Neurobiological correlates of a putative risk allele for Alzheimer's disease on chromosome 12q

Objective: To explore the clinical, neuropathologic, and neurochemical corr elates of the D12S1045 91 base pair (bp) allele in a group of 50 autopsy-co nfirmed cases of AD who lacked other concomitant brain diseases. Background : In a previous genome survey for novel risk loci for typical-onset (greate r than or equal to 60 years) AD conducted at 10 cM resolution, we detected associations of alleles at six microsatellite loci with AD. These included the 91bp allele of the D12S1045 locus that resides in the telomeric region of 12q. Methods: Clinical assessment was performed as part of a longitudina l study of AD and related disorders. Standardized pathologic methods, genot yping, morphometry, and neurochemical analyses were performed with postmort em brain tissue. Results: Patients with AD who carried the D12S1045 91bp al lele manifested earlier ages at symptomatic onset and death, greater densit ies of cortical neurofibrillary tangles, and substantially greater reductio ns in cortical dopamine levels compared to noncarriers. A dosage effect of the number of D12S1045 91bp alleles on cortical dopamine levels was also ob served. Conclusions: Carrying the D12S1045 91bp allele was associated with greater clinical, neuropathologic, and neurochemical severity independent o f sex and APOE genotype. These findings suggest that a novel susceptibility gene for AD resides at or in close proximity to the D12S1045 locus.