Dr. Flicker and colleagues have performed an analysis of genetic factors and specific proteins associated with cognition and depression in a group of 299 healthy older men taking part in a large, ongoing cohort study. These men, aged 75 years or older, were hypertensive or had previously received treatment for hypertension. None had depression or cognitive impairment.

As part of the study, investigators looked at levels of beta-amyloid peptide, which are the primary components of the amyloid plaques that characterize Alzheimer’s disease. Researchers believe the production of amyloid protein is the first step in the pathogenesis of Alzheimer’s disease. Previous investigations have found a correlation between plasma levels of beta-amyloid and presence of Alzheimer’s disease.

Investigators also quantified levels of homocysteine, which in high levels is both prothrombotic and atherogenic, in relation to a common genetic mutation of the MTHFR gene. This mutation reduces enzyme activity, which can result in increased serum concentrations of homocysteine. It is still unclear what effect this mutation has on risk of dementia or depression.

The mean age of men in this investigation was 78.9 years, and the mean Mini-Mental State Exam score was 27.6. Homocysteine levels ranged from 6.7 to 70.5 µmol/L (mean of 13.5 µmol/L). Levels of Aβ40, one of the predominant beta-amyloid types, ranged from 16.2 to 403.3 pg/mL (mean 143 pg/mL).

The scatterplot of log homocysteine against log Aβ40 shows an association between serum levels of homocysteine and serum levels of the amyloid protein. Both of these proteins are actually related to renal function; if renal function deteriorates, serum levels tend to rise. However, even after investigators adjusted for renal function (calculated glomerular filtration rate), this association remained significant.

The study also had some negative findings. Investigators also looked at apolipoprotein E epsilon 4 (APOE E4), an established risk factor for Alzheimer’s disease. However, they found no relationship between the APOE E4 allele and cognition. This is probably because the study included only cognitively intact subjects. The association between APOE E4 and cognition could be most evident in cognitively impaired individuals.

They also found no effect of the MTHFR gene mutation on homocysteine levels. This could be because intrinsic and environmental factors diluted the effect of this polymorphism in these older men. Factors that may be more important for homocysteine levels in older men include B12 deficiency, renal dysfunction and cell aging.

On the other hand, the positive correlation they did find between homocysteine and amyloid protein levels could be an important finding. In these older men, who had no major health problems besides hypertension, the relationship was significant.

The finding strengthens the hypothesis that homocysteine is involved in the pathogenesis of Alzheimer’s disease. The finding, if corroborated by other studies, could also have implications for prevention, since specific interventions can reduce homocysteine levels. Dr. Flicker said that an intervention to reduce homocysteine might be started before individuals have any evidence of Alzheimer’s disease.

One approach to lowering homocysteine is with vitamins such as folate and B12. Dr. Flicker and colleagues are completing a trial looking at the effects of homocysteine-lowering vitamins on the mental health of older men. Results, which should be available in about one year, could provide further evidence to support the link between homocysteine and cognition levels in healthy older individuals.