Atherosclerotic disease and cognitive decline

BMJ 1994; 309 doi: https://doi.org/10.1136/bmj.309.6951.411a (Published 06 August 1994) Cite this as: BMJ 1994;309:411
  1. M N Payne,
  2. A F Jones,
  3. R G Murray,
  4. J M Beattie
  1. Birmingham Heartlands Hospital, Birmingham B9 5SS.

    EDITOR, - Monique M B Breteler and colleagues describe an association between the clinical manifestations of atherosclerotic disease and cognitive decline in elderly people. They conclude that atherosclerotic disease may account for considerable cognitive impairment and suggest it is time to study whether population wide atherosclerotic risk factor intervention can prevent such cognitive decline.1

    The assumption made is that the potentially modifiable atherosclerotic process is the major determinant of the observed cognitive impairment. This may be so for “multi-infarct” dementia, but in many patients cognitive impairment will be due to Alzheimer's disease. As with atherosclerosis, this condition probably evolves from a complex interaction of genetic and environmental factors but is unlikely to respond to conventional risk factor modification. However, one common pathogenic mechanism may link these apparently distinct entities.

    The e4 allele of apolipoprotein E has been independently linked with both atherosclerosis and Alzheimer's disease. Carriage of the e4 allele is associated with increased risk of coronary heart disease2 and peripheral atherosclerosis,3 clinical features used in the study as surrogate markers of the extent of cerebrovascular disease. The influence of apolipoprotein E4 is likely to be mediated through effects on plasma lipids as this isoform contributes to higher plasma low density lipoprotein concentrations than the wild-type E3, although apolipoprotein E may also regulate smooth muscle proliferation and differentiation.

    Apolipoprotein E is also involved in brain lipid metabolism, and regeneration after injury to the peripheral and central nervous system. The e4 allele frequency in patients with Alzheimer's disease is reported as 0.40-0.50 compared with around 0.12 in control populations. In addition, apolipoprotein E accumulates in the amyloid plaques and neurofibrillary tangles found in this condition, with apolipoprotein E4 showing particular avidity.4,5

    Thus the apolipoprotein E gene and its protein product may mediate two major mechanisms contributing to cognitive decline in the elderly. While the vascular component potentially related to apolipoprotein E4 may be influenced by targeting conventional risk factors for vascular disease as proposed by the authors, this strategy is unlikely to yield major preservation in cognitive function since the non-atherogenic expression of apolipoprotein E4 in this condition is currently not modifiable. However, intervention at the genetic and molecular level is worth further investigation as this may exclude both mechanisms and confer a dual benefit in apolipoprotein E related cognitive attrition.


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