ApoE4 – The Ancestral Allele

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Better Episodic Memory in Young E4s (Paper)

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One of the things we’ll probably do a lot here is to summarize relevant papers.  For a dose of optimism, let’s start with a paper about the advantages of E4, Better Memory and Neural Efficiency in Young Apolipoprotein E ε4 Carriers.  Researchers are interested in this topic because E4 (the ancestral allele) still sticks around at significant frequencies in all populations – it hasn’t been totally displaced by the more recent E2 and E3.  So unlike a genetic disease caused by a rare mutation, where one really can think of the gene as “a disease gene”, it seems likely that ApoeE4 has some benefits, and there is a hypothesis that it is being maintained by “balancing selection”.


The apolipoprotein E (APOE) ε4 allele is the major genetic risk factor for Alzheimer’s disease, but an APOE effect on memory performance and memory-related neurophysiology in young, healthy subjects is unknown. We found an association of APOE ε4 with better episodic memory compared with APOE ε2 and ε3 in 340 young, healthy persons. Neuroimaging was performed in a subset of 34 memory-matched individuals to study genetic effects on memory-related brain activity independently of differential performance. E4 carriers decreased brain activity over 3 learning runs, whereas ε2 and ε3 carriers increased activity. This smaller neural investment of ε4 carriers into learning reappeared during retrieval: ε4 carriers exhibited reduced retrieval-related activity with equal retrieval performance. APOE isoforms had no differential effects on cognitive measures other than memory, brain volumes, and brain activity related to working memory. We suggest that APOE ε4 is associated with good episodic memory and an economic use of memory-related neural resources in young, healthy humans.

So basically, they watched the brains of people with various APOE alleles while they did some brain tests.  The allele made no difference to overall performance, the big difference came in the efficiency episodic memory (memorizing facts from the recent past, as opposed to working memory, which is based on how much you can hold in your head at any one time).  Specifically, there was an interesting effect where E4s used less energy (less brain activity) each time they learned a repeated fact, whereas E2s and E3s used more energy each time.  They all used the same amount of energy the first time, and they performed equally at remembering the fact, but E4s needed less energy to reinforce the memory each time while E2s and E3s needed more.

The paper has a good summary in the intro of what’s known about ApoE4:

Although the frequency of the APOE4 allele is low in humans (15% in Caucasians), studies in primates suggest that it is the ancestral allele (Finch and Sapolsky 1999). The common (75% in Caucasians) and uniquely human APOE3 allele appeared as a mutation, and its frequency increased during human evolution (Finch and Sapolsky 1999). Because the APOE4 allele has been related to several deleterious biological effects, the question arises why it existed in the first place (Finch and Sapolsky 1999). From an evolutionary point of view, a possible advantageous effect of the APOE4 allele in childhood and early adulthood could explain its existence and further persistence in humans. Support for this notion comes from studies where APOE4 has been associated with higher IQ scores (Yu et al. 2000), a higher educational level (Hubacek et al. 2001), a reduced cardiovascular response to experimentally induced stress (Ravaja et al. 1997), and a protective effect against spontaneous abortion during embryogenesis (Zetterberg et al. 2002) and against perinatal death (Becher et al. 2006). Advantageous effects of the APOE4 allele have also been found for memory-related functions in young animals. Hippocampal long-term potentiation (LTP) was enhanced at a young age in knock-in mice lacking mouseAPOE but instead expressing human APOE4 (Kitamura et al. 2004). This LTP enhancement was age dependent and disappeared in adult knock-in mice. Moreover, APOE4, but not APOE3, stimulated the transcriptional activity of cyclic adenosine 3′,5′-monophosphate response element-binding protein (CREB) by activating the extracellular signal-regulated kinase (ERK) cascade in rat primary hippocampal neurons (Ohkubo et al. 2001).

It’s worth remembering that almost all evolutionary changes involve tradeoffs, because any simple change that’s a pure advantage will quickly get discovered and spread by evolution.  Everything left involves tradeoffs, where the optimal balance shifts as the environment changes.  The novel ApoE alleles E2 & E3 have increased in number over the last tens of thousands of years because of their net benefit – in one theory, the main benefit is the longer lives they allow by reducing heart disease and Alzheimer’s, which became important as grandparents took on an increased role in child-rearing.  Here we see one of their costs: increased energy use in episodic memory storage for the young.


Written by patrissimo

July 23, 2011 at 5:18 pm

Posted in E4 Benefits, Research