Clinical and neurobiological correlates of D10S1423 genotype in Alzheimer's disease.
BACKGROUND
In a previous genome survey, we detected associations of alleles at six microsatellite loci with typical-onset AD, including the 234bp allele of the D10S1423 locus. The goal of the current study was to explore the clinical, neuropathological, and neurochemical correlates of the D10S1423 234bp allele in a group of 50 autopsy-confirmed cases of Alzheimer's disease (AD) who lacked other brain diseases.


METHODS
Clinical assessments were performed as part of a longitudinal study of AD and related disorders. Autopsies were performed using standardized methods and diagnoses were made according to established criteria. Genotyping, morphometry, and neurochemical analyses were performed using postmortem brain tissue.


RESULTS
Patients with AD who carried the D10S1423 234bp allele manifested substantial reductions in dopamine levels in all six cortical regions examined. In contrast, carriers tended to have higher concentrations of cortical norepinephrine and revealed a dosage effect of the D10S1423 234bp allele.


CONCLUSIONS
These findings support the results of our genome survey and suggest that a novel susceptibility gene for AD resides near the D10S1423 locus. The characterization of biologically meaningful subtypes, including genotypic subtypes with particular neurobiological derangements, may be important for the advancement of experimental therapeutics in AD.
Zubenko
G S
GS
Department of Psychiatry, School of Medicine, University of Pittsburgh, Pennsylvania, USA.
Hughes
H B
HB
Stiffler
J S
JS
D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D001921:Brain / Q000378:metabolism; D046508:Culture Techniques; D004298:Dopamine / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D016133:Polymerase Chain Reaction / Q000379:methods
D004298:Dopamine