Figure 1.

ND pathologies, combinations and categories of combinations. Eight clinically defined cohorts were examined including unimpaired individuals and those with clinical Alzheimer’s disease, mixed dementia, ALS, FTD, MSA, probable LBD, or probable tauopathies. Ten assessed pathologies (see the ‘Materials and methods’ section) resulted in a heterogeneous mix of 161 pathological combinations, including 35 combinations in the unimpaired cohort. To better understand this heterogeneity, we organized the pathological combinations into five broad categories based on their age-related frequency: ‘Ageing only’ for the unimpaired group combinations; ‘ND only’ if only the expected pathology for that individual’s clinical phenotype was present; ‘ND + ageing’ if the expected pathology was present together with ageing-related pathologies at a similar prevalence as the unimpaired group; ‘ND + associated’ if the expected pathology was present together with other pathologies not observed in the unimpaired group or observed at a greater frequency and ‘Other ND’ if the expected pathology was not present. As an example, a subset of observed pathological combinations is shown for clinical Alzheimer’s disease. In this cohort, the combinations A-B-C and A-B-C-CAA are the ND only combinations. A-B-C-CVD was an ND + ageing combination, while A-B-C-TDP and A-B-C-LB-CAA were ND + associated combinations. Only rarely did clinical Alzheimer’s disease involve Other ND combinations such as TDP-B or Tau or Ageing only combinations such as CVD, A or A-B.