Here, we leverage a unique collection of 708 prospectively collected autopsied brains to assess the methylation state of the brain's DNA in relation to Alzheimer's disease (AD). We find that the level of methylation at 71 of the 415,848 interrogated CpGs is significantly associated with the burden of AD pathology, including CpGs in the ABCA7 and BIN1 regions, which harbor known AD susceptibility variants. We validate 11 of the differentially methylated regions in an independent set of 117 subjects. Further, we functionally validate these CpG associations and identify the nearby genes whose RNA expression is altered in AD: ANK1, CDH23, DIP2A, RHBDF2, RPL13, RNF34, SERPINF1 and SERPINF2. Our analyses suggest that these DNA methylation changes may have a role in the onset of AD since (1) they are seen in presymptomatic subjects and (2) six of the validated genes connect to a known AD susceptibility gene network.

In our functional dissection of the CD33 Alzheimer’s disease susceptibility locus, we find that the rs3865444C risk allele is associated with greater cell surface expression of CD33 in monocytes (t50 = 10.06, pjoint=1.3×10–13) of young and older individuals. It is also associated with (1) diminished internalization of Aβ42) (2) accumulation of neuritic amyloid pathology and fibrillar amyloid on in vivo imaging and (3), increased numbers of activated human microglia.

There is increased tongue volume and deposition of fat at the base of tongue in apneics compared to controls. Increased tongue fat may begin to explain the relationship between obesity and obstructive sleep apnea.