Aims

Objectives. Basal forebrain cholinergic neurons (BFCN) and their cortical axons sustain substantial loss in the amnestic variant of AD, and this loss forms the basis of cholinergic therapy. The status of BFCN in non-amnestic variants of AD, other tauopathies, and TDP-43 proteinopathies is not clear. The objective of these experiments was to investigate cholinergic neuronal and axonal pathology in the aphasic variant of AD, in corticobasal degeneration (CBD), and in primary progressive aphasia (PPA) with TDP-43 inclusions to determine if cholinergic therapy is also indicated in these disorders.

Methods

Methods. Brains from 5 PPA participants with confirmed pathological diagnosis of AD, 5 participants with confirmed CBD, and 5 PPA participants with TDP-43 proteinopathy were used. Cortical cholinergic axons were stained for acetylcholinesterase activity. Phosphorylated tau (AT8), phosphorylated TDP-43, and Aβ were visualized immunohistochemically. Numbers of BFCN, density of cholinergic axons and BFCN with inclusions were quantified.

Results

Results. Substantial BFCN tangles and loss, and significant degeneration of cortical cholinergic axons were observed in PPA with AD pathology. Variable proportions of BFCN in CBD contained tau inclusions. However, BFCN number and density of cortical cholinergic axons remained intact. No mature inclusions were present in BFCN of PPA participants with TDP-43 proteinopathy; only pre-inclusions were present.

Conclusions

Conclusions. The aphasic variant of AD displays significant degeneration of BFCN and their axons. In contrast, this system remains intact in the tauopathy of CBD, and TDP-43 proteinopathy of PPA. Therefore, cholinergic therapy is likely to be beneficial in the former, but not the latter two disorders.