By Shyama Ghosh, PhD, of the Incidence and Prevalence Database, and Robert Kimball, Staff Writer

Apolipoprotein E, Gender,
and Alzheimer's Disease

Risk from Gender-specific APOE4 Frequency: The e4 allele of the apolipoprotein E gene (APOE4) is a potent genetic risk factor for sporadic and late-onset familial Alzheimer's disease (AD). The APOE4 allele is typically present in more than 50 percent of AD patients but is found only in about 15 percent of healthy older controls. Among patients with mild cognitive impairment (MCI), APOE4 carriers are more likely to convert to AD.

One critical feature of the APOE4 link to AD is that several lines of evidence suggest it is far more pronounced in women than in men, as reported in a study where a prominent interaction between APOE and gender was seen. The first large meta-analysis of APOE4 studies found that women in their sixties with one APOE4 allele had a 4-fold increased risk, whereas male APOE4 heterozygotes did not bump their risk much, if at all. Even among the APOE4 homozygotes, there appeared to be a gender interaction, in that female APOE4 homozygotes' risk peaked around 12-fold compared to 10-fold in the male APOE4 homozygotes.

This study reviewed previous literature on APOE4 by gender interaction, with a particular focus on imaging-related studies. APOE4 is found in more than half of AD patients across most studies and in closer to 65 percent of patients of Northern European descent. Reports linking late-onset familial and sporadic AD to APOE4 showed that APOE4 increases AD risk 2–3 fold in heterozygotes and 10-fold in homozygotes while moving the age of onset earlier. The less common e2 allele (APOE2) is protective against AD. In addition to increasing the risk of developing AD, APOE4 tends to move the age of onset 5–15 years earlier. APOE4-carrying MCI patients had a 4-fold increased risk of converting to AD over 5 years compared with non-carriers. The following year, it was reported that APOE4, in isolation, was not predictive of conversion from MCI to AD but was predictive when used in combination with measures of memory performance.

Gender and Healthy Aging: Even in healthy aging, it appears that female E4 carriers have worse cognitive performance, especially in memory tasks. One study of 189 Danish subjects 50–80 years who did not have dementia showed that APOE4 was associated with a rapid cognitive decline (performance IQ and verbal IQ) in women after the age of 70, but not in men. Additionally, a separate study found that the interaction effects not only episodic memory, but working memory as well. In terms of cerebrospinal fluid biomarkers, another study recently demonstrated that there are higher spinal fluid levels of tau in female APOE4 carriers, and that the difference between female APOE4 carriers and female APOE3 heterozygotes was significant (see Article Review: Apolipoprotein E, Gender, and Alzheimer's Disease: An Overlooked, but Potent and Promising Interaction" as cited in the Incidence and Prevalence Database).

Medtronic implants Tyrx
envelope with DBS systems

Medtronic (Dublin) reported the first implants of the Tyrx absorbable antibacterial envelope with the company's Deep Brain Stimulation (DBS) systems. Medtronic recently received FDA clearance for the Tyrx neuro absorbable antibacterial envelope for use with implantable neurostimulators (INS), and the product is now commercially available across the U.S. as an option for use with all DBS systems. In the coming months, Medtronic also plans to make the Tyrx absorbable antibacterial envelope available as an option for use with implantable neurostimulators to treat chronic pain and bladder and bowel control disorders. The Tyrx envelope is a mesh envelope that securely holds an INS or cardiac implantable electronic device. It is designed to stabilize the device after implantation while releasing two antimicrobial agents, minocycline and rifampin, over a minimum of seven days to help prevent surgical-site infections, which are associated with substantial morbidity, mortality and cost.

Ambry Genetics launches
new suite of testing panels

Ambry Genetics (Aliso Viejo, California) said it is launching a new suite of seven genetic testing panels for epilepsy. Ambry's new epilepsy tests include: EpiFirst-Neonate, a targeted panel of genes most likely to cause neonatal seizures; EpiFirst-Fever, a targeted panel of genes most likely to cause febrile seizures; EpiFirst-IS, a targeted panel of genes most likely to cause infantile spasms; EpiFirst-Focal, a targeted panel of genes most likely to cause non-lesional focal epilepsy; PMEFirst, a targeted panel of genes most likely to cause progressive myoclonus epilepsy; PMENext, a broad panel of genes known to cause progressive myoclonus epilepsy; and EpiNext, a broad panel of genes known to cause a variety of epilepsy syndromes Testing can begin with a targeted gene panel, and move to a broader panel if desired. Alternatively, the broadest panel could be ordered as the first test if appropriate for the clinical situation. This flexible model gives healthcare providers the ability to control and choose their testing approach to best suit their patient.

Multiple sclerosis: B cells . . .

The Canadian B Cells in MS team has published work identifying a subtype of B cell that was important in the progression of multiple sclerosis (MS). B cells are one of the major cell types of the adaptive immune system and are best known for their function producing antibodies. But recent work has suggested that just as different subtypes of T cells have been identified, there are different kinds of B cells. In their experiments, the authors identified one such subtype that activated pro-inflammatory myeloid responses and was more frequent in MS patients than in healthy controls. When B cells were depleted and allowed to reconstitute themselves in MS patients, the proportion of pro-inflammatory cells was less after depletion. "These data implicate a pro-inflammatory B cell/myeloid cell axis in disease and underscore the rationale for selective targeting of distinct B cell populations in MS and other human autoimmune diseases," the authors wrote. Their work appeared in the Oct. 21, 2015, issue of Science Translational Medicine.

. . . And dietary fatty acids

A group from the German Ruhr-University Bochum and University of Erlangen has identified a direct effect of dietary fatty acids on the progression of experimental autoimmune encephalitis, an animal model of multiple sclerosis. The gut microbiome is increasingly being recognized as important for immune system development, and the authors showed that the type of fatty acids consumed affected the type of T cell that predominated in the animals. Specifically, dietary short-chain fatty acids promoted the development of regulatory T cells, while long-chain fatty acids led to higher levels of pathogenic T cells. "These data demonstrate a direct dietary impact on intestinal-specific, and subsequently central nervous system-specific, [T] cell responses in autoimmunity, and thus might have therapeutic implications for autoimmune diseases such as multiple sclerosis," the authors concluded. They published their results in the Oct. 22, 2015, online issue of Immunity.

Cancer drug for Parkinson's disease?

Researchers from Georgetown University Medical Center reported that the chronic myelogenous leukemia drug Tasigna (nilotinib, Novartis AG) improved symptoms of Parkinson's disease (PD). In the phase I trial of 12 patients, researchers observed "meaningful clinical improvement" of both motor and nonmotor symptoms in 10 patients. There was also a significant reduction in several PD biomarkers. Nilotinib is a tyrosine kinase inhibitor, but part of its activity stems from its activation of autophagy, a cellular disposal process that apparently reduced the levels of toxic protein aggregates that are a key feature of neurodegenerative disease. The authors plan additional clinical studies of the drug in patients with Parkinson's disease and Lewy body dementia, which has similar symptoms to Parkinson's but also some features of Alzheimer's disease.

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