Early onset familial Alzheimer's disease: Mutation frequency in 31 families.
BACKGROUND
Three causative genes have been identified for autosomal dominant AD.


OBJECTIVE
To determine the proportion of patients with early onset AD with a positive family history accounted for by mutations in these genes.


METHODS
A mutational analysis of the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes was performed in 31 probands with probable or definite AD from UK families with an age at onset (AAO) <61 years.


RESULTS
The mean AAO was 46.9 years (median 45 years; range 33 to 60 years). The majority of patients (23 of 31; 74%) fulfilled recognized criteria for autosomal dominant inheritance. In 17 (55%) probands the authors identified eight novel PSEN1 sequence variants and eight recognized pathogenic mutations. In 4 (13%) probands the authors identified one novel APP sequence variant (H677R) and two recognized mutations. Thus in this series 21 of 31 (68%) probands were associated with a sequence variant in APP or PSEN1. Nine of the 11 (82%) probands with neuropathologically confirmed AD who additionally fulfilled recognized criteria for autosomal dominant inheritance were associated with a sequence variant in APP or PSEN1. The 10 patients in whom the authors were unable to identify a mutation in APP, PSEN1, or PSEN2 were older than the probands with sequence variants (55.4 vs 44.7 years: p = 0.001).


CONCLUSIONS
Sequence variants in APP and PSEN1 accounted for the majority of neuropathologically confirmed autosomal dominant early onset AD; no mutations in PSEN2 were detected. There may be a further genetic factor involved in the etiology of autosomal dominant early onset AD.
Janssen
J C
JC
Dementia Research Group, Department of Clinical Neurology, Institute of Neurology, The National Hospital for Neurology and Neurosurgery, London, UK.
Beck
J A
JA
Campbell
T A
TA
Dickinson
A
A
Fox
N C
NC
Harvey
R J
RJ
Houlden
H
H
Rossor
M N
MN
Collinge
J
J
D000328:Adult; D017668:Age of Onset; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics*; D019943:Amino Acid Substitution; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics; D004252:DNA Mutational Analysis; D005787:Gene Frequency; D005799:Genes, Dominant / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D053764:Presenilin-1; D053766:Presenilin-2; D017384:Sequence Deletion; D006113:United Kingdom / Q000453:epidemiology
D016564:Amyloid beta-Protein Precursor; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2