Are comorbidities compatible with a molecular pathological classification of neurodegenerative diseases?

The purpose of this review is to provide an update on comorbidities in neurodegenerative conditions. The term comorbidity is used here to distinguish cases with overlapping pathogenic mechanisms, which includes combinations of neurodegenerative proteinopathies from cases with multimorbidity, which is defined as concomitant brain and systemic disorders with different pathogenic mechanisms.

Comorbid proteinopathies are more frequent in both sporadic and hereditary neurodegenerative diseases than previously assumed. The most frequent additional proteinopathies are related to Alzheimer's disease, Lewy body disorder, and limbic predominant transactive response DNA-binding protein 43 proteinopathy, however, different forms of tau pathologies are also increasingly recognized. In addition to ageing, synergistic interaction of proteins, common disease pathways, and the influence of genetic variations are discussed as possible pathogenic players.

Comorbid proteinopathies might influence the clinical course and have implications for biomarker and therapeutic development. As pure forms of proteinopathies are still observed, the notion of current molecular classification is justified. This corroborates elucidation of various pathogenic pathways leading to neurodegeneration. Assuming that single proteins and associated pathways are targeted in therapy trials, efforts are needed to better stratify patients and to select pure proteinopathy forms lacking unfavorable genetic constellations. Otherwise combined therapeutic strategies might be necessary for comorbid proteinopathies.