Lewy bodies commonly occur in
Alzheimer's disease, and
Alzheimer's disease pathology is frequent in Lewy body diseases, but the burden of co-pathologies across
neurodegenerative diseases is unknown. We assessed the extent of tau,
amyloid-β, α-
synuclein and
TDP-43 proteinopathies in 766 autopsied individuals representing a broad spectrum of clinical
neurodegenerative disease. We interrogated pathological
Alzheimer's disease (n = 247); other
tauopathies (n = 95) including
Pick's disease, corticobasal disease and
progressive supranuclear palsy; the
synucleinopathies (n = 164) including
multiple system atrophy and
Lewy body disease; the
TDP-43 proteinopathies (n = 188) including
frontotemporal lobar degeneration with TDP-43 inclusions and
amyotrophic lateral sclerosis; and a minimal pathology group (n = 72). Each group was divided into subgroups without or with co-pathologies. Age and sex matched logistic regression models compared co-pathology prevalence between groups. Co-pathology prevalence was similar between the minimal pathology group and most
neurodegenerative diseases for each
proteinopathy: tau was nearly universal (92-100%),
amyloid-β common (20-57%); α-
synuclein less common (4-16%); and TDP-43 the rarest (0-16%). In several
neurodegenerative diseases, co-pathology increased: in
Alzheimer's disease, α-
synuclein (41-55%) and TDP-43 (33-40%) increased; in
progressive supranuclear palsy, α-
synuclein increased (22%); in corticobasal disease, TDP-43 increased (24%); and in neocortical
Lewy body disease,
amyloid-β (80%) and TDP-43 (22%) increased. Total co-pathology prevalence varied across groups (27-68%), and was increased in high
Alzheimer's disease,
progressive supranuclear palsy, and neocortical
Lewy body disease (70-81%). Increased age at death was observed in the minimal pathology group,
amyotrophic lateral sclerosis, and
multiple system atrophy cases with co-pathologies. In
amyotrophic lateral sclerosis and neocortical
Lewy body disease, co-pathologies associated with
APOE ɛ4.
Lewy body disease cases with
Alzheimer's disease co-pathology had substantially lower Mini-Mental State Examination scores than pure
Lewy body disease. Our data imply that increased age and
APOE ɛ4 status are risk factors for co-pathologies independent of
neurodegenerative disease; that
neurodegenerative disease severity influences co-pathology as evidenced by the prevalence of co-pathology in high
Alzheimer's disease and neocortical
Lewy body disease, but not intermediate
Alzheimer's disease or limbic
Lewy body disease; and that tau and α-
synuclein strains may also modify co-pathologies since
tauopathies and
synucleinopathies had differing co-pathologies and burdens. These findings have implications for clinical trials that focus on monotherapies targeting tau,
amyloid-β, α-
synuclein and TDP-43.