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We conducted dense linkage disequilibrium (LD) mapping of a series of 25 genes putatively involved in lipid metabolism in 1567 dementia cases [including 1270 with Alzheimer disease (AD)] and 2203 Swedish controls. Across a total of 448 tested genetic markers, the strongest evidence of association was as anticipated for  APOE  (rs429358 at  P  ∼ 10 −72 ) followed by a previously reported association of  ABCA1  (rs2230805 at  P  ∼ 10 −8 ). In the present study, we report two additional markers near the  SREBF1  locus on chromosome 17p that were also significant after multiple testing correction (best  P  = 3.1 × 10 −6  for marker rs3183702). There was no convincing evidence of association for remaining genes, including candidates highlighted from recent genome-wide association studies of plasma lipids ( CELSR2/PSRC1/SORT1 ,  MLXIPL ,  PCSK9 ,  GALNT2  and  GCKR ). The associated markers near  SREBF1  reside in a large LD block, extending more than 400 kb across seven candidate genes. Secondary analyses of gene expression levels of candidates spanning the LD region together with an investigation of gene network context highlighted two possible susceptibility genes including  ATPAF2  and  TOM1L2 . Several markers in strong LD ( r  2  &gt; 0.7) with rs3183702 were found to be significantly associated with AD risk in recent genome-wide association studies with similar effect sizes, providing independent support of the current findings.

Analysis of lipid pathway genes indicates association of sequence variation near SREBF1/TOM1L2/ATPAF2 with dementia risk