Genetic linkage studies in Alzheimer's disease families

doi:10.1016/0014-4886(88)90220-8

Experimental Neurology

Volume 102, Issue 3, December 1988, Pages 271-279

https://doi.org/10.1016/0014-4886(88)90220-8 Get rights and content

Abstract

Alzheimer's disease is a devastating neurological disorder and the leading cause of dementia among the elderly. Recent studies have localized the gene for familial Alzheimer's disease to chromosome 21 in a series of early onset AD families (mean age of onset < 60). Familial late onset AD (mean age of onset > 60) is a more common clinical form of the disorder. Thirteen families with multiply affected Alzheimer's disease family members were identified and sampled. Ten of these families were of the late onset Alzheimer's disease type. Simulation studies were used to evaluate the usefulness of these pedigrees in linkage studies in familial Alzheimer's disease. Linkage studies undertaken to test the localization of both early onset and late onset Alzheimer's disease families to chromosome 21 failed to establish linkage and excluded linkage from a large portion of the region where the early onset Alzheimer's disease gene was localized. These findings suggest that more than one etiology may exist for familial Alzheimer's disease and indicate the need for continued screening of the genome in familial Alzheimer's disease families.

References (38)

R.J. Bartlett et al.
A new probe for the diagnosis of myotonic muscular dystrophy
Science
(1987)
T.D. Bird et al.
Evidence for linkage of CMT neuropathy to the Duffy locus on chromosome 1
Am. J. Hum. Genet.
(1982)
T.D. Bird et al.
Genetic linkage evidence for heterogeneity in CMT neuropathy (HMSN Type I)
Ann. Neurol.
(1983)
M. Boehnke
Estimating the power of a proposed linkage study: A practical computer simulation approach
Am. J. Hum. Genet.
(1986)
J.C.S. Breitner et al.
Familial Alzheimer's dementia: A prevalent disorder with specific clinical features
Psychol. Med.
(1984)
J.C.S. Breitner et al.
Familial aggregation in Alzheimer's disease: Comparison of risk among relatives of early-and-late-onset cases, and among male and female relatives in successive generations
Neurology
(1988)
S. Cavalli-Sforza et al.
P. Chomczynski et al.
B.K. Farris et al.
Neuro-ophthalmologic findings in vestibulocerebellar ataxia
Arch. Neurol.
(1986)
C.M. Filley et al.
Neuropsychologic features of early and late onset Alzheimer's disease
Arch. Neurol.
(1986)

C.M. Filley et al.

Is Alzheimer's disease inherited: A methologic review

Integr. Psychiatr.

(1984)

J.M. Gilchrist et al.

Clinical and genetic investigation in autosomal dominant limb-girdle muscular dystrophy

Neurology

(1988)

R.J. Guiloff et al.

Linkage of autosomal dominant type I hereditary motor and sensory neuropathy to the Duffy locus on chromosome 1

J. Neurol. Neurosurg. Psych.

(1982)

C.S. Haynes et al.

Analysis of Huntington disease linkage and age-of-onset distributions

Genet. Epid. Suppl.

(1986)

A. Heyman et al.

Alzheimer's disease: A study of epidemiologic aspects

Ann. Neurol.

(1984)

S.E. Hodge et al.

Age-of-onset correction available for linkage analysis (LIPED)

Am. J. Hum. Genet.

(1979)

E.S. Lander et al.

T. Larsson et al.

Senile demenita: A clinical sociomedical and genetic study

Acta. Psychiat. Scand.

(1963)

G.M. Lathrop et al.

Easy calculations of lod scores and genetic risks on small computers

Am. J. Hum. Genet.

(1984)

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²: R. J. Bartlett is a recipient of an ADRDA/Allied Signal Faculty Scholar Award.

¹: The authors thank Drs. J. F. Gusella and G. D. Stewart for providing the DNA probes D21S1/D21S11 and D21S16; Drs. Michael Boehnke and R. C. Elston for their helpful comments; Wendy Smith, Fiona Francis, James Koh, Edward Hanson, Kenneth M. Wilkinson, and Sharon Musick for expert assistance with the polymorphism and DNA analysis; Peggy Pate and Helen Harbett for technical assistance with the family data analysis; Laurita Melton and Penny Ligon for manuscript preparation. This work was supported by the Joseph and Kathleen Bryan Alzheimer's Disease Research Center (AG05128), by NS19999 and NS23008 from the NINCDS, by a grant from the Denver Foundation for Health and Research, and by Clinical Research Unit M01-RR-30 from the NIGMS.

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Genetic linkage studies in Alzheimer's disease families

Abstract

A new probe for the diagnosis of myotonic muscular dystrophy

Science

Evidence for linkage of CMT neuropathy to the Duffy locus on chromosome 1

Am. J. Hum. Genet.

Genetic linkage evidence for heterogeneity in CMT neuropathy (HMSN Type I)

Ann. Neurol.

Estimating the power of a proposed linkage study: A practical computer simulation approach

Am. J. Hum. Genet.

Familial Alzheimer's dementia: A prevalent disorder with specific clinical features

Psychol. Med.

Familial aggregation in Alzheimer's disease: Comparison of risk among relatives of early-and-late-onset cases, and among male and female relatives in successive generations

Neurology

Neuro-ophthalmologic findings in vestibulocerebellar ataxia

Arch. Neurol.

Neuropsychologic features of early and late onset Alzheimer's disease

Arch. Neurol.

Is Alzheimer's disease inherited: A methologic review

Integr. Psychiatr.

Clinical and genetic investigation in autosomal dominant limb-girdle muscular dystrophy

Neurology

Linkage of autosomal dominant type I hereditary motor and sensory neuropathy to the Duffy locus on chromosome 1

J. Neurol. Neurosurg. Psych.

Analysis of Huntington disease linkage and age-of-onset distributions

Genet. Epid. Suppl.

Alzheimer's disease: A study of epidemiologic aspects

Ann. Neurol.

Age-of-onset correction available for linkage analysis (LIPED)

Am. J. Hum. Genet.

Senile demenita: A clinical sociomedical and genetic study

Acta. Psychiat. Scand.

Easy calculations of lod scores and genetic risks on small computers

Am. J. Hum. Genet.