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

TL;DR

This study examines how often altered proteins linked to Alzheimer's disease appear in aging brains and their potential as diagnostic markers.

Contribution

The study provides new insights into the frequency of Alzheimer's-related protein changes in older individuals and their detectability in biological fluids.

Findings

Alzheimer's disease neuropathological changes (ADNC) were detected in 64% of subjects, increasing with age.

28% of subjects showed ADNC at levels potentially detectable in cerebrospinal fluid, including many non-demented individuals.

Most subjects with ADNC had other brain pathologies, complicating the link between specific protein changes and cognitive decline.

Abstract

In 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).

To evaluate, based on brain pathology, how frequently Aβ would be detectable in blood or cerebrospinal fluid in older individuals.

We 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.

The 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 5th decade to 81% in the 9th 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.

Common 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.

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