Concussion Sequelae Boost Alzheimer's Risk

Post-traumatic amnesia (PTA) and chronic vascular lesions caused by traumatic brain injury (TBI) is tied to an increased risk of subsequent Alzheimer's disease (AD), new research suggests.

Results from a case-controlled retrospective study showed the presence of PTA or of vascular lesions on neuroimaging in patients with TBI was significantly associated with up to an almost fourfold increased risk of AD.

The study highlights the seriousness of TBIs, which some people still consider "just a hit on the head," co-investigator Jehane H. Dagher, MD, associate professor, Department of Physical Medicine and Rehabilitation, University of Montreal, and head of the TBI program at the Montreal Rehabilitation Institute, Quebec, Canada, told Medscape Medical News.

Dr Jehane Dagher

"These patients end up with cognitive decline, difficulties organizing, planning, getting back into the workforce, and getting back to regular life. They require a lot of help from their loved ones and from their community and medical systems," Dagher added.

The findings were published online December 30, 2021, in Alzheimer Disease & Associated Disorders.

Increasing Prevalence

The prevalence of neurocognitive disorders (NCDs) is increasing due, in part, to the aging population, Dagher noted. AD is the most common cause of NCDs and about 35% of individuals 85 years and older develop the disorder.

TBI is increasingly recognized as a major risk factor for NCDs. The fact that fewer than 7% of patients with TBI go on to develop dementia suggests some patients might be more vulnerable than others.

Using medical records and medical insurance data, researchers identified 5642 patients with a TBI admitted to a tertiary trauma center over a 12-year period (2000 to 2012). The TBIs, most of which were mild, were the result of motor vehicle accidents, falls, assaults, and sports-related accidents.

The current analysis included 30 patients with TBI who developed AD dementia before the end of 2018 and 80 individuals who did not have dementia to act as the control group.

Patients in the dementia group had a median age at injury of 58.3 years vs 70.4 years for the control group. Median time to diagnosis of dementia following the injury was 3.3 years.

Among the study population, 25.5% were diagnosed with PTA, which is characterized by confusion and disorientation; 16.7% had a history of at least one TBI. A history of diabetes (19.4%), hypertension (55.5%), dyslipidemia 37.0%), or coronary artery disease (25.0%) was also recorded. None of the participants had a history of peripheral artery disease.

Initial scans showed vascular lesions and atrophy in 23.6% and 27.6% of patients, respectively.

Significant Association

Results showed a significant association between PTA and AD dementia, with higher odds for those with vs without an AD diagnosis (odds ratio [OR], 2.88; 95% CI, 1.06-7.81; P = .04).

As PTA is related to severity of the brain injury, this finding suggests "someone with a severe TBI is more at risk for developing dementia," Dagher noted.

The odds of developing AD dementia were also higher for those with evidence of vascular lesions on neuroimaging compared with those who did not have lesions (OR, 3.81; 95% CI, 1.04-4.07; P = .04).

Chronic vascular lesions may indicate small vessel disease (SVD), which could act in synergy with tau proteins, a hallmark of AD, the investigators note. It could be that the ischemia resulting from SVD accelerates the pathogenesis of AD and that TBI may hasten this process, they add.

Risk factors such as diabetes, hypertension and dyslipidemia did not significantly affect dementia risk, likely because of the small number of participants with dementia, said Dagher. Age also was not a significant factor in dementia risk, possibly because patients were followed for only 10 years, she noted.

Dagher added that the lack of association with the Glasgow Coma Scale (GCS) was because most of the study population had mild TBI.

Researchers excluded patients with a dementia diagnosis within 6 months of injury to avoid reverse causation. For example, falls causing a brain injury may be an early sign of dementia.

This strengthens the suggestion that TBI is a factor leading to and not a consequence of dementia, the investigators write.

Dagher emphasized the importance of having trauma neurosurgeons caring for TBI patients, and for these doctors to follow "the appropriate guidelines to minimize damage" after an injury.

In the longer term, preventing TBI-linked dementia should involve improving resources for testing and treating TBI patients, she said.

Strengths, Weaknesses

Commenting for Medscape Medical News, David Knopman, MD, professor of neurology, Mayo Clinic, Rochester, Minnesota, said the finding that PTA and brain vascular disease are associated with dementia "makes sense."

In addition, a strength of the study was its large sample size of older individuals, said Knopman, who was not involved with the research.

However, he noted several study features that limit interpretation. "The main one is that an insurance record diagnosis of 'Alzheimer disease' has a very noisy and imprecise relationship to the biological diagnosis of plaque and tangle disease, for example, Alzheimer disease," he said.

In addition, the use of the term AD dementia in the study is "misleading" because in clinical practice it corresponds to dementia from any number of etiologies, Knopman noted. "It creates a false impression of specificity for the plaque and tangle pathology that actually is Alzheimer disease."

It would have been clearer if the investigators had referred to the main outcome as "all cause dementia," he said.

Knopman also questioned excluding patients with a diagnosis of dementia for only up to 6 months after their TBI to avoid reverse causality. Instead, the researchers "should have at least provided analyses where they excluded persons where the lag between TBI and the dementia diagnosis was up to 2 or 3 years," he said.

"The TBI could have been caused by a fall that in turn was due to incipient brain vascular or neurodegenerative disease," such as Parkinson disease, Knopman added.

The shorter cut-off could mean "what was diagnosed as dementia was really a direct extension of the post-traumatic cognitive impairment and not truly a separate event,” he said.

Knopman also would have liked an analysis that stratified by age, for example, those under the age of 70 years vs those who were older. "I would be surprised if age didn't have some role in the findings," although it wasn't significant in the main analysis, he concluded.

The study was funded by the Research Institute, McGill University Health Centre. The investigators have reported no relevant financial relationships.

Alzheimer Disease & Associated Disorders. Published online December 30, 2021. Abstract

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