BioWorld International Correspondent

LONDON - Those who develop Alzheimer's disease and vascular dementia are more likely to have a particular genetic variant of the cytokine known as TNF-α, researchers in Northern Ireland have found. The scientists say their findings will stimulate further studies into the role of inflammation in both types of dementia, and whether anti-inflammatory drugs could help ameliorate the conditions.

Stephen McIlroy, lecturer in the Department of Geriatric Medicine at Queen's University of Belfast, Northern Ireland, told BioWorld International, "This study needs to be replicated and extended in other populations, but it suggests that, in vascular dementia and perhaps in Alzheimer's disease, too, anti-inflammatory drugs may decrease the incidence or delay the onset of dementia. Trials could begin soon using the common anti-inflammatory drugs."

McIlroy predicted that clinicians would want to find out whether use of anti-inflammatory drugs after a stroke could reduce the proportion who go on to develop vascular dementia, which stands at around 30 percent.

The group reports its results in a paper in the Feb. 10, 2001, issue of The Lancet titled "Association between polymorphism in regulatory region of gene encoding tumour necrosis factor-a and risk of Alzheimer's disease and vascular dementia: a case-control study."

TNF-α is one of the best known pro-inflammatory cytokines, and has been found in significantly higher concentrations in the brains of patients with Alzheimer's disease and vascular dementia. Earlier research had also suggested that inflammation may be to blame for some of the tissue damage that occurs in Alzheimer's disease, and that the localized ischemia that occurs in the brains of people with vascular dementia could also trigger inflammatory reactions.

The polymorphism that McIlroy and his colleagues concentrated on had either a CC, a CT or a TT, 850 base pairs before the start of the gene encoding TNF-α. The team analyzed this polymorphism in 242 patients with sporadic (nonfamilial) Alzheimer's disease, 81 with vascular dementia, 61 stroke patients without dementia and 235 normal controls.

They found that people in the vascular dementia group were 2.51 times more likely to have the CT or TT genotype than those in the stroke or normal control group.

There was an increasing trend when the heterozygous and homozygous genotypes were compared. Those who were CT were 1.97 more likely to have vascular dementia than those in the stroke group, and 2.09 more likely to have vascular dementia than those in the normal control group. Those who were TT were 3.72 times more likely to have vascular dementia than those in the stroke group, and 4.34 times more likely to have vascular dementia than those in the normal control group.

Tests also were carried out on all four study groups to discover whether they had a known polymorphism in their gene encoding the protein apolipoprotein E. People with the e4 allele of apolipoprotein E are known to be between four and six times more likely to develop Alzheimer's disease than the general population.

In this study, McIlroy and colleagues found that those who had the apolipoprotein Eε4 allele, but who were CC for the TNF-α polymorphism, were 2.73 times more likely to have Alzheimer's disease than controls. However, those who had both the apolipoprotein Eε4 allele and were either CT or TT for the TNF-α polymorphism, were 4.62 times more likely to have Alzheimer's disease than controls.

There was, however, no significant difference between the distribution of the TNF-α polymorphism between the Alzheimer's disease group and the normal controls.

McIlroy told BioWorld International, "TNF-α is a quandary molecule. Several reports have said that it is pro-inflammatory, but other reports have said that it is trophic for neurons and helps their survival. So the effect of this polymorphism, which is in the regulatory region of the gene, could be one way or the other. Polymorphisms have been reported which both increase its secretion and which decrease its secretion." The team is currently trying to find out exactly what effect the polymorphism has on the gene's function.

It also plans to study other polymorphisms affecting TNF-α, as well as looking at the incidence of polymorphisms in other pro-inflammatory and anti-inflammatory cytokines in different patient groups. They also plan to expand their database of patients with vascular dementia.