Neuropathological correlates of cerebral multimorbidity

Age associated neurodegenerative diseases are characterized by intra- and extracellular aggregation and deposition of misfolded proteins. The neuropathological classification of neurodegenerative diseases is based on the semiquantitative assessment of these misfolded proteins, that constitute the neuropathological hallmark lesion for the respective disease: e.g. Alzheimer's disease (AD), amyloid-β (Aβ) hyperphosphorylated tau (tau); Lewy body diseases, α- synuclein (α-syn); frontotemporal lobar degeneration, tau, TDP-43, ubiquitin or FUS. In addition, cerebrovascular lesions are assessed for the diagnosis of vascular dementia. However, in brains of elderly patients suffering from neurodegenerative diseases multiple pathologies are usually present and even in clinically characterized prospective cohorts additional pathologies are frequently found at post mortem examination. On the other hand, various amounts of AD pathology are frequently seen in brains of non-demented elderly and the threshold to cause clinical overt dementia is ill defined as additional co-morbidities (e.g., cerebrovascular lesions) might lower the threshold for clinical dementia in some cases. It becomes increasingly clear that the clinical picture of dementia in most aged patients results from a multimorbid condition in the CNS rather than from one single disease and data from animal studies suggest that Aβ, tau, and α-syn interact in vivo to promote the aggregation and accumulation of each other. We suggest that clinico-pathological correlative studies using a more quantitative approach in the assessment of neuropathological lesions are warranted to elucidate cerebral multimorbidity and to identify suitable targets for targeted therapeutic strategies against age associated neurodegeneration.