Clinical and neurobiological correlates of DXS1047 genotype in Alzheimer'sdisease

Background: The goal of the current study was to explore the clinical, neur opathological, and neurochemical correlates of the DXS1047 202bp allele in a group of 50 autopsy-confirmed cases of Alzheimer's disease (AD) who lacke d other concomitant brain diseases. We previously published the results of a genome survey for novel risk loci for typical-onset (greater than or equa l to 60 years) AD conducted at 10cM resolution (Zubenko et al 1998a, b). Th is survey detected associations of alleles at six microsatellite loci with AD, including the 202bp allele of the DXS1047 locus that resides within Xq2 5 on the human cytogenetic map, Methods: Clinical assessments were performed as part of a longitudinal stud y of AD and related disorders. Autopsies were performed using standardized methods and the resulting diagnoses were made according to established crit eria. Genotyping, morphometry, and neurochemical analyses were performed us ing postmortem brain tissue. Results: Patients with AD who carried the DXS1047 202bp allele manifested c ortical norepinephrine levels that ranged from 2.1 to 3.6 times the corresp onding values for noncarriers (p = .002), controlling for the potential eff ects 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 surv ey and suggest that the DXS1047 locus, or a locus in close proximity, modul ates biological variables relevant to the pathophysiology of AD. In additio n to providing insights into the clinical biology of AD, the characterizati on of biologically meaningful subtypes, including genotypic subtypes associ ated with particular neurobiological derangements, may be important to the advancement of experimental therapeutics in AD. (C) 1999 Society of Biologi cal Psychiatry.