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ACAT1 is not associated with Alzheimer's disease in two independent family-based samples

Molecular Psychiatry volume 10, pages 522–524 (2005)Cite this article

SIR — Recently, a study in Molecular Psychiatry reported significant association of a noncoding single-nucleotide polymorphism (SNP) in the gene encoding acyl-Coenzyme A: cholesterol acyltransferase (ACAT1) with reduced risk for Alzheimer's disease (AD) in two small case–control samples from Central and Southern Europe.1 The same study also described evidence linking the putative protective genotype (ie ‘A/A’ for SNP rs1044925) to brain amyloid load and CSF cholesterol levels. ACAT1 is a strong AD candidate gene on both biochemical and positional grounds. First, cholesterol has been implicated in the regulation of β-amyloid peptide (Aβ) production, and ACAT1, which regulates the cellular levels of free cholesterol and cholesteryl esters, has been shown to reduce the Aβ levels in vitro.2 Second, the gene encoding ACAT1 (SOAT1) is located near a chromosomal region (1q25) that full genome screens suggest may harbor a novel AD gene.3, 4 We present here the results of a comprehensive genetic assessment of SOAT1 (including all three variants previously analyzed)1 in the NIMH AD Genetics Initiative Study sample.4, 5 Marginally significant findings were also assessed in a smaller, independent sample of sibships discordant for AD, the ‘Consortium on AD Genetics’ (CAG) Study sample.6 In contrast to the previous findings,1 we were unable to detect any consistent evidence of genetic association with the SNPs analyzed here.

AD is a genetically complex and heterogenous disorder. To date, mutations in three genes (APP, PSEN1, PSEN2) have been established to cause early-onset autosomal dominant forms of the disease. The fourth established AD gene, encoding the brain's main cholesterol transporter apolipoprotein E (APOE) on chromosome 19q13, acts as an AD susceptibility gene.7 While the functional basis of this risk effect has not yet been fully elucidated, it seems that APOE-ɛ4 is involved in the accumulation and aggregation of Aβ, possibly via its role in brain cholesterol metabolism.8 Several lines of evidence suggest that numerous risk-modifying genes exist in addition to APOE. However, despite their good candidacy, none of the putatively associated cholesterol-related genes (other than APOE) has yet received more than sporadic confirmation in independent studies. This situation is quite common in AD and may be attributed to a variety of factors including small gene effects, locus and allelic heterogeneity, population admixture (in case–control studies), as well as type-I error, and publication bias.9, 10

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Acknowledgements

We thank all families for participating in this study. This work was sponsored by grants from the NIMH, NIA (ADRC) and the Alzheimer Association. LB was a fellow of the Deutsche Forschungsgemeinschaft (DFG) and now receives funding from the Harvard Center for Neurodegeneration and Repair (HCNR), and the National Alliance on Research on Schizophrenia and Depression (NARSAD).

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Authors and Affiliations

  1. Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

    L Bertram, M Hsiao, K Mullin, M Parkinson, R Menon & R E Tanzi

  2. Gerontology Research Unit, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

    T J Moscarillo & D Blacker

  3. Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA

    D Blacker

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  1. L Bertram
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  2. M Hsiao
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Correspondence to R E Tanzi.

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Bertram, L., Hsiao, M., Mullin, K. et al. ACAT1 is not associated with Alzheimer's disease in two independent family-based samples. Mol Psychiatry 10, 522–524 (2005). https://doi.org/10.1038/sj.mp.4001646

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