Læknablaðið - 15.10.1997, Blaðsíða 33

LÆKNABLAÐIÐ 1997; 83
655
Erfðafræði Alzheimers sjúkdóms
Gísli Ragnarsson
Ragnarsson G
The Genetics of Alzheimer’s Disease
Læknablaðið 1997; 83: 655-63
The aetiology of Alzheimer’s disease (AD) is still
unknown, but a small fraction of AD patients have a
dominant inherited defect in one of three genes.
These patients often develop Alzheimer’s disease
between 40 to 65 years of age. The majority of
patients, however, get the disease after the age of 65
and do not have a gene defect in any of these three
genes. Apart from age of onset, no symptomatic or
pathological difference exists between AD patients
with or without known genetic defect.
In patients with AD before the age of 65 a germ-line
gene defect in the APP gene ((S-amyloid precursor
protein) at chromosome 21q21.2, the PS-1 gene (pre-
senilin) at chromosome 14q24.3 and the PS-2 gene at
chromosome lq42.1 has been identified. The first
mutation was discovered 1991 in the APP gene in a
family with early-onset AD. Since then hundreds of
families have been screened for mutations in this
gene but they have only been found in 10 to 15
families. On the other hand more than 35 different
mutations in over 60 unrelated families have been
discovered in the PS-1 gene and nearly half of AD
patients with familial early-onset AD have muta-
tions in this gene. Patients with mutation in the PS-1
gene often get AD before the age of 50 and even
before the age of 40. The third germ line gene defect
was discovered 1995 in the PS-2 gene by screening
the genome in search for PS-1 gene homology. Two
different mutations have been found in PS-2 gene in
unrelated families.
Fyrirspurnir, bréfaskipti: Gísli Ragnarsson, frumulíffræði-
deild Rannsóknastofu Háskóla Islands I meinafræði, Land-
spítalanum, 101 Reykjavík. Sími: 560 1906;
netfang: gislira@rsp.is
Lykilorð: Alzheimers sjúkdómur, [S-amýloid-forveraprótín,
presenilin-1, presenilin-2, apólípóprótín E-4.
An increased risk of late-onset AD has been asso-
ciated with apolipoprotein E (ApoE). ApoE exists
in three different isoforms: ApoE2, ApoE3 and
ApoE4. Three alleles (e2, e3, and e4) on chromo-
some 19ql3.2 encode these different kinds of ApoE.
Those who are e4 homozygous (e4/e4) have in-
creased risk of late-onset AD, and usually develop
symptoms earlier in live than e4 negatives. The same
applies to e4 heterozygous (e3/e4 or e2/e4) individu-
als even though their risk does not increase as much
as e4 homozygous.
Other chromosome regions have been linked to
late-onset AD, an example is a region on chromo-
some 12. Furthermore mutations in the mitochon-
drial genes that encode the enzyme cytochrome c
oxidase have also recently been shown to be associ-
ated with AD.
Correspondence: Gísli Ragnarsson, Laboratory of Cell
Biology, Dpt. of Pathology, Landspítalinn, 101 Reykjavík,
lceland. Telephone: (354) 560 1906; e-mail: gislira@rsp.is
Key words: Alzheimer's disease, fi-amyloid-precursorpro-
tein, Presenilin-1, Presenilin-2, apolipoprotein E-4.
Ágrip
Orsakir Alzheimers sjúkdóms eru ekki
þekktar, en vitað er að nokkur hluti Alzheim-
ers sjúklinga er með ríkjandi erfðagalla í ein-
hverju af þremur genum með nær 100% sýnd.
Þessir sjúklingar fá sjúkdóminn yfirleitt á aldr-
inum 40 til 65 ára. Flestir sjúklingar með AI-
zheimers sjúkdóm greinast eftir 65 ára aldur og
hafa ekki galla í þessum genum. Ekki er munur
á meingerð Alzheimers sjúkdóms hjá sjúkling-
um með þekkta genagalla og þeim sem ekki
hafa slíka galla.
Margir sem greinast með Alzheimers sjúk-
dóm fyrir 65 ára aldur hafa kímlínugenagalla í
APP (þ-amyloid precursor protein, App) geni
á litningi 21q21.2, PS-1 (presenilin, Ps) geni á
litningi 14q24.3 eða PS-2 geni á litningi lq42.1.