In addition to raising the risk of Alzheimer’s disease, the apolipoprotein E e4 allele appears to confer strong risks for Lewy body and Parkinson’s dementia – diseases that do not exhibit Alzheimer’s characteristic beta-amyloid plaques.

The findings suggest that, in addition to causing a toxic buildup of the amyloid protein, the gene could cause neurodegeneration by some other pathway, Dr. Debby Tsuang and her colleagues wrote in the Nov. 19 online issue of Archives of Neurology (doi: 10.1001/jamaneurol.2013.600).

Dr. Tsuang’s case-control study compared ApoE genetic status among 640 patients with dementia and 269 controls, all of whom were deceased. The investigators used both clinical diagnoses and histopathology to identify patients as having either Alzheimer’s disease without Lewy bodies (244), Alzheimer’s with Lewy bodies (224), pure Lewy body dementia (91), or Parkinson’s dementia without Alzheimer’s neuropathology (81).

The ApoE e4 genotype was present in 7% of the control subjects, 19% of patients with Parkinson’s dementia, 32% of those with pure Lewy body dementia, 41% of those with Alzheimer’s and Lewy bodies, and 38% of those with pure Alzheimer’s.

Since ApoE e4 increases the risk of Alzheimer’s by up to four times, the investigators were not surprised to find it in a large proportion of patients with Alzheimer’s. However, noted Dr. Tsuang of the Veterans Affairs Puget Sound Health Care System, Seattle, “the finding that e4 was overrepresented in pure Lewy body dementia and pure Parkinson’s dementia was unexpected.”

Compared with controls in a model that controlled for gender and age at death, ApoE e4 was associated with a 10-fold increase in the risk of pure Alzheimer’s, a 13-fold increase in the risk of Alzheimer’s with Lewy bodies, a 6-fold increase in the risk of pure Lewy body dementia, and a 3-fold increase in the risk of Parkinson’s dementia.

The finding offers a tantalizing glimpse of what might be a new understanding of ApoE’s influence on neuronal function, the authors said. In Alzheimer’s, the gene is assumed to affect the metabolism of the beta-amyloid protein, slowing clearance and, thus, causing it to clump onto neurons.

“However, our observation of an elevated e4 frequency in the [pure Lewy body] and [Parkinson’s dementia] groups in which the overall brain neuritic plaque burden is low suggests the possibility that ApoE isoforms also might modulate neurodegeneration by nonamyloidogenic mechanisms,” they said.

Some early evidence supports this idea. In experimental models, some fragmentary forms of apolipoprotein are directly neurotoxic, perhaps impairing mitochondrial function or disrupting the normal cytoskeleton. The protein also seems to impair neuronal plasticity when it occurs in the presence of lipids.

“Also,” the authors noted, “greater microglia-mediated neurotoxicity has been observed in mice expressing human ApoE e4 than other ApoE isoforms.”

The study was supported by the National Institutes of Health and the Department of Veterans Affairs. None of the authors had any financial disclosures.