So far, the consensus among scientists has been that the ApoE4 gene is the main marker of Alzheimer’s disease and many other dementias. But new research adds another key player into the mix: the so-called TOMM40 gene.

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The genetic narrative behind Alzheimer’s disease may need to be adjusted, according to a new study.

The ApoE gene is instrumental in forming lipoproteins, which are molecules that carry cholesterol and other fats through our bloodstream.

ApoE has several slightly different versions, and one of them, called e4, has been strongly associated with the risk of developing Alzheimer’s disease.

Moreover, the ApoE4 gene is linked to the buildup of amyloid plaque, which is a clumpy protein found in the brain tissue of Alzheimer’s patients.

These data have led researchers to agree, by and large, that ApoE4 is the main genetic culprit behind Alzheimer’s disease. But a new study published in the journal PLOS ONE reverses this narrative, suggesting that another gene may be “orchestrating” the cognitive decline typical of dementia.

The research was conducted by scientists at the University of Southern California (USC) in Los Angeles, in collaboration with those at the University of Manchester in the United Kingdom.

The study’s first author is Thalida Em Arpawong, a postdoctoral fellow in the USC Dornsife College of Letters, Arts, and Sciences Department of Psychology. The senior investigator is Carol A. Prescott, who is a professor of psychology at the USC Dornsife College.

Arpawong summarizes the findings, saying, “Typically, ApoE4 has been considered the strongest known genetic risk factor for cognitive decline, memory decline, Alzheimer’s disease, or dementia-related onset.”

“[But our] study found that a TOMM40 variant was actually more influential than ApoE4 on the decline in immediate memory – the ability to hold onto new information.”

Prof. Prescott and team set out to examine two kinds of memory ability: immediate and delayed recall. She explains the difference between these two types of memory, saying, “An example of immediate recall is someone tells you a series of directions to get somewhere, and you’re able to repeat them back.”

“Delayed recall is being able to remember those directions a few minutes later, as you’re on your way,” she adds.

The researchers studied how these abilities change over time, together with genetic markers. Prof. Prescott and her colleagues used the verbal memory test results from two nationally representative surveys: the United States Health and Retirement Survey (HRS) and the English Longitudinal Study of Ageing (ELSA).

The former interviewed participants once every 2 years between 1996 and 2012, and the latter did so between 2002 and 2012.

For the test of immediate recall, the participants were read a list of 10 nouns and were asked to say them back to the interviewer immediately. But for the delayed recall test, the interviewer waited 5 minutes before asking participants to repeat the list.

The two memory types were ranked on a scale from 0 to 10. Too large a difference between the scores from one type of memory and the other may be a sign of Alzheimer’s disease or another dementia.

As Prof. Prescott explains, “You would be more worried about a person who has scores of 10 and 5 than a person with scores of 6 and 4.” In these tests, participants scored 5.7 for the immediate recall and 4.5 for the delayed recall, on average.

To avoid population bias, the researchers focused on participants of European descent. They also excluded participants who said that they had been diagnosed with “Alzheimer disease, dementia, senility, or serious memory-related problem.”

In total, the researchers examined 20,650 HRS participants and 11,391 ELSA participants, all aged 50 and above. They adjusted the data for age and sex. Prof. Prescott and colleagues also examined the genetic data from 7,486 HRS participants and 6,898 ELSA participants.

Overall, the scientists examined 1.2 million genetic variations in the human genome, looking for associations between these gene variations and the results of the memory tests.

Only TOMM40 was found to be strongly associated with a decline in immediate and delayed recall. The results also showed an association with the “traditional” genetic culprit, ApoE4, but the link was not as strong.

Additionally, the analysis revealed that the e3 variant of the ApoE gene was also associated with a low memory score, when found in conjunction with the TOMM40 gene.

These results suggest that TOMM40 may affect memory decline independently of the e4 version of the ApoE gene. “Our findings indicate that TOMM40 plays a larger role, specifically, in the decline of verbal learning after age 60,” say the authors. “Other studies may noy have detected the effects of TOMM40,” adds Prof. Prescott.

The results from this study provide more evidence that the causes of memory decline are even more complicated than we thought before, and they raise the question of how many findings in other studies have been attributed to ApoE4 that may be due to TOMM40 or a combination of TOMM40 and ApoE4.”

Prof. Carol A. Prescott

Further studies, the researchers note, should focus on the link between ApoE3 and TOMM40, in order to show how their conjugated effect impacts memory and cognitive decline.