Another way to study Alzheimer’s

Until I read the paper PLOS Genet. 14, e1007791 (2018)., I thought that this was a sure way to win Nobel prize.  It’s still pretty interesting.  The abstract in Science was misleading, implying that there was an APOE4 variant which was actually protective against Alzheimer’s disease. That would have been fantastic, as it would provide a clue as to just what the APOE4 allele was doing to increase the risk of Alzheimer’s disease.

A huge amount of work has been done on APOE4.   Googling produced 433,000 results (0.46 seconds).  Theories abound but we still don’t know.

The authors studied Blacks and Puerto Ricans and found that if you inherited the APOE4 allele from an African source (rather than a European source), your chance of developing Alzheimer’s disease was significantly less.  A total of 1,766 African American and 220 Puerto Rican individuals with late-onset Alzheimer disease, and 3,730 African American and 169 Puerto Rican cognitively healthy individuals (> 65 years) participated in the study.

The numbers: ApoE ε4 alleles on an African background conferred a lower risk than those with a European ancestral background, regardless of population (Puerto Rican: OR = 1.26 on African background, OR = 4.49 on European; African American: OR = 2.34 on African background, OR = 3.05 on European background).

Note that the ORs are still up for Alzheimer’s if you have APOE4, but the differences are significant and certainly real given the size of the study.

The authors think it’s the area around the APOE  gene, rather than the total genetic background (African vs. European etc. etc.)

It still might be worth doing the following.  Take skin fibroblasts from all four types of people (Puerto Ricans with APOE4 on African background, Puerto Ricans with APOE4 on European background, Blacks with APOE4 on African background, APOE4 on a European background).

Make induced pluripotent stem cells (iPSCs) from them (the technology to do so is quite advanced). Differentiate these iPSCs into neurons  and others into glia (technology quite available).  Study protein and mRNA expression, epigenetic modifications in neurons and glia from all 4 groups.  This might tell you just what APOE4 was doing in high and lower risk people, and possibly might give a clue as to how it was increasing Alzheimer’s risk.

My hopes were really up, because the abstract in Science implied that APOE4 in Blacks and Puerto Ricans was actually absolutely rather than relatively protective, which would have given us some serious clues to Alzheimer pathogenesis, when APOE4 protective cells were contrasted with APOE4 increased risk cells.

Oh well.

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