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

From the Department of Psychiatry (Dr. Zubenko, and H.B. Hughes and J.S. Stiffler), School of Medicine, University of Pittsburgh; and the Department of Biological Sciences (Dr. Zubenko), Mellon College of Science, Carnegie-Mellon University, Pittsburgh, PA.

Address correspondence and reprint requests to Dr. George S. Zubenko, Western Psychiatric Institute and Clinic, Room E-1230, 3811 O’Hara Street, Pittsburgh, PA 15213.

OBJECTIVE: To explore the clinical, neuropathologic, and neurochemical correlates of the D12S1045 91 base pair (bp) allele in a group of 50 autopsy-confirmed cases of AD who lacked other concomitant brain diseases.

BACKGROUND: In a previous genome survey for novel risk loci for typical-onset (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 longitudinal study of AD and related disorders. Standardized pathologic methods, genotyping, morphometry, and neurochemical analyses were performed with postmortem brain tissue.

RESULTS: Patients with AD who carried the D12S1045 91bp allele manifested earlier ages at symptomatic onset and death, greater densities of cortical neurofibrillary tangles, and substantially greater reductions in cortical dopamine levels compared to noncarriers. A dosage effect of the number of D12S1045 91bp alleles on cortical dopamine levels was also observed.

CONCLUSIONS: Carrying the D12S1045 91bp allele was associated with greater clinical, neuropathologic, and neurochemical severity independent of sex and APOE genotype. These findings suggest that a novel susceptibility gene for AD resides at or in close proximity to the D12S1045 locus.

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