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Joseph H. Lee, DrPH; Rong Cheng, PhD; Vincent Santana, MBA; Jennifer Williamson, MS; Rafael Lantigua, MD; Martin Medrano, MD; Alex Arriaga, MD; Yaakov Stern, PhD; Benjamin Tycko, MD, PhD; Ekaterina Rogaeva, PhD; Yosuke Wakutani, PhD; Toshitaka Kawarai, MD; Peter St George–Hyslop, MD; Richard Mayeux, MD, MSc

Arch Neurol. 2006;63:1591-1598.

Objectives  To identify novel candidate regions for late-onset Alzheimer disease (LOAD) and to confirm linkage in previously identified chromosomal regions.

Design  Family-based linkage analysis.

Setting  Probands with familial LOAD identified in clinics in the Dominican Republic, Puerto Rico, and the United States.

Patients  We conducted a genome scan in 1161 members primarily clinically diagnosed as having LOAD; these members were from 209 families of Caribbean Hispanic ancestry.

Main Outcome Measures  We analyzed 376 microsatellite markers with an average intermarker distance of 9.3 centimorgan. We conducted linkage analysis using possible and probable LOAD, and we performed affecteds-only 2-point linkage analyses assuming either an autosomal dominant or a recessive model. Subsequently, we conducted a multipoint affected sibling pair linkage analysis.

Results  Two-point parametric linkage analysis identified a locus at 3q28 with a genomewide empirical P value of .03 (logarithm of odds [LOD], 3.09) in a dominant model for probable and possible LOAD. Other regions suggestive of linkage included 2p25.3 (LOD, 1.77), 7p21.1 (LOD, 1.82), and 9q32 (LOD, 1.94). Under a recessive model, we also identified loci at 5p15.33 (LOD, 1.86), 12q24.21 (LOD, 2.43), 14q22.3 (LOD, 2.53), and 14q23.1 (LOD, 2.16) as suggestive for linkage. Restricted to probable LOAD, many of these loci continued to meet criteria suggestive for linkage, as did loci at 2p25.3 (LOD, 2.72), 3q28 (LOD, 2.28), 6p21.31 (LOD, 2.19), and 7p21.1 (LOD, 2.05). APOE conditional analysis indicated that the observed linkage at 3q28 was independent of the APOE 4 allele. Multipoint nonparametric affected sibling pair linkage analysis provided confirmation of suggestive linkage for most, but not all, loci.

Conclusions  Seven loci with LOD scores greater than 2.0 were identified among multiple affected Caribbean Hispanic families with LOAD. The highest LOD score was found at chromosome 3q28. At least 2 other independent studies have observed support for significant linkage at chromosome 3q28, highlighting this region as a locus for further genetic exploration.

Author Affiliations: Gertrude H. Sergievsky Center (Drs Lee, Cheng, Arriaga, Stern, and Mayeux; Mr Santana; and Ms Williamson) and Departments of Neurology (Drs Stern and Mayeux), Psychiatry (Drs Stern and Mayeux), Medicine (Dr Lantigua), and Pathology (Dr Tycko), College of Physicians and Surgeons, Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Drs Lee, Cheng, Lantigua, Arriaga, Stern, Tycko, and Mayeux; Mr Santana; and Ms Williamson), and Department of Epidemiology, School of Public Health (Drs Lee and Mayeux), Columbia University, New York, NY; Universidad Tecnologica de Santiago, Santiago de los Caballeros, Dominican Republic (Dr Medrano); and Centre for Research in Neurodegenerative Diseases and Department of Medicine, University of Toronto, and Toronto Western Hospital Research Institute, Toronto, Ontario (Drs Rogaeva, Wakutani, Kawarai, and St George–Hyslop).