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Genetic risk for Alzheimer’s progression differs with sex

It is well documented that the genetic risk for Alzheimer’s has a sex bias.

Sex bias in Alzheimer’s

Carrying a copy of the “Alzheimer’s gene” variant of ApoE4 does not significantly increase a male’s risk of developing the disease, but the gene does increase a women’s risk. Like many disorders, Alzheimer’s is a genetically complex disease and there are many other variants implicated in its progression.

Researchers led by Anders Dale at the University of California have recently reported that the polygenic hazard score for Alzheimer’s disease is sex-specific.

Polygenic hazard scores

The researchers found that sex-matched scores are better at predicting disease onset, progression, and neuropathy than scores that calculate for all study participants together. Chun Chieh Fan, co-first author of the study said that “the finding suggests that sex differences in genetic risk go beyond ApoE4”.

To study the link between Alzheimer’s and sex, the team calculating polygenic risk scores (PRS) and polygenic hazard scores (PHS) for each sex. While PRS can help predict whether a person will get Alzheimer’s disease, the PHS can help predict at what age they are likely to become symptomatic.

The researchers capitalised on a polygenic hazard score previously developed. They correlated the genetic variants with Alzheimer’s Disease in men and women separately using genome-wide association of 7,158 men and 10,697 women who had volunteered for the Alzheimer’s Disease Genetic consortium to identify sex differences in genetic risk.

Using the sex-based GWAS data, the researchers calculated polygenic hazard scores and polygenic risk scores separately for 2,628 men and 3,448 women in the National Alzheimer’s Coordinate Cohort (NACC).  They then calculated how polygenic scores for women predicted for women and the same for men in a crossover design.

Results of sex bias

The crossover analysis was based on genetic, diagnostic and pathology data. It turned out that the male and female PRS had a stronger predictive power when they applied to their sex.  The sex-matched PHS also better predicted neuropathologically confirmed AD and annual progression of dementia.

Overall, the study indicates that the genetic risk of Alzheimer’s disease is tied to sex but that it only affects progression, not prevalence, as the male and female PRS scores equally foretold AD in men and women.

Further studies will be needed to fully understand the genetic variants involved in the sex difference in AD. However, the GWAS study hinted towards effect sizes in the BIN1, MS4A6A, DNAJA2 and FERMT2 genes, all being higher in women while FAM193B, C2ord47 and TYW5 variants appeared stronger in men.

Fan believes it is important to correlate sex-dependent cognitive scores and genetic data with biomarkers and gene-expression analysis to be confident about the underlying biology we can predict from genetics.

Image credit: Technology photo created by kjpargeter –