The presence of four misfolded proteins linked to neurodegeneration is common in the brains of older adults and is associated with dementia and impaired cognition, researchers have found. The misfolded proteins - tau neurofibrillary tangles, amyloid-beta, alpha-synuclein, and transactive response DNA-binding protein 43 (TDP-43) - are often seen in older brains. But few studies have investigated the phenotype of "quadruple misfolded proteins," or QMP, as Dr. Erin L. Abner and colleagues at the University of Kentucky, in Lexington, named the co-existence of all four proteinopathies. To describe this phenotype, including the trajectories of global cognition, the team used brain-autopsy data from 375 individuals who had participated in a longitudinal community-based cohort study of aging and dementia conducted by the University of Kentucky Alzheimer Disease Center. The mean age at death was 86.9 years, and most patients were women (61.9%) and white (96.8%). Multiple proteinopathies were common: 43.2% of the participants had two misfolded proteins, 38.1% had three, and 12.3% had four, the researchers report in JAMA Neurology. The prevalence of dementia was highest among individuals in the QMP group (89.1%), followed by those with tau, amyloid-beta, and TDP-43 (81.7%); tau Braak stage V to VI and amyloid-beta (71.9%); and tau, amyloid-beta, and alpha-synuclein (61.1%). In contrast, among the 45 individuals with a final diagnosis of mild cognitive impairment (MCI), none had QMP. The mean time spent in the MCI state was shortest among those in the QMP group, suggesting a more aggressive disease course for these individuals. The lowest final mean Mini-Mental State Examination (MMSE) score was observed in the QMP group overall and in the subgroup of individuals with initially normal cognition, even 12 years before death. "These observations have potentially significant implications for clinical practice and public health, given that strategies to prevent or manage Alzheimer disease dementia may be complicated by the unrecognized presence of multiple additional neuropathologies," the authors conclude. The study did not have commercial funding. Dr. Abner did not respond to a request for comments. —Reuters Staff Source
