A study published in the July 16 issue of the New England Journal of Medicine indicates that people who inherit the ApoE4 gene allele are likely to experience signs of early dementia. 815 subjects were followed for about five years, 317 of which were carriers of the APOE4 Gene SNP, and 498 noncarriers. “Longitudinal decline in memory in carriers began before the age of 60 years and showed greater acceleration than in noncarriers (P=0.03), with a possible allele–dose effect (P=0.008). We observed similar although weaker effects on measures of visuospatial awareness and general mental status.” — “Conclusions Age-related memory decline in APOE 4 carriers diverges from that of noncarriers before the age of 60 years, despite ongoing normal clinical status(ref).“
For some time, abnormalities in the APOE gene has been known to be associated with susceptibility to dementia and Alzheimer’s disease(ref)(ref). Aberrations in that gene have also been associated with susceptibility to multiple sclerosis(ref). Back in 2000, a project was set up to investigate common SNPs in the APOE gene and to look at dementia-related disease associations(ref). One perception was that there was a relationship between the presence of APOE4, mitochondrial and oxidative damage and cognitive dysfunction. “The results suggest that mitochondrial/oxidative damage may be more important for the cognitive dysfunction in AD patients who carry APOE4 than in those who do not(ref).” Later it was confirmed that mitochondrial dysfunction and the TOM40 gene are also associated with accumulation of amaloid and the development of Alzheimer’s Disease(ref).
Until recently, however, it was not clear how the presence of the APOE4 Gene variant impacted on the prognosis for developing Alzheimer’s Disease. “In research presented Sunday at the International Conference on Alzheimer’s Disease in Vienna, Dr. Roses and his team looked at the area of DNA surrounding the APOE gene. They found that a gene linked to APOE called TOMM40 had mutations that involved a small number of extra copies of a particular building block of DNA in some individuals and a large number of extra copies in others.” – “Individuals with the large number of extra copies — known as the “long repeat” version of TOMM40 — coupled with APOE3 develop Alzheimer’s an average of seven years earlier — about age 70 — compared with APOE3 individuals with a “short repeat” version of TOMM40(ref).” The extra-copy alteration in TOMM40 is known as a copy number variation (CNV). The recent blog post Gene variations and diseases – far from simple provides an overview of CNVs and how they can affect disease conditions.