1. Complete lack of endogenous Apolipoprotein E (apoE) was associated with altered lipid metabolism, including high cholesterol.
2. Lack of apoE was not associated with neurocognitive or visual deficits.
Evidence Rating Level: 4 (Poor)
Study Rundown: Apolipoprotein E (apoE) is a molecule expressed both in the astrocytes of the brain and in the retinal pigment epithelium of the eye. It has been hypothesized that this protein, through its role in low density lipoprotein (LDL) receptor pathways, impacts cognition and vision. Notably, presence of the apoE4 isoform has been associated with increased risk of neurodegenerative disorders, such as Alzheimer Disease. However, studies in mice with total deficiency of apoE have been equivocal regarding its importance. This case study analyzed a patient with a homozygous apoE frameshift mutation, resulting in total absence of apoE. Clinical examination of neurologic function, including most notably cognition and vision, failed to reveal significant deficits. Magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analysis further failed to reveal phenotypic effects of this patient’s genotype aside from alterations in blood lipid composition, despite demonstrable apoE deficiency.
Examination of this patient revealed elevated total cholesterol, particularly of very low density lipoprotein (VLDL). The patient was also found to have multiple xanthomas. Of note, increased blood cholesterol increases the risk of development for atherosclerosis, which may cause cognitive sequelae. If an appreciable deficit had been seen in this patient, this may have representing a confounding variable. However, no such deviation from the norm was found. Also, as a study of one singular patient, this report cannot be generalized to the population at large. Moreover, this patient was 40 years old, younger than the median age of presentation of most neurodegenerative disorders. Nevertheless, this report suggests that apoE knockdown can be explored as having potential benefit in Alzheimer Disease as compared to the apoE4 isoform.
In-Depth [case study]: This case study examined a 40 year old African American patient who was seen at the University of California San Francisco. This patient underwent DNA analysis using PCR, which identified a frameshift mutation in apoE (c.291del,pE.97fs) resulting in complete loss of apoE. Blood was drawn which was analyzed for cholesterol and triglyceride content. The patient’s vision was examined for deficits in acuity, perimetry, color vision, dark adaptation, and electro-oculography. These examinations were unremarkable. Color vision was mildly abnormal. The retinal structure was normal in terms of thickness.
Neuropsychiatric testing via the Mini-Mental Status exam and an examination by a neurologist were performed to evaluate for neurologic deficits. MRI and lumbar puncture were performed. MRI showed normal hippocampal volumes bilaterally. CSF analysis for amyloid beta and tau failed to detect presence of amyloid or evidence of neurodegeneration. The patient’s cardiovascular health was assessed as well, via carotid duplex, echocardiogram, and treadmill stress test. The duplex was notable for mild intimal thickening of the common carotids and 0-15% stenosis of the internal carotids. The stress test revealed ST depressions at peak stress suggestive of ischemia at high levels of exercise. Laboratory tests including fasting glucose level, complete blood cell count, renal, liver, and thyroid tests were within normal limits. Serum cholesterol was high (760 mg/dL). There was also high cholesterol to triglycerides ratio (1.52) in VLDL molecules with elevated levels of small-diameter high-density lipoproteins.
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