After the recent suicide of Dave Duerson, however, and last Monday’s announcement that he also had chronic traumatic encephalopathy, the brain damage formerly associated with boxers, the finding shocked no one. Duerson became the 14th retired N.F.L. player — of 15 examined by Boston University researchers — to test positive for the condition.  Waters and Duerson bookend a remarkable shift in the understanding of football brain trauma: four years after a few positive tests begged explanation, questions mainly surround the absence of negatives.  “It makes you worry as a player — I would imagine all of us have it,” said Chidi Ahanotu, 40, who played defensive lineman mostly for Tampa Bay from 1993 to 2004. “To what degree, I don’t know. But I don’t know how you can’t think that.”  So far, though, each successive case of C.T.E. has said more about the existence of the disease than the true breadth of it.  The set of 15 players tested by B.U. researchers to this point is far from a random sample of N.F.L. retirees that could represent the wider population. Many of the players died under conditions that could be related to C.T.E.: Waters and Duerson by suicide, John Grimsley from a gun accident, Tom McHale from a drug overdose. Their families then donated the brains largely to seek an explanation for their behavior.  “There’s a tremendous selection bias, so you can’t make any conclusions about the incidence or prevalence of disease,” said Dr. Ann McKee, the B.U. group’s lead neuropathologist and director of neuropathology at New England Veterans Administration Medical Centers.  She added: “A family is much more likely to donate the brain of a loved one if they have even the smallest suspicion that something was wrong. If they were perfectly confident that they were functioning 100 percent normally, they’re much less likely to go through the process.”  In other words, although 93 percent of players tested so far have had C.T.E., that does not mean that 93 percent of retired players living today have it. Even if they do, the disease might not be compromising their memory, emotional state or impulse control in noticeable ways.  The only test for the condition is brain autopsy after death.  Along with a West Virginia University group that has found similarly high rates of C.T.E. in retired football players, what the Boston University researchers crave most today is not more middle-aged N.F.L. veterans who died with symptoms, but players of all ages — and nonplayers — who never showed symptoms.  B.U. has received brain-donation commitments from 128 living, current and retired N.F.L. players, but only 11 have died and have brains awaiting autopsy. McKee said that she has examined about 300 nonplaying males and never found C.T.E. — but not many of them were middle-aged, impeding sound comparisons to cases like Waters and Duerson.  “What we desperately need is what one would call healthy brains,” said Dr. Robert Cantu, a co-director of the B.U. group. “If those have C.T.E., then that opens up lots of other questions.”  If tests find asymptomatic players without the disease, then the 93 percent figure would fall drastically and give a fairer estimate of a player’s actual chance of having or developing it. If the brains of high-functioning players still show the protein deposits and other pathologies that mark C.T.E., that would raise the issue of why some people with the disease are affected by the damage and others not.  “Individuals with mild disease may be resilient — resilient for various reasons, their genetic makeup being the most likely,” McKee said. “So they would be considered positive, but an asymptomatic case.  “The other thing about any brain disease, not just C.T.E. but say Alzheimer’s disease, is there’s this thing called cognitive reserve. Some individuals who are intelligent and have great capacity for rewiring their nervous system or taking different routes to access the same information can have a lot of structural damage without exhibiting any symptoms.”  The fact that 14 retired N.F.L. players have been found to have C.T.E. can be spun in many directions, of course. Adding the “out of 15 tested” part accentuates the presence of a problem. Saying that it’s “only ‘x’ cases” of a population of about 15,000, as skeptics inside and outside the N.F.L. once did with each successive case, only minimized what the presence of even “x” positives means — that some players wound up with a devastating disease that simply is not found in people who haven’t sustained repeated brain trauma.  As recently as last year, Johns Hopkins University held an N.F.L.-sponsored symposium pointedly titled “Traumatic Brain Injury in Professional Football: An Evidence-Based Perspective,” whose brochure cited “hype” and “assertions” of a problem, and whose director accused McKee of misleading people.  “The only players I know of who have been examined are those who have died and have ended up on Dr. McKee’s table,” that doctor, Constantine Lyketsos of Johns Hopkins, said in an interview before the symposium. “We don’t know the denominator here. It could be 12 or 15 or 15,000.”  It’s neither, naturally. The rate of brain disease among retired N.F.L. players may wind up stunningly high — particularly among linemen — but that 93 percent figure will assuredly be diluted by the slower inclusion of healthy brains. Then again, to suggest that the only 14 players with C.T.E. have been found and that the other 14,986 men will be unaffected is absurd.  Put another way: If 14 of 15 people who died in a town of 15,000 later received diagnoses of various degrees of water poisoning, the rest would have legitimate reason to worry. And to avoid water fountains.
Researchers at Boston University acknowledge they need to study a wider sample of the brains of former N.F.L. players to validate findings on trauma.