Clinical and neurobiological correlates of DXS1047 genotype in Alzheimer's disease.
BACKGROUND
The goal of the current study was to explore the clinical, neuropathological, and neurochemical correlates of the DXS1047 202 bp allele in a group of 50 autopsy-confirmed cases of Alzheimer's disease (AD) who lacked other concomitant brain diseases. We previously published the results of a genome survey for novel risk loci for typical-onset (> or = 60 years) AD conducted at 10 cM resolution (Zubenko et al 1998a, b). This survey detected associations of alleles at six microsatellite loci with AD, including the 202 bp allele of the DXS1047 locus that resides within Xq25 on the human cytogenetic map.


METHODS
Clinical assessments were performed as part of a longitudinal study of AD and related disorders. Autopsies were performed using standardized methods and the resulting 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 DXS1047 202 bp allele manifested cortical norepinephrine levels that ranged from 2.1 to 3.6 times the corresponding values for noncarriers (p = .002), controlling for the potential effects of gender, age at symptomatic onset or death, and postmortem interval. In contrast, carriers tended to have lower cortical levels of dopamine (p = .10).


CONCLUSIONS
These findings support the results of our previous genome survey and suggest that the DXS1047 locus, or a locus in close proximity, modulates biological variables relevant to the pathophysiology of AD. In addition to providing insights into the clinical biology of AD, the characterization of biologically meaningful subtypes, including genotypic subtypes associated with particular neurobiological derangements, may be important to the advancement of experimental therapeutics in AD.
Department of Psychiatry, School of Medicine, University of Pittsburgh, PA, USA.
G S
GS
Zubenko
H B
HB
Hughes
J S
JS
Stiffler
D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000473:pathology; D046508:Culture Techniques; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics; D014960:X Chromosome / Q000235:genetics