Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated

Abstract

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.

Figure 1

Pathological tau, amyloid-β, α-synuclein and TDP-43 staging. Tau, amyloid-β, α-synuclein and TDP-43 pathologies were individually staged according to established criteria across 13 neuropathologically-defined groups. (A) Tau pathology principally took the form of Alzheimer’s disease-type neurofibrillary tangles, except in FTLD-Tau (i.e. PiD, CBD and PSP), allowing us to assign Braak stages and compare tau prevalence and severity (Montine et al., 2012). Co-pathological tau was nearly universal, and was commonly observed in the hippocampal formation (Braak I–II). (B) McKeith criteria staging of α-synuclein positive Lewy pathology was applied to all cases except the MSA group (McKeith et al., 2017). α-Synuclein (A-syn) co-pathological affected a minority of cases across neurodegenerative disease and was frequently limited to a brainstem or amygdala distribution except in the hAD group. (C) Amyloid phases were used to stage amyloid-β (Aβ) plaques (Montine et al., 2012). Amyloid-β plaque co-pathology was variably abundant across neurodegenerative disease except the nLBD group, which had an increased burden. (D) Distinct distributions of TDP-43 pathology defined the primary TDP-43 proteinopathies, but a common staging was possible for the remaining groups (Josephs et al., 2014). TDP-43 was rare to non-existent in several groups and frequently had a limbic distribution.

Figure 2

Frequency of single and multiple neurodegenerative disease co-pathologies. Pie charts depict amyloid-β (Aβ), α-synuclein (a-syn) and TDP-43 co-pathologies and multiple co-pathologies in separate colours with each pure neurodegenerative disease indicated in grey. Tau—represented by a black border—was ubiquitously present with the other co-pathologies, and only rarely negative in pure neurodegenerative disease cases. Table 2 has the exact percentages for each co-pathology. (A) The minimal pathology group (MPG) was defined by a low level of ageing-related tau or amyloid-β. Pure iAD and hAD were in the minority as α-synuclein and TDP-43 co-pathologies were common in both groups. (B) In the tauopathy groups, PiD had the lowest level of total co-pathology, CBD had an increased burden of multiple co-pathologies—principally amyloid-β and TDP-43—and PSP had the highest level of co-pathology involving amyloid-β, α-synuclein and TDP-43. (C) Pathological amyloid-β and α-synuclein were similarly prevalent as co-pathologies and multiple co-pathologies across the TDP-43 proteinopathies. (D) In the synucleinopathy groups, amyloid-β was the only significant co-pathology in MSA and bLBD. Amyloid-β affected the majority of lLBD and nLBD cases while TDP-43 was present in a minority as well. Rare cases (n = 1) for single and multiple co-pathology combinations not depicted.

Figure 3

Alzheimer’s disease neuropathological change co-pathology. The level of ADNPC was measured in all groups (Montine et al., 2012). Intermediate and high levels of ADNPC were rare except in the PSP and nLBD group. Definite and possible PART was common across the majority of groups (Crary et al., 2014). AD = Alzheimer’s disease; MPG = minimal pathology group.

Figure 4

Co-pathology in Lewy body disease results in a faster cognitive decline. MMSE test scores estimated from a linear mixed-effect model were plotted over a 10-year path. Primary Lewy body disease (LBD) cases without any co-pathologies (solid line) declined significantly over the course of disease (P-value < 0.001). Lewy body disease with co-pathologies (short dashes) had a slightly higher annual rate of decline. Cases with Lewy body disease with Alzheimer’s disease (AD) pathology (dotted line) declined significantly faster than pure Lewy body disease cases.