Applied Neurogenomics “contains detailed methods relevant to the genomics of neurodegenerative diseases, particularly Alzheimer’s disease and Huntington’s disease”

The book contains on chapter on targeted re-sequencing of genes written by Peter Weber and myself. The chapter can be accessed directly here.

Here is the abstract:

The method presented here enables researchers to sequence a target region in the genome in a large number of subjects at comparatively low cost. The method relies heavily on modern massively parallel sequencing (MPS) technologies, and the costs and workload for DNA sample preparation are major factors in targeted re-sequencing studies involving many individual samples. In order to reduce costs during sample preparation, we propose to sequence pools of subjects rather than individual subjects. Thus, our approach is divided into four subparts: (1) non-barcoded sample pooling, (2) enrichment of the target region, (3) sequencing using standard MPS protocols, and (4) tailored bioinformatics analysis of the data, which identifies rare variants in the pools.

Check here for Germany, Greece, Spain and Switzerland (NZZ).

Our paper was published in Annals of Neurology!

Click here for Stanford’s Press release.

Title: Sex modifies the APOE-related risk of developing Alzheimer disease

Abstract:

Objective
The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer disease (AD). Case–control studies suggest the APOE4 link to AD is stronger in women. We examined the APOE4-by-sex interaction in conversion risk (from healthy aging to mild cognitive impairment (MCI)/AD or from MCI to AD) and cerebrospinal fluid (CSF) biomarker levels.

Methods
Cox proportional hazards analysis was used to compute hazard ratios (HRs) for an APOE-by-sex interaction on conversion in controls (n = 5,496) and MCI patients (n = 2,588). The interaction was also tested in CSF biomarker levels of 980 subjects from the Alzheimer’s Disease Neuroimaging Initiative.

Results
Among controls, male and female carriers were more likely to convert to MCI/AD, but the effect was stronger in women (HR = 1.81 for women; HR = 1.27 for men; interaction: p = 0.011). The interaction remained significant in a predefined subanalysis restricted to APOE3/3 and APOE3/4 genotypes. Among MCI patients, both male and female APOE4 carriers were more likely to convert to AD (HR = 2.16 for women; HR = 1.64 for men); the interaction was not significant (p = 0.14). In the subanalysis restricted to APOE3/3 and APOE3/4 genotypes, the interaction was significant (p = 0.02; HR = 2.17 for women; HR = 1.51 for men). The APOE4-by-sex interaction on biomarker levels was significant for MCI patients for total tau and the tau-to-Aβ ratio (p = 0.009 and p = 0.02, respectively; more AD-like in women).

Interpretation
APOE4 confers greater AD risk in women. Biomarker results suggest that increased APOE-related risk in women may be associated with tau pathology. These findings have important clinical implications and suggest novel research approaches into AD pathogenesis

Our paper with the title “Apolipoprotein E, Gender, and Alzheimer’s Disease: An Overlooked, but Potent and Promising Interaction” was accepted for publication in Brain Imaging and Behavior. The paper is a review on the current literature regarding a gender by genotype (ApoE) interaction in Alzheimer’s disease.

“Alzheimer’s disease (AD) is an increasingly prevalent, fatal neurodegenerative disease that has proven resistant, thus far, to all attempts to prevent it, forestall it, or slow its progression. The ε4 allele of the Apolipoprotein E gene (APOE4) is a potent genetic risk factor for sporadic and late-onset familial AD. While the link between APOE4 and AD is strong, many expected effects, like increasing the risk of conversion from MCI to AD, have not been widely replicable. One critical, and commonly overlooked, feature of the APOE4 link to AD is that several lines of evidence suggest it is far more pronounced in women than in men. Here we review previous literature on the APOE4 by gender interaction with a particular focus on imaging-related studies.”

Authors: Leo Unger, Andre Altmann, Michael Greicius