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

Alzheimer's disease neuropathological change (ADNC), defined as the combination of Aβ and hyperphosphorylated τ, was detected in 64% of all subjects examined.

• Brain tissue from 1825 deceased subjects was assessed, 20% of whom were demented.
• ADNC prevalence increased significantly from 46% in the 5th decade to 81% in the 9th decade (Pearson's Chi-Square p = 0.001).
• Detection was performed using immunohistochemistry following current consensus criteria.
• The cohort included subjects across multiple decades of age.

Intermediate or high levels of ADNC, at an extent considered assessable in cerebrospinal fluid, were observed in 506 subjects (28% of the cohort).

• Of these 506 subjects, 235 were non-demented and would have been identified as being at risk of Alzheimer's disease.
• This represents a substantial portion of cognitively normal older individuals who would test positive on biological diagnostic markers.
• The findings raise questions about the interpretation of positive biomarker results in older non-demented individuals.

Among the 506 subjects with intermediate or high ADNC levels, the majority (74%) displayed concomitant pathologies.

• Concomitant pathologies examined included TDP-43 and α-synuclein (αS) in addition to Aβ and hyperphosphorylated τ.
• The presence of multiple concurrent pathologies makes it impossible at this stage to determine which pathology will eventually lead to cognitive impairment.
• All four altered proteins (Aβ, HPτ, TDP-43, and αS) were assessed using immunohistochemistry.

Current biological diagnostic tests are insufficient for detecting early or low-level ADNC.

• Present diagnostic tests were characterized as 'too crude to detect early or low-level ADNC.'
• Current tests can confirm that a subject displays ADNC but cannot provide a definitive diagnosis.
• A definitive diagnosis can only be achieved through postmortem neuropathological assessment.
• Therapeutic interventions directed at defined protein targets, including immunotherapy, have been launched following development of diagnostic biological markers for Aβ.

The prevalence of ADNC increased substantially with advancing age across the study cohort.

• ADNC prevalence rose from 46% in the 5th decade to 81% in the 9th decade of life.
• The increase was statistically significant (Pearson's Chi-Square p = 0.001).
• The cohort of 1825 subjects included individuals with and without dementia, with 20% being demented.
• The high background prevalence of ADNC in aging individuals has direct implications for the interpretation of biological diagnostic markers.