Pathological combinations in neurodegenerative disease are heterogeneous and disease-associated.

Abstract

Pathologies that are causative for neurodegenerative disease (ND) are also frequently present in unimpaired, older individuals. In this retrospective study of 1,647 autopsied individuals, we report the incidence of ten pathologies across ND and normal ageing in attempt to clarify which pathological combinations are disease-associated and which are ageing-related. Eight clinically defined groups were examined including unimpaired individuals and those with clinical Alzheimer's disease, mixed dementia, amyotrophic lateral sclerosis, frontotemporal degeneration, multiple system atrophy, probable Lewy body disease, or probable tauopathies. Up to seven pathologies were observed concurrently resulting in a heterogenous mix of 161 pathological combinations. The presence of multiple, additive pathologies associated with older age, increasing disease duration, APOE e4 allele, and presence of dementia across the clinical groups. 15-67 combinations occurred in each group with the unimpaired group defined by 35 combinations. Most combinations occurred at a < 5% prevalence included 86 that were present in only 1-2 individuals. To better understand this heterogeneity, we organized the pathologic combinations into five broad categories based on their age-related frequency: 1) Ageing only for the unimpaired group combinations, 2) ND only if only the expected pathology for that individual's clinical phenotype was present, 3) Other ND if the expected pathology was not present, 4) ND + ageing if the expected pathology was present together with aging-related pathologies at a similar prevalence as the unimpaired group, and 5) ND + associated if the expected pathology was present together with other pathologies either not observed in the unimpaired group or observed at a greater frequency. ND only cases comprised a minority of cases (19-45%) except in the amyotrophic lateral sclerosis (56%) and multiple system atrophy (65%) groups. The ND + ageing category represented 9-28% of each group, but was rare in Alzheimer's disease (1%). ND + associated combinations were common in Alzheimer's disease (58%) and Lewy body disease (37%) and were observed in all groups. The Ageing only and Other ND categories accounted for a minority of individuals in each group. This observed heterogeneity indicates that the total pathological burden in ND is frequently more than a primary expected clinicopathological correlation with a high frequency of additional disease- or age-associated pathologies.