Sources: Mesulam M-M, et al. Apolipoprotein E genotypes in primary progressive aphasia. Neurology 1997;49:51-55; Olichney JM, et al. The impact of apolipoprotein e4 on cause of death in Alzheimer’s disease. Neurology 1997;49:76-81; Jordan B, et al. Apolipoprotein E e4 associated with chronic traumatic brain injury in boxing. JAMA 1997;278:136-140.
Mesulam first identified late life primary progressive aphasia (PPA) as a clinically expressed, selective degeneration of brain language mechanisms (Ann Neurol 1982;11:592-598); five years later, he empirically concluded that the condition was both unique and distinct from Alzheimer’s disease (AD) (Ann Neurol 1987;22:533-534). He and his colleagues have now investigated the apolipoprotein genotype in 12 consecutively evaluated persons with PPA. The 24 single alleles expressed the following: e2 = 1; e3 = 20; e4 = 3. The pattern resembles that of control populations and not that of patients with autopsy-verified AD, leading Mesulam to support his original conclusion. (But see commentary.)
Olichney et al investigated the potential association between the apolipoprotein e4 and cerebrovascular disease in a nonselected population of 114 cases of fatal AD. As our readers know, the presence of an e4 allele is associated with an earlier onset of AD as well as an increased risk of this form of senile dementia. The study confirms an earlier one by Kosunen et al (Stroke 1995;26:743-748) that more severe coronary atherosclerosis occurs in AD patients possessing the APOE e4 allele compared to those without it. Similarly, the Framingham study found that the e4 allele posed a risk factor of 1.5-2.0 for coronary artery atherosclerosis (Wilson, et al. JAMA 1994;272:1666-1671). Eichner et al (Am J Cardiol 1993;71:160-165) identified an even greater chance: risk for coronary heart disease relative to the general population was increased 2.3 times for persons with e3/4 alleles and 8.7 times for e4/4.
In a study of 30 retired professional boxers with varying degrees of career exposure to their sport, Jordan and coworkers found that the APOE e4 allele increases the severity of chronic traumatic brain injury (CTBI). CTBI describes the spectrum of neurologic impairments that sometimes follows repeated head trauma in contact sports such as boxing. The endstage of CTBI is dementia pugilistica, also called the punch drunk syndrome, which occurs in an estimated 17% of professional boxers over age 50. This study found that among boxers with more than 12 professional fights, possession of APOE e4 was associated with approximately twice the overall severity of motor, cognitive, and behavioral impairments that were observed in similarly aged boxers with comparable careers in the ring but lacking the e4 allele.
COMMENTARY
While it is reasonable to question whether genetic factors such as APOE influence the evolution of lobar dementias such as PPA, 12 clinical cases are clearly too few to draw conclusions. A study of nine patients with progressive aphasia by Pickering-Brown et al (Neurosci Letters 1995;188:205-207) found a 33% e4 allele frequency, three times higher than the current investigation. Although PPA is an established and recognizable clinical entity, the associated neuropathology is somewhat heterogeneous and may overlap that of Pick’s, Alzheimer’s, Dementia with Lewy Bodies, and other disorders. As such, it may be more productive to look for genetic correlations in postmortem tissue than in small, clinically characterized populations.
Neither the Framingham study nor that by Eichner et al identified increased atherosclerosis as the cause of increasing mortality in AD, nor was such an association found by Olichney et al. Nevertheless, as Olichney et al emphasize, patients with single or multiple strokes may have been diagnosed as having cerebrovascular dementia without recognition that an important degree of AD may have contributed to their dementia. Since the appearances of both illnesses are heavily genetically influenced, one can’t help wondering whether they represent etiologically distinct inroads into a final common pathway of neurodegeneration. The study implicating APOE e4 in boxing-related brain injury further suggests that APOE genotype may be an important determinant of the effectiveness of the brain’s response to injury, be it traumatic, vascular, or age-related in origin. fp and nrr
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