Prevalence and Clinical Phenotype of Quadruple Misfolded Proteins in Older Adults

Importance Quadruple misfolded proteins (tau neurofibrillary tangles, amyloid-beta [A beta], alpha-synuclein, and transactive response DNA-binding protein 43 [TDP-43]) in the same brain are relatively common in aging. However, the clinical presentation, associated factors, frequency in community-based cohorts, genetic characteristics, and cognitive trajectories associated with the quadruple misfolded proteins phenotype are not well understood. Objective To describe the quadruple misfolded proteins phenotype, including the trajectories of global cognition, in an autopsy cohort. Design, Setting, and Participants This retrospective cohort study used brain autopsy data from the University of Kentucky Alzheimer Disease Center (UK-ADC) Brain Bank. Participants were deceased individuals who were enrolled in a longitudinal community-based cohort study of aging and dementia in central Kentucky conducted by the UK-ADC. Included participants were enrolled in the UK-ADC cohort between January 1, 1989, and December 31, 2017; aged 55 years or older at baseline; and followed up for a mean duration of 10.4 years. The participants had Alzheimer disease pathology (tau and A beta), alpha-synuclein, and TDP-43 data, along with Braak neurofibrillary tangle stage I to VI. Data analysis was conducted between February 1, 2019, and September 30, 2019. Main Outcomes and Measures Frequency of quadruple misfolded proteins was estimated, and proteinopathy group characteristics and associations with global cognition were evaluated. Multinomial logistic regression was used to estimate the association of proteinopathy group with participant characteristics, including age at death, sex, and apolipoprotein epsilon 4 (APOE epsilon 4) allele. Generalized estimating equations were used to estimate the probability of obtaining Mini-Mental State Examination (MMSE) scores within the normal cognition (27-30 points) and severe impairment (<= 13 points) ranges during the 12 years before death. Results The final sample included 375 individuals (mean [SD] age at death, 86.9 [8.0] years); 232 women [61.9%]). Quadruple misfolded proteins were detected in 41 of 214 individuals with dementia (19.2%). Overall, 46 individuals (12.3%) had quadruple misfolded proteins, whereas 143 individuals (38.1%) had 3 proteinopathies. Dementia frequency was highest among those with quadruple misfolded proteins (41 [89.1%]), and participants with quadruple misfolded proteins had the lowest final mean (SD) MMSE scores of 13.4 (9.8) points. Adjusting for age at death and sex, the APOE epsilon 4 allele was associated with higher odds of quadruple misfolded proteins (adjusted odds ratio, 2.55; 95% CI, 1.16- 5.62; P = .02). The quadruple misfolded proteins group had both the lowest probability of obtaining MMSE scores in the normal cognition range, even 12 years before death, and the highest probability of having MMSE scores in the severe impairment range. Conclusions and Relevance Quadruple misfolded proteins appear to be a common substrate for cognitive impairment and to be associated with an aggressive course of disease that typically ends with severe dementia. The prevalence of comorbid alpha-synuclein and TDP-43 with Alzheimer disease pathology (tau and A beta) may complicate efforts to identify therapies to treat and prevent Alzheimer disease. This cohort study examines brain autopsy data for the presence of quadruple misfolded proteins (tau, amyloid-beta, alpha-synuclein, and transactive response DNA-binding protein 43) and their association with cognitive decline in older adults. Question How frequently are both comorbid alpha-synuclein and transactive response DNA-binding protein 43 observed simultaneously in brains of individuals with Alzheimer disease (defined by amyloid-beta and tau proteins), and do the characteristics associated with the presence of quadruple misfolded proteins differ from those of other proteinopathies? Findings In this cohort study of brain autopsy data from 375 older adults, quadruple misfolded proteins (tau, amyloid-beta, alpha-synuclein, and transactive response DNA-binding protein 43) were commonly detected. Mild cognitive impairment transitioned to dementia most rapidly for those with these 4 proteinopathies, which were present in 19% of individuals with dementia. Meaning This study suggests that quadruple misfolded proteins are a common but underappreciated phenotype that is associated with impaired cognition.