Frequency of LATE neuropathologic change across the spectrum of Alzheimer's disease neuropathology: combined data from 13 community-based or population-based autopsy cohorts

Abstract

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and Alzheimer's disease neuropathologic change (ADNC) are each associated with substantial cognitive impairment in aging populations. However, the prevalence of LATE-NC across the full range of ADNC remains uncertain. To address this knowledge gap, neuropathologic, genetic, and clinical data were compiled from 13 high-quality community- and population-based longitudinal studies. Participants were recruited from United States (8 cohorts, including one focusing on Japanese-American men), United Kingdom (2 cohorts), Brazil, Austria, and Finland. The total number of participants included was 6196, and the average age of death was 88.1 years. Not all data were available on each individual and there were differences between the cohorts in study designs and the amount of missing data. Among those with known cognitive status before death (n = 5665), 43.0% were cognitively normal, 14.9% had MCI, and 42.4% had dementia-broadly consistent with epidemiologic data in this age group. Approximately 99% of participants (n = 6125) had available CERAD neuritic amyloid plaque score data. In this subsample, 39.4% had autopsy-confirmed LATE-NC of any stage. Among brains with "frequent" neuritic amyloid plaques, 54.9% had comorbid LATE-NC, whereas in brains with no detected neuritic amyloid plaques, 27.0% had LATE-NC. Data on LATE-NC stages were available for 3803 participants, of which 25% had LATE-NC stage > 1 (associated with cognitive impairment). In the subset of individuals with Thal Aβ phase = 0 (lacking detectable Aβ plaques), the brains with LATE-NC had relatively more severe primary age-related tauopathy (PART). A total of 3267 participants had available clinical data relevant to frontotemporal dementia (FTD), and none were given the clinical diagnosis of definite FTD nor the pathological diagnosis of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In the 10 cohorts with detailed neurocognitive assessments proximal to death, cognition tended to be worse with LATE-NC across the full spectrum of ADNC severity. This study provided a credible estimate of the current prevalence of LATE-NC in advanced age. LATE-NC was seen in almost 40% of participants and often, but not always, coexisted with Alzheimer's disease neuropathology.

Keywords: ACT; ADRD; APOE; Biobank for aging studies; CC75C; CFAS; Epidemiology; HAAS; Mayo clinic study of aging; NFT; Nondemented; Nun study; Oldest-old; ROS-MAP; Tau; The 90 + study; VITA; Vantaa 85 +.

Fig. 1

Frequencies of clinical/cognitive features among the included participants. All cohorts had data about whether participants had normal cognition or dementia prior to death, and most (12 cohorts) had some measure for an intermediate clinical status, usually mild cognitive impairment (MCI). The finding of slightly over 40% cognitive normal prior to death is consistent with epidemiologic data of human populations in this age range [21, 60, 86, 90]. The result of each cohort was weighted equally in order to convey the cohort-to-cohort variance. For numbers of participants included from each cohort, see Table 1. Error bars denote 25th and 75th percentiles. *-MCI data were present for all cohorts except Vantaa 85 +

Fig. 2

The association between the percentage of included LATE-NC + participants in each cohort (x-axis) with percentages carrying the APOE ε4 allele (a), average age at death (b), sex (percent female (c), and, proportion with neocortical Lewy bodies (LBs), (d) on the y-axes. Each of the autopsy cohorts is indicated by a separate circular marker. The only association that was statistically significant in a simple regression analysis was APOE ε4 carrier frequency rate (a). APOE data were missing from a single cohort; see Table 1 for the numbers of research participants from each contributory cohort

Fig. 3

LATE-NC absence or presence, stratified by CERAD neuritic amyloid plaques scores. All LATE-NC stages were combined and the results from each of the cohorts averaged. The frequency of LATE-NC increased with greater neuritic amyloid plaque densities. The distribution of CERAD plaques by frequencies is shown in (a). Note that subgroups with none or minimal ADNC were the most well represented in this combined meta-cohort (see Table 2). Correlation with LATE-NC status is shown in (b). Given the study design differences between cohorts, the results were generally consistent. For these charts, the results of each cohort were weighted equally in order to convey the cohort-to-cohort variance. For exact numbers of participants included from each cohort, see Supplemental Table 3, online resource. Error bars denote 25th and 75th percentiles

Fig. 4

LATE-NC absence or presence, stratified by Braak NFT stages. Here, all LATE-NC stages were combined and the results from each of the cohorts averaged. The distribution of Braak NFT stage groups by frequencies is shown in (a). Correlation with LATE-NC status is shown in (b). The frequency of LATE-NC increased with higher Braak NFT stages. Given the study design differences between cohorts, the results were generally consistent. For these charts the results of each cohort were weighted equally to convey the cohort-to-cohort variance. For exact numbers of participants included from each cohort, see Supplemental Table 3, online resource. Error bars denote 25th and 75th percentiles

Fig. 5

Findings in the 3803 participants with available LATE-NC stage data (a), Thal Aβ phases (b), and Braak NFT staging, which indicate an association between LATE-NC and PART pathology. A pie chart (a) shows the relative frequencies of the different LATE-NC stages. Note that ~ 25% of participants have LATE-NC stage 2 (21% of participants) or stage 3 (4% of participants). A separate pie chart (b) depicts the relative frequencies of different Thal Aβ phases. The bar chart in panel (c) shows the number of cases with Thal Aβ phase = 0, stratified by Braak NFT stages. In these brains lacking Aβ amyloid pathology, the presence of LATE-NC was associated with higher Braak NFT stages (more severe PART pathology). For exact numbers, see Table 5, and for a breakdown of the numbers of participants included from each cohort, see Supplemental Table 3, online resource

Fig. 6

There is a tendency for LATE-NC to be associated with cognitive impairment, across a broad range of Braak NFT stages, in ten community-based cohorts. Data were gathered on cognitive status, stratifying by LATE-NC status and Braak NFT stages. Trends were evaluated from each cohort as to whether the cognitive status tended to be lower in persons with LATE-NC (down-going black arrow) or higher (up-going white arrow) in given Braak NFT stages. To operationalize global cognitive status, final Mini-Mental State Examination scores [33] were used, except HAAS used the Cognitive Abilities Screening Instrument [107] and the Brazil BAS and MCSA cohorts used the Clinical Dementia Rating sum of boxes scores [27]. There was a tendency for participants with LATE-NC to have lower cognition across the full range of Braak NFT stages

Fig. 7

Selected findings and context of the current study. Data were analyzed from participants in 13 high quality community- and population-based cohorts comprising over 6000 individuals followed longitudinally to autopsy. As such, the findings (with appropriate caveats) have broad implications. In participants that had none or minimal ADNC, a substantial proportion (~ 25%) had LATE-NC. This indicates that there are ADNC-independent TDP-43 pathology-driving mechanisms, which probably include gene variants in TMEM106B and GRN [26, 87, 96]. LATE-NC also was associated with more severe PART pathology (and vice versa), indicating pathologic synergy between LATE-NC and PART. Approximately 2/3rd of subjects in advanced age showed moderate or severe ADNC at brain autopsy, in concordance with the published literature [15]. In these individuals, there was a relatively high frequency of LATE-NC: approximately 50% of participants with moderate to severe ADNC had LATE-NC. The “mixed” ADNC-LATE-NC may be driven by pleiotropic genetic factors (e.g., APOE ε4 allele [114]) and there may also be pathologic synergies downstream from genetics. For example, intracellular tauopathy may promote TDP-43 pathology in the same cell [44, 103, 111]. The neuron shown here is stained with immunofluorescence in the hippocampal dentate gyrus, and is immunolabeled green (tau), and red (phospho-TDP-43) with overlap depicted in white [103]