Advanced chronic traumatic encephalopathy (CTE) is associated with a fourfold increased risk of dementia and is often misdiagnosed as Alzheimer's disease (AD).

Results of a large autopsy study of more than 600 donor brains from individuals with a history of repeated head trauma offer the clearest evidence to date that advanced CTE (stages III and IV) is independently linked to a significantly increased risk of dementia.

Among donors with advanced CTE but no evidence of AD pathology, AD was the most common diagnosis made during life. 

The researchers noted that the frequent misclassification of CTE as AD highlights the importance of including CTE in the differential diagnosis of dementia — particularly among individuals with a history of repeated head trauma. They also called for the use of blood-based biomarkers to help exclude AD and recommended that CTE be incorporated into the group of disorders recognized as AD-related dementias. 

“That is an important finding. Clinicians need to be aware that CTE can clinically manifest very similarly to Alzheimer’s disease,” principal investigator Michael Alosco, PhD, clinical neuropsychologist and associate professor of neurology at the Chobanian and Avedisian School of Medicine, Boston University, Massachusetts, told Medscape Medical News. 

The study was published online January 27 in Alzheimer’s & Dementia.

Highest Risk Among Athletes

CTE is a degenerative brain disease that stems from multiple head impacts and can only be accurately diagnosed on autopsy. Although the incidence is highest among athletes, CTE has also been found in nonathletes. 

The disease can be comorbid with other neurodegenerative disorders such as AD, which has made it difficult for researchers to assess the specific impact CTE might have on neurologic symptoms in previous studies.

To better understand the link between CTE stage and cognitive, functional, and neuropsychiatric symptoms, investigators analyzed brains from 614 donors (97% male; 81% White; mean age of death, 52 years) with a history of head impacts. Of these, 366 had autopsy-confirmed CTE and 248 did not. 

Diagnosis was based on CTE pathognomonic lesion criteria, and CTE severity was ranked from mild (I) to severe (IV) using the McKee CTE progressive staging scheme. Neuropathologists were blinded to donors' clinical data and history during CTE diagnosis.

Donors who had major progressive brain diseases including AD, Lewy body dementia, motor neuron disease, or frontotemporal lobar degeneration were excluded so that researchers could better isolate the relationship between CTE and dementia.

Donors' friends and family completed surveys, clinical interviews, and scales to evaluate donors' cognition, function, mood, and behavior during life. 

Advanced CTE and Dementia Risk

Most of the sample were former American football players. Those with more advanced CTE had played more years of football (P < .001) and at a higher level (P < .001).

Compared to no CTE, those with the most severe form of the disease were four times more likely to have dementia (odds ratio [OR], 4.48; P = .001). CTE stage III was associated with a doubling of dementia risk (OR, 2.12; P = .011). 

Stages I and II were not associated with increased odds of having dementia. This result wasn’t surprising, said Alosco, as the pathology in low-stage CTE is likely not dense enough to cause dementia, he said.

After adjusting for white matter rarefaction, cerebrovascular pathologies, and history of substance use treatment, CTE stage IV was still associated with similar odds of dementia.

Among those who had dementia and CTE, 40% were diagnosed with AD during life, and 38% were told they had an unspecified cause of dementia.

Higher CTE stage was associated with worse cognitive symptoms. Those with CTE stage IV had cognitive symptom scores that were almost twice as high as those without CTE. There were no associations between CTE and mood or behavioral symptoms. 

Study limitations were that the research may not have accounted for all potential neuropathologies, symptom accuracy could be affected by recall bias, and selection bias was possible as the donors were more likely to have CTE neuropathology.

Some Surprise Findings

The robust study was well-designed, and the dose-response of CTE pathology and increased odds of dementia further reinforce the findings, David Dodick, MD, immediate past chair of the American Brain Foundation, and chief science and medical officer at the Atria Health Institute in New York City, told Medscape Medical News. 

“I'm not surprised that there was an increased odds of dementia. CTE is fairly well established now as a cause for dementia,” said Dodick, who was not part of the study.

“What I was surprised by is that even in those with higher levels of neuropathology, there was no association with neurobehavioral dysfunction,” Dodick said, noting that part of the definition of traumatic encephalopathy syndrome — the clinical criteria for suspected CTE — is neurobehavioral symptoms.

But Alosco said the lack of a relationship between CTE and mood or behavior symptoms is potentially positive.

“It brings hope that these symptoms of depression or aggression that we often hear about in this setting might be treatable,” he said. 

CTE an AD-Related Dementia?

Based on the study findings, the investigators called for CTE to be formally considered as an AD-related dementia. 

“It is a cause of dementia, so I do think it should be formally recognized, but it does take several legislative efforts and advocacy to get to that place,” Alosco said, although he is not aware of any ongoing efforts to enact this.

Dodick agreed: “From a funding and caregiving standpoint, it makes sense, at this time, to include CTE as an Alzheimer’s-related dementia.” 

Grouping CTE and other AD-related dementias together allows for large unified federal budgets and reflects the fact that many people have mixed pathology. In terms of caregiving, patients with any of these diseases eventually need the same types of high-level support, memory care facilities, and palliative care, Dodick said.

Alosco and colleagues are currently conducting various studies to develop blood and brain biomarkers for CTE, which would be a significant step toward making it a treatable disease, he said.

“In our new study, we identified cognitive symptoms as an important outcome of CTE, and hopefully, we can combine this with a biomarker in the future (once developed) to get to an accurate diagnosis,” Alosco said.

The study was supported by the National Institutes of Health, National Institute of Neurological Disorders and Stroke, and National Institute on Aging. Alosco has reported receiving research support from Life Molecular Imaging. Dodick has disclosed a collaboration with Boston University Researchers.