APOE, memory impairment, diet and N-3 PUFAs

APOE is a curious gene. It has roles in both lipid/cholesterol homeostasis and memory impairment with its associations with Alzheimer disease. For example, see this entry in OMIM and the section titled "Role of APOE in Abnormalities of Blood Lipids and in Cardiovascular Disease." If you read through that long section, over 2600 words, you'll learn that APOE is an important contributor to the management of low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL). If LDL and VLDL levels are not in homeostasis, triglyceride levels can become elevated, which increases risk of atherosclerosis.

A recent report in Nature Medicine by Mapstone, et al. entitled "Plasma phospholipids identify antecedent memory impairment in older adults" identified a panel of ten blood-based lipid biomarkers for "detecting preclinical
Alzheimer's disease in a group of cognitively normal older adults." Those ten lipids include two acylcarnitines and eight
phosphatidylcholines (PC), specifically:

propionylacylcarnitine
3-OH-hexadecenoylcarnitine (C16:1-OH)
phosphatidylcholine diacyl C36:6 (PC aa C36:6) *
lysophosphatidylcholine acyl C18:2 (lysoPC a C18:2)
phosphatidylcholine diacyl C38:0 (PC aa C38:0) *
phosphatidylcholine diacyl C38:6 (PC aa C38:6) *
phosphatidylcholine diacyl C40:1 (PC aa C40:1)
phosphatidylcholine diacyl C40:2 (PC aa C40:2)
phosphatidylcholine diacyl C40:6 (PC aa C40:6) *
phosphatidylcholine acyl-alkyl C40:6 (PC ae C40:6) *

These were noted by the study to be lower in the group of cases compared to controls.

Curiously, this group did not reference the findings from a 2013 study by Rudowska, et al., that characterized the transcriptomic and metabolomic signatures of adding N-3 polyunsaturated fatty acid (N-3 PUFA) to the diet in a Caucasian population. Of their findings, it is most notable that five of the eight above-listed PCs were increased after the six-week N-3 PUFA intervention. These are noted with an asterisk above.

Whether a diet rich in N-3 PUFAs could decrease risk of memory impairment or Alzheimer disease (AD) is a matter for further investigation. Nonetheless, that five of these eight PCs show opposite changes when comparing an N-3 PUFA intervention with the group of cases in the Mapstone, et al. study is highly interesting. Consider also for the moment gene by diet or gene by environment (GxE) interactions. A GxE interaction is an association between a genetic marker and a phenotype that is modified by an environmental factor such as the diet, macronutrient (ie, fat, protein or carbohydrate) intake, physical activity or any of many other lifestyle choices. The risk allele will not show itself as risk until the environmental factor passes a given threshold, say too much saturated fat and now the risk is elevated.

The overlap of the five PCs highlighted here, coupled with the large number of gene-environment interactions we see for the common AD/blood lipid variants of APOE - SNPs rs429358 and rs7412 - strengthen my personal view that lifestyle has a significant role in cognitive decline.