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

• Authors: Peter T Nelson, University of Kentucky; Carol Brayne, University of Cambridge; Margaret E Flanagan, Northwestern University; Erin L Abner, University of Kentucky; Sonal Agrawal, Rush University; Johannes Attems, Newcastle University; Rudolph J Castellani, Northwestern University; Maria M Corrada, University of California Irvine; Matthew D Cykowski, Houston Methodist Hospital; Jing Di, University of Kentucky; Dennis W Dickson, Mayo Clinic; Brittany N Dugger, University of California Davis; John F Ervin, Duke University; Jane Fleming, University of Cambridge; Jonathan Graff-Radford, Mayo Clinic; Lea T Grinberg, University of California San Francisco; Suvi RK Hokkanen, University of Cambridge; Sally Hunter, University of Cambridge; Alifiya Kapasi, Rush University; Claudia H Kawas, University of California Irvine; Hannah AD Keage, University of South Australia; Dirk C Keene, University of Washington; Mia Kero, University of Helsinki; David S Knopman, Mayo Clinic, Rochester; Naomi Kouri, Mayo Clinic, Jacksonville; Gabor G Kovacs, University of Toronto; Sydney A Labuzan, Mayo Clinic, Jacksonville; Eric B Larson, Kaiser Permanente Washington Health Research Institute; Caitlin S Latimer, University of Washington; Renata EP Leite, University of Sao Paulo Medical School; Billie J Matchett, Mayo Clinic, Jacksonville; Fiona E Matthews, Newcastle University; Richard Merrick, University of Cambridge; Thomas J Montine, Stanford University; Melissa E Murray, Mayo Clinic, Jacksonville; Liisa Myllykangas, University of Helsinki; Sukriti Nag, Rush University; Ruth S Nelson, Emory University; Janna H Neltner, University of Kentucky; Aivi T Nguyen, Mayo Clinic; Ronald C Petersen, University of Kentucky; Tuomo Polvikoski, Newcastle University; Ross R Reichard, Mayo Clinic, Rochester; Roberta D Rodriguez, University of Sao Paulo Medical School; Claudia K Suemoto, University of Sao Paulo Medical School; Shih-Hsiu J Wang, Duke University; Stephen B Wharton, University of Sheffield; Lon White, Pacific Health Research and Education Institute; Julie A Schneider, Rush University
• Journal Title: ACTA NEUROPATHOLOGICA
• Volume: Volume 144, Number 1
• Publisher: SPRINGER | 2022-06-13, Pages 27-44
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1007/s00401-022-02444-1
• Subjects: Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Life Sciences & Biomedicine; Clinical Neurology; Neurosciences; Pathology; Neurosciences & Neurology; ADRD; Tau; NFT; Nondemented; Oldest-old; Epidemiology; APOE; ROS-MAP; Vantaa 85+; HAAS; CFAS; CC75C; The 90+study; ACT; VITA; Nun study; Biobank for aging studies; Mayo clinic study of aging; FRONTOTEMPORAL LOBAR DEGENERATION; APOLIPOPROTEIN-E EPSILON-4; TDP-43 PATHOLOGY; HIPPOCAMPAL SCLEROSIS; COGNITIVE FUNCTION; CLINICAL-FEATURES; OLDER PERSONS; DEMENTIA; PREVALENCE; ASSOCIATION

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.