic pathology in Alzheimer's disease . Ann Neurol . 1995;;38:653-658.
53 +
Xia Y, Rohan de Silva HA, Rosi BL, et al.  Genetic studies in Alzheimer's disease with an NACP/α-synuclein polymorphism . Ann Neurol . 1996;;40:50-58.
54 +
Kamboh MI, Sanghera DK, Ferrell RE, DeKosky ST.  APOE*4-associated Alzheimer's disease risk is modified by αl-antichymotrypsin polymorphism . Nat Genet . 1995;;10:486-488.
55 +
Nacmias B, Tedde A, Latorraca S, et al.  Apolipoprotein E and αl-antichymotrypsin polymorphism in Alzheimer's disease . Ann Neurol . 1996;; 140:678-680.
56 +
Muller U, Bodeker R-H, Gerundt I, Kurz A.  Lack of association between αl-antichymotrypsin polymorphism, Alzheimer's disease, and allele є4 of apolipoprotein E . Neurology . 1996;;47:1575-1577.
57 +
Wragg M, Hutton M, Talbot C, Alzheimer's Disease Collaborative Group.  Genetic association between intronic polymorphism in presenilin-1 gene and late-onset Alzheimer's disease . Lancet . 1996;; 347:509-512.
58 +
White L, Petrovitch H, Ross GW, et al.  Prevalence of dementia in older Japanese-American men in Hawaii: the Honolulu-Asia Aging Study . JAMA . 1996;;276:955-960.

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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 +
Goate A, Chartier-Harlin M-C, 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.
2 +
Sherrington R, Rogaev EI, Liang Y, et al.  Cloning of a novel gene bearing missense mutations in early onset familial Alzheimer disease . Nature . 1995;; 375:754-760.
3 +
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.
4 +
Li J, Ma J, Potter H.  Identification and expression analysis of a potential familial Alzheimer disease gene on chromosome 1 related to AD3 . Proc Natl Acad Sci U S A . 1995;;92:12180-12184.
5 +
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.
6 +
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.
7 +
Van Broeckhoven C.  Presenilins and Alzheimer's disease . Nat Genet . 1995;;11:230-232.
8 +
Levy E, Carman MD, Fernandez-Madrid IJ, et al.  Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutchtype . Science . 1990;;248:1124-1126.
9 +
Hendriks L, van Duijn CM, 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.
10 +
Haltia M, Viitanen M, Sulkava R, et al.  Chromosome 14-encoded Alzheimer's disease: genetic and clinicopathological description . Ann Neurol . 1994;;36:362-367.
11 +
Lampe TH, Bird TD, Nochlin D, et al.  Phenotype of chromosome 14-linked familial Alzheimer's disease in a large kindred . Ann Neurol . 1994;;36:368-378.
12 +
Kennedy AM, Newman SK, Frackowiak RS, et al.  Chromosome 14 linked familial Alzheimer's disease: a clinico-pathological study of a single pedigree . Brain . 1995;;118:185-205.
13 +
Bird TD, Lampe TH, Nemens EJ, et al.  Characteristics of familial Alzheimer's disease in nine kindreds of Volga Germany ancestry . Prog Clin Biol Res . 1989;;317:229-234.
14 +
Campion D, Brice A, Hannequin D, et al.  A large pedigree with early-onset Alzheimer's disease: clinical, neuropathologic, and genetic characterization . Neurology . 1995;;45:80-85.
15 +
Cornejo W, Lopera F, Uribe CS, Salinas M.  Descripción de una familia con demencia presenil tipo Alzheimer . Acta Med Colombiana . 1987;;12:55-61.
16 +
Lopera F, Arcos M, Madrigal L, et al.  Demencia tipo Alzheimer con agregacion familiar en Antioquia, Colombia . Acta Neurol Colombiana . 1994;; 10:173-187.
17 +
Lendon CL, Martinez A, Behrens IM, et al. The E280A mutation causes Alzheimer's, but age of disease onset is not determined by ApoE alleles. Hum Mutat. In press.
18 +
McKhann G, Drachman D, Folstein M, Katzman R, Price DL, Stadlan EM.  Clinical diagnosis of Alzheimer's disease: a report of the NINCDSADRDA Work Group, Department of Health and Human Services Task Force on Alzheimer's Disease . Neurology . 1984;;34:939-944.
19 +
Khachaturian ZS.  Diagnosis of Alzheimer's disease . Arch Neurol . 1985;;42:1097-1105.
20 +
Rogers JD, Brogan D, Mirra SS.  The nucleus basalis of Meynert in neurological disease: a quantitative morphological study . Ann Neurol . 1985;;17:163-170.
21 +
Morris JC, Heyman A, Mohs RC, et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD), part I: clinical and neuropsychological assessment of Alzheimer's disease . Neurology . 1989;;39:1159-1165.
22 +
Folstein MF, Folstein SE, McHugh PR.  'Mini-Mental State': a practical method for grading the cognitive state of patients for the clinician . J Psychiatr Res . 1975;;12:189-198.
23 +
Reitan RM, Wolfson D. The Halsted-Reitan Neuropsychological Test Battery: Theory and Clinical Interpretation . Tucson, Ariz: Neuropsychology Press; 1993;.
24 +
Raven JC. Revised Manual for Raven's Progressive Matrices and Vocabulary Scale . Oxford, England: Oxford Psychologists Press Ltd; 1976;.
25 +
Wechsler D. Manual for the Wechsler Memory Scale-Revised . San Antonio, Tex: The Psychological Corp; 1987;.
26 +
Kaplan E, Goodglass H, Weintraub S. The Boston Naming Test . Philadelphia, Pa: Lea & Febiger; 1983;.
27 +
Goodglass H, Kaplan H. Evaluación de las Afasias y de Transtornos Similares . Buenos Aires, Argentina: Editorial Medica Panamericana; 1983;.
28 +
Taylor EM. The Appraisal of Children With Cerebral Deficits . Cambridge, Mass: Harvard University Press; 1959;.
29 +
Ardila A, Rosselli M, Puente A. Neuropsychological Evaluation of the Spanish Speaker . New York, NY: Plenum Press; 1994;.
30 +
Ardila A, Rosselli M.  Neuropsychological characteristics of normal aging . Dev Neuropsychol . 1989;; 5:307-320.
31 +
Ardila A, Rosselli M.  Development of language, memory and visuospatial abilities in 5- to 12-year-old children using a neuropsychological battery . Dev Neuropsychol . 1994;;10:97-120.
32 +
Rossselli M, Ardila A, Florez A, Castro C.  Normative data on the Boston Diagnostic Aphasia Examination in a Spanish-speaking population . J Clin Exp Neuropsychol . 1990;;12:313-322.
33 +
Rosselli M, Ardila A.  Effects of age, education and gender on the Rey-Osterrieth Complex Figure . Clin Neuropsychologist . 1991;;5:370-376.
34 +
Mirra SS, Heyman A, McKeel D, et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD), part II: standardization of the neuropathologic assessment of Alzheimer's disease . Neurology . 1991;;41:479-486.
35 +
Lemere CA, Lopera F, Kosik KS, et al.  The E280A presenilin 1 Alzheimer mutation produces increased Aβ42 deposition and severe cerebellar pathology . Nat Med . 1996;;2:1146-1148.
36 +
Schottyky J.  Uber prasenile verblodungen . Z Gesamte Neurol Psychiatr . 1932;;140:333-387.
37 +
Bird TD.  Familial Alzheimer's disease . Ann Neurol . 1994;;36:335-336.
38 +
Gomez JR, Bravo ML. Estudio de la Estructura Genetica de la Poblacion del Santuario Antioquia . Medellin, Colombia: Universidad de Antioquia; 1985;:93H.
39 +
Arcos OM. Epidemiologia Genetica de Hendidura Facial no Sindromatica en la Poblacion de Antioquia . Medellin, Colombia: Universidad de Antioquia; 1992;.
40 +
Mullan M, Tsuji S, Miki T, et al.  Clinical comparison of Alzheimer's disease in pedigrees with the codon 717 Val->Ile mutation in the amyloid precursor protein gene . Neurobiol Aging . 1993;;14:407-419.
41 +
Ardila A.  Directions of research in cross-cultural neuropsychology . J Clin Exp Neuropsychol . 1995;;17:143-150.
42 +
Ardila A, Rosselli M, Rosas P.  Neuropsychological assessment in illiterates: visuospatial and memory abilities . Brain Cogn . 1989;;11:147-166.
43 +
Rosselli M, Ardila A, Rosas P.  Neuropsychological assessment in illiterates, II: language and praxic abilities . Brain Cogn . 1990;;12:281-296.
44 +
Erkinjuntti T.  Differential diagnosis between Alzheimer's disease and vascular dementia: evaluation of common clinical methods . Acta Neurol Scand . 1987;;76:433-442.
45 +
Mendez MF, Catanzaro P, Doss RC, Arguello R, Frey WH.  Seizures in Alzheimer's disease: clinicopathologic study . J Geriatr Psychiatry Neurol . 1994;;7:230-233.
46 +
McAreavey MJ, Ballinger BR, Fenton GW.  Epileptic seizures in elderly patients with dementia . Epilepsia . 1992;;33:657-660.
47 +
Hauser WA, Morris ML, Heston LL, Anderson VE.  Seizures and myoclonus in patients with Alzheimer's disease . Neurology . 1986;;36:1226-1230.
48 +
Mega MS, Cummings JL, Fiorello T, Gornbein J.  The spectrum of behavioral changes in Alzheimer's disease . Neurology . 1996;;46:130-135.
49 +
Koss E, Edland S, Fillenbaum G, et al.  Clinical and neuropsychological differences between patients with earlier and later onset of Alzheimer's disease: a CERAD analysis, part XII . Neurology . 1996;;46:136-141.
50 +
Mann DM, Iwatsubo T, Cairns NJ, et al.  Amyloid beta protein (Aβ) deposition in chromosome 14—linked Alzheimer's disease: predominance of Aβ42 (43) . Ann Neurol . 1996;;40:149-156.
51 +
Corder EH, Saunders AM, Strittmatter WJ, 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.
52 +
Chen X, Xia Y, Alford M, et al.  The CYP2D6B allele is associated with a milder synaptic pathology in Alzheimer's disease . Ann Neurol . 1995;;38:653-658.
53 +
Xia Y, Rohan de Silva HA, Rosi BL, et al.  Genetic studies in Alzheimer's disease with an NACP/α-synuclein polymorphism . Ann Neurol . 1996;;40:50-58.
54 +
Kamboh MI, Sanghera DK, Ferrell RE, DeKosky ST.  APOE*4-associated Alzheimer's disease risk is modified by αl-antichymotrypsin polymorphism . Nat Genet . 1995;;10:486-488.
55 +
Nacmias B, Tedde A, Latorraca S, et al.  Apolipoprotein E and αl-antichymotrypsin polymorphism in Alzheimer's disease . Ann Neurol . 1996;; 140:678-680.
56 +
Muller U, Bodeker R-H, Gerundt I, Kurz A.  Lack of association between αl-antichymotrypsin polymorphism, Alzheimer's disease, and allele є4 of apolipoprotein E . Neurology . 1996;;47:1575-1577.
57 +
Wragg M, Hutton M, Talbot C, Alzheimer's Disease Collaborative Group.  Genetic association between intronic polymorphism in presenilin-1 gene and late-onset Alzheimer's disease . Lancet . 1996;; 347:509-512.
58 +
White L, Petrovitch H, Ross GW, et al.  Prevalence of dementia in older Japanese-American men in Hawaii: the Honolulu-Asia Aging Study . JAMA . 1996;;276:955-960.

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