Cognitive Impairment and Dementia-Related Diagnoses in Chronic Traumatic Encephalopathy: A Systematic Review and Meta-Analysis

Abstract

Background and objectives: Clinical features of individuals with autopsy findings of chronic traumatic encephalopathy (CTE) have been described for 50 years. Clinical criteria have been proposed, although cognitive correlates of CTE remain unknown. This study examined whether CTE was related to dementia and patterns of cognitive impairment to summarize the clinicopathologic evidence.

Methods: A systematic review and meta-analysis was performed, composed of a multicenter interdisciplinary team. Five databases were searched from their inception to March 2025. Original studies involving participants with neuropathologic findings of CTE and neuropsychological data were included. A multistage selection approach was used, including a review by neuropathologists to ensure that studies conformed to CTE consensus criteria. Methodological quality was rated from 9 items using a modified Murad Case Report Methodological Quality Tool. The main outcomes of interest were domains of cognitive functioning, based on objective testing, and prevalence of dementia-related clinical diagnoses in individuals with CTE. A random-effects meta-analysis examined prevalence of dementia-related diagnoses, and meta-regression examined whether Alzheimer-type neuropathology or any comorbid neuropathology was a moderator.

Results: A total of 36 studies comprising 563 unique CTE cases were included. Only 22 CTE cases (<5%) had objective neuropsychological data available from studies (k = 10) of acceptable quality. Deficits in memory, language, and attention were the most prevalent cognitive features, but all cases had comorbid non-CTE neuropathologies that may have been associated with cognitive impairment. Diverse neuropsychological impairments were observed, resulting in no consistent cognitive pattern, even for high CTE severity. Dementia-related diagnoses were prevalent (62%; 95% CI 48%-75%) in the meta-analysis (k = 13; n = 492), yet not strongly related to non-CTE neuropathologies recorded (estimate = 0.14, 95% CI -0.62 to 0.91; p = 0.714), including Alzheimer-type neuropathology (estimate = 0.21, 95% CI -0.03 to 0.45; p = 0.084).

Discussion: Limited CTE cases have been published with objective neuropsychological information. CTE cases show cognitive deficits resembling Alzheimer dementia, but a direct clinicopathologic link is inconclusive. While the meta-analytic findings suggest that CTE may be associated with cognitive impairment, further investigation is needed because heterogeneity in study designs prohibits clear conclusions. To realize any clinicopathologic links and inform future iterations of clinical criteria, a transition in how cognition is investigated in CTE will be needed and several research directions are proposed.