Incidence of altered proteins in the aging brain: Implications for biological diagnostic markers

BackgroundIn aging-related neurodegeneration, therapeutic interventions directed at defined protein targets have been launched. A key step has been developing diagnostic biological markers, followed by immunotherapy. These steps have been achieved for amyloid-β protein (Aβ).ObjectiveTo evaluate, based on brain pathology, how frequently Aβ would be detectable in blood or cerebrospinal fluid in older individuals.MethodsWe assessed brain tissue from 1825 deceased subjects, 20% of whom were demented. We examined the presence of Aβ, hyperphosphorylated τ (HPτ), Transactive DNA-binding protein 43 (TDP-43), and α-synuclein (αS) using immunohistochemistry. The extent of these alterations was assessed following current consensus criteria.ResultsThe combination of Aβ/HPτ, constituting Alzheimer's disease neuropathological change (ADNC), was detected in 64% of subjects, increasing significantly (Pearson's Chi-Square p = 0.001) from 46% in the 5^th decade to 81% in the 9^th decade. In 506 subjects (28% of the cohort), intermediate or high levels of ADNC were observed an extent reported as assessable in cerebrospinal fluid. Among these, 235 were non-demented and would have been identified as being at risk of Alzheimer's disease. Most (74%) displayed concomitant pathologies, making it impossible at this stage to determine which pathology will eventually lead to cognitive impairment.ConclusionsCommon ADNC and frequent concomitant pathologies in older individuals will influence the interpretation of diagnostic biological tests. Current tests can confirm that a subject displays ADNC; however, a definite diagnosis can only be achieved through postmortem neuropathological assessment. Present diagnostic tests are too crude to detect early or low-level ADNC.