Extreme cerebrospinal fluid amyloid beta levels identify family with late-onset Alzheimer's disease presenilin 1 mutation.
OBJECTIVE
Aggregation and deposition of amyloid beta (Abeta) in the brain is thought to be central to the pathogenesis of Alzheimer's disease (AD). Recent studies suggest that cerebrospinal fluid (CSF) Abeta levels are strongly correlated with AD status and progression, and may be a meaningful endophenotype for AD. Mutations in presenilin 1 (PSEN1) are known to cause AD and change Abeta levels. In this study, we have investigated DNA sequence variation in the presenilin (PSEN1) gene using CSF Abeta levels as an endophenotype for AD.


METHODS
We sequenced the exons and flanking intronic regions of PSEN1 in clinically characterized research subjects with extreme values of CSF Abeta levels.


RESULTS
This novel approach led directly to the identification of a disease-causing mutation in a family with late-onset AD.


CONCLUSIONS
This finding suggests that CSF Abeta may be a useful endophenotype for genetic studies of AD. Our results also suggest that PSEN1 mutations can cause AD with a large range in age of onset, spanning both early- and late-onset AD.
Kauwe
John S K
JS
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
Jacquart
Sarah
S
Chakraverty
Sumi
S
Wang
Jun
J
Mayo
Kevin
K
Fagan
Anne M
AM
Holtzman
David M
DM
Morris
John C
JC
Goate
Alison M
AM
D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005838:Genotype; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics* / Q000502:physiology*; D009483:Neuropsychological Tests; D010957:Plasmids / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics*; D012307:Risk Factors; D012727:Sex Characteristics; D014162:Transfection
D016229:Amyloid beta-Peptides; D053764:Presenilin-1