Alzheimer's Risk Allele Linked to Disease Severity in CTE  

Deborah Brauser

May 10, 2017

BOSTON — Carrying the APOE Ɛ4 gene variant is associated with increased disease severity in patients with chronic traumatic encephalopathy (CTE), new research suggests.

Dr Jesse Mez

A study of about 150 male patients who had played some level of football and had autopsy-confirmed CTE showed that APOE Ɛ4 was significantly linked to stage of disease, as well as to increased risk for dementia and perivascular hyperphosphorylated tau (ptau) density.

"There's a lot of data on APOE and its relationship to Alzheimer's disease, but there's less evidence relating it to other neurodegenerative diseases," Jesse Mez, MD, Boston University (BU) School of Medicine and the BU Alzheimer's Disease and CTE Center, Massachusetts, told Medscape Medical News.

"I think it's important to make the distinction here that the finding wasn't a risk for disease incidence, as we didn't compare cases to controls," said Dr Mez. "But we did find that it increases odds of having more tau pathology among cases and it increases risk for developing dementia among those with CTE pathology."

He presented the study results here at the American Academy of Neurology 2017 Annual Meeting (AAN).

Repetitive Head Impacts and PTau

CTE is a disease associated with repetitive head impacts (RHI), with a neuropathology of ptau deposition.

"All cases of neuropathologically confirmed CTE have had a history of RHI exposure; however, only a subset exposed to RHI develop CTE, suggesting a role for genetic risk factors," write the investigators.

They add that past research findings have been mixed on whether APOE Ɛ4 is a risk factor for CTE itself, but whether the so-called Alzheimer's gene is a risk factor for CTE ptau severity hasn't been shown before.

For their study, they wanted to evaluate whether the gene variant was associated with CTE disease severity based on three outcomes: CTE stage, ptau immunoreactivity density in the dorsolateral frontal lobe (using digital pathology slide scanning), and dementia status.

The researchers examined data from the VA-BU-CLF Brain Bank for 151 male football players (mean age at death, 62.9 years) with neuropathologic CTE. All were white, based on self-report.

In addition, friends and family members of the decedents served as "informants" during postmortem phone interviews and online surveys. Age at onset of symptoms, disease severity and progression, demographic characteristics, RHI exposure, and years of organized football played were collected.

The majority of the participants had played professional football (53%); 36% reached college-level play; and 9% and 3%, respectively, reached high school and youth levels only. The mean duration of play was 13.2 years.

Significant Risk Factors

In the full group, 33% had stage 4 CTE (the most severe form), 31% had stage 3, 24% had stage 2, and 13% had stage 1. Also, 17% had Alzheimer's disease (AD) pathology in addition to CTE, 54% had dementia, and 19.5% had the APOE Ɛ4 allele.

Although the odds ratio (OR) for CTE stage wasn't statistically significant for AD pathology (2.45; 95% confidence interval [CI], 0.95 - 6.31; P = .06), the ORs were significant for APOE Ɛ4, duration of play, and age at death.

Table 1. Associations Between Risk Factors and CTE Stage


OR of Being 1 Stage Higher (95% CI)

P Value

APOE Ɛ4 (per additional allele)

1.98 (1.13 - 3.46)


Duration of play (per year)

1.14 (1.07 - 1.21)


Age at death (per year)

1.06 (1.04 - 1.08)



The following tables show the relationships between these factors and ptau density and with dementia.

Table 2. Associations Between Risk Factors and Ptau Density


OR of Being 1 Quartile Higher (95% CI)

P Value

APOE Ɛ4 (per additional allele)

2.41 (1.25 - 4.66)


Duration of play (per year)

1.09 (1.02 - 1.17)


Age at death (per year)

1.04 (1.02 - 1.06)


AD pathology

6.86 (2.11 - 22.33)



Table 3. Associations Between Risk Factors and Dementia


OR (95% CI)

P Value

APOE Ɛ4 (per additional allele)

2.52 (1.06 - 5.95)


Age at death (per year)

1.12 (1.07 - 1.16)



"There was no significant interaction between APOE Ɛ4 and duration of play for any outcome," reported Dr Mez, noting that this was different from the abstract they originally submitted for the meeting. "And APOE Ɛ4 did not predict age of symptom onset," he added.

"In conclusion, it does appears to be a risk factor for CTE disease severity, both clinically and neuropathologically, so this is potentially a target for therapies that could slow CTE down."

However, Dr Mez pointed out that replication is needed by "an independent cohort" and that future research should examine how APOE Ɛ4 may affect CTE incidence among individuals who have been exposed to RHI.

Dr Frank Conidi

After the presentation, official discussant Frank Conidi, DOMS, private practice in headache and sports neurology in South Florida, asked whether the investigators looked at player position and whether that had any effect. Dr Mez reported that, unfortunately, they weren't able to determine positions within their patient population.

Early Screening for Athletes?

Dr Conidi then led a lively talk among the session attendees. He started off by asking: Given the possible possibility of APOE Ɛ4 as a risk for both CTE and AD, "as well as poor outcome in concussion," should athletes be screened early on?

"Should we do this in an effort to help them and their parents to make informed decisions on participation in high-impact contact sports?"

"I think early screening is a good idea, but I don't think we can jump that far yet," answered audience member Kevin E. Crutchfield, MD, director of the Comprehensive Sports Concussion Program at the Sandra and Malcolm Berman Brain & Spine Institute at LifeBridge Health in Baltimore, Maryland.

"Screening early will get a better denominator of the population that has APOE Ɛ4 participating in sports and following them longitudinally. But we're seeing a biased population with a high correlation. So we can't make that jump to screen genes in a population-wide study and make those specific recommendations at this time," said Dr Crutchfield.

He noted that kids are active less and less on their own and are looking more toward organized sports to remain physically active. "If we look at the potential risk for CTE versus the growing trend of obesity in our children in America, that's a big difference."

"I think most kids only exercise in organized sports, so we need to be careful," Dr Crutchfield added.  

Former National Football League player Fred Willis, founder and CEO of HPN Neurologic in West Newbury, Massachusetts, also weighed in during the discussion.

"Because of what's going on with concussion today and the liability factor, all of the pressure is being put on parents regarding returning to play. A simple way to approach this, I think, would be coming up with an effective way to baseline test these kids," said Willis.

"Programs in place in high schools are extremely ineffective, so we need to come up with a protocol with contact sports to effectively baseline kids against such things as SIS [second-impact syndrome] and get parents more involved."

Genetic Biomarkers as the "Holy Grail"

Dr Conidi later told Medscape Medical News that he thought the study was "excellent" and noted that the investigators have the largest brain bank in the country from athletes with CTE.

"To start looking at genetic biomarkers is probably going to be the Holy Grail, not just for APOE Ɛ4, but for others too. And as we look, we may find that there is a genetic predisposition to CTE," he said.

Also, "CTE may not even be its own disease," speculated Dr Conidi. "It could possibly be another tauopathy that we already know exists, whether in the form of Alzheimer's or frontal lobe dementia or whatever."

Session co-moderator, Jeffrey Kutcher, MD, Sports Neurology Clinic in Brighton, Michigan, noted that he is pleased to see how far research in this area has come over the last 4 to 5 years.

His fellow session co-moderator, Carmela Tartaglia, MD, University of Toronto, Ontario, Canada, agreed. But she also agreed with earlier comments that screening people at this time for APOE Ɛ4 "needs to be taken with a grain with salt."

Dr Carmela Tartaglia

"Obesity is at epidemic levels and we really don’t want to frighten people from exercising," said Dr Tartaglia. "We screen in cancer but we have treatments that will change the outcome. In Alzheimer's we don't screen, and people who screen themselves at home come into our offices frightened of their future, and we don't know what to tell them."

She stressed that it's important to put the current findings in context. "I think the way forward is for us to think of resiliency genes or factors and vulnerability factors. Thinking about it in that way makes sense."

Dr Mez, Dr Kutcher, and Dr Tartaglia have disclosed no relevant financial relationships. Dr Conidi reported being a consultant to the National Football League, the National Hockey League, Major League Baseball, the Pro Golf Association, the United States Tennis Association, and the National Collegiate Athletic Association. He also receives research support from the Seeing Stars Foundation.

American Academy of Neurology 2017 Annual Meeting (AAN). Abstract S9.001. Presented April 23, 2017.

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