Gene associated with Alzheimer’s may have been innocent this whole time

[The title was written by my editor. It does not represent with accuracy the research or the news summary.]

The case study of a man lacking a gene linked to higher risk for Alzheimer’s disease demonstrates that the gene is not essential for normal cognitive function and may thus be targeted by new therapies.

by John Tyburski

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First published at Daily Digest News on August 12, 2014

A variant form of a gene involved in cholesterol transport has been known for two decades to be a primary risk factor for developing Alzheimer’s disease. However, what stood in the way between this discovery and targeting the apolipoprotein (APO) E (apoE) gene variant 4, apoE4 was a concern that disruption of the protein the gene encodes, APOE, may adversely affect neurological function. Now a report published Monday online in the journal JAMA Neurology describes a case study that suggests the gene may yet be a viable therapeutic target.

The case study of a man who completely lacked the apoE gene and hence, had no APOE function yet maintained normal cognitive and retinal (eye) function, opens up new therapeutic possibilities for Alzheimer’s patients. The 40-year-old California man was examined by physicians at the University of California, San Francisco, for severe cholesterol elevation that was not responsive to treatment. APOE is directly involved in cholesterol regulation. It is also expressed in the central nervous system and the pigmented epithelium of the eye, under the retinas.

“Despite complete absence of apoE, he had normal vision, exhibited normal cognitive, neurological, and retinal function, had normal findings on brain magnetic resonance imaging, and had normal cerebrospinal fluid levels of β-amyloid and tau proteins,” wrote the authors of the report. Tau and β-amyloid proteins accumulate to form plaques in the brain cells of Alzheimer’s patients.

“Failure of detailed neurocognitive and retinal studies to demonstrate defects in our patient suggests either that the functions of apoE in the brain and eye are not critical or that they can be fulfilled by a surrogate protein,” they continued. “Surprisingly, with respect to central nervous system function, it appears that having no apoE is better than having the apoE4 protein.”

“Despite two decades of research into the mechanisms by which apoE4 contributes to disease pathogenesis, a seemingly simple question remains unresolved: Is apoE good or bad for brain health?” wrote Courtney Lane-Donovan and Joachim Herz in an editorial that accompanied the report. “[T[he lack of neurological findings in this patient would appear to answer the question of whether apoE is necessary for brain function with a resounding no.”

The authors of the report concluded by suggesting that apoE4 may be a viable therapeutic target in treating Alzheimer’s.