Abstract
While there are currently over 40 replicated genes with mapped risk alleles for Late Onset Alzheimer’s disease (LOAD), the
Apolipoprotein
E locus E4 haplotype is still the biggest driver of risk, with odds ratios for neuropathologically confirmed E44 carriers exceeding 30 (95% confidence interval 16.59–58.75). We sought to address whether the
APOE
E4 haplotype modifies expression globally through networks of expression to increase LOAD risk. We have used the Human Brainome data to build expression networks comparing
APOE
E4 carriers to non-carriers using scalable mixed-datatypes Bayesian network (BN) modeling. We have found that
VGF
had the greatest explanatory weight. High expression of
VGF
is a protective signal, even on the background of
APOE
E4 alleles. LOAD risk signals, considering an APOE background, include high levels of
SPECC1L
,
HLA-DRA
and
RANBP3L
. Our findings nominate several new transcripts, taking a combined approach to network building including known LOAD risk loci.