A full genome scan for late onset Alzheimer's disease

We have genotyped 292 affected sibling pairs (ASPs) with Alzheimer's diseas e (AD) according to NINCDS-ADRDA diagnostic criteria and with onset ages of greater than or equal to 65 years using 237 microsatellite markers separat ed by an average distance of 16.3 cM, Data were analysed by SPLINK and MAPM AKER/SIBS on the whole sample of 292 ASPs and subsets of 162 ASPs where bot h members possessed an apolipoprotein E (APOE) epsilon 4 allele and 63 pair s where neither possessed an epsilon 4 allele, Sixteen peaks with a multipo int lod score (MLS) >1 either in the whole sample, the epsilon 4-positive o r -negative subgroups were observed on chromosomes 1 (two peaks), 2, 5, 6, 9 (two peaks), 10(two peaks), 12, 13, 14, 19, 21 and X (two peaks). Simulat ion studies revealed that these findings exceeded those expected by chance, although many are likely to be false positives. The highest lod scores on chromosomes 1 (MLS 2.67), 9 (MLS 2.38), 10 (MLS 2.27) and 19 (MLS 1.79) ful fil Lander and Kruglyak's definition of 'suggestive' in that they would be expected to occur by chance once or less per genome scan. Several other pea ks were only marginally less significant than this, in particular those on chromosomes 14(MLS 2.16), 5 (MLS 2.00), 12, close to alpha 2-macroglobulin (MLS 1.91), and 21, close to amyloid precursor protein (MLS 1.77), This is the largest genome scan to date in AD and shows for the first time that thi s is a genetically complex disorder involving several, perhaps many, genes in addition to APOE, Moreover, our data will be of interest to those hoping to identify positional candidate genes using information emerging from neu robiological studies of AD.