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

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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.

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Acknowledgements

We are profoundly grateful to the research participants, caregivers, clinicians, staff, and colleague scientists who contributed to this study.

Funding

We acknowledge National Institutes of Health grants P30 AG072958 (S.-H. J.W.), P30 AG072977 (M.E.F.), K08 AG065463 (M.E.F.), RF1 AG072080 (M.E.F.), K08 AG 065426 (C.S.L), R01 AG038651 (E.L.A.), UF1 AG057707 (T.J.M and L.W), R01AG021055 (CK and MC), P30 AG066519 (UCI ADRC), R01 AG061111 (P.T.N.), R01 AG057187 (P.T.N.), P30 AG072946 (P.T.N.), RF1 NS118584 (M.D.C.), R01 AG054449 (M.E.M.), RF1 AG069052 (J.G.R), P30 AG072972 (UC Davis ADRC), R01 AG062517 (B.N.D.), U19 AG069701 (M.E.M.), K24 AG053435 (L.T.G.), R01AG067482 (J.A.S.), R01AG064233 (J.A.S.), R01AG022018 (J.A.S.), P30AG010161/P30AG072975 (J.A.S.), P30 AG062677 (Mayo ADRC), UF1 NS125417 (R.C.P.), U01 AG006786 (MCSA), R01 AG034676 (REP), P30 AG66509 (UW ADRC), and U19 AG066567 (ACT Study). Academy of Finland (341007) (L.M.); State funding for university-level health research (TYH2020231, TYH2022316) (L.M.); Liv och Hälsa Foundation (L.M.); Rossy Foundation and the Edmond Safra Philanthropic Foundation (G.G.K.); Sao Paulo Research Foundation (FAPESP 06/55318-1, 09/09134-4, 16/24326-0) (C.K.S.); the Nancy and Buster Alvord Endowment (C.D.K.); Alzheimer’s Research UK (ARUK) doctoral studentship (ARUK-PhD2017-34) (R.M.); ARUK-PhD2014-19 (S.R.K.H.). UK Medical Research Council (MRC) (MRC/G9901400, U.1052.00.0013, G0900582). NHMRC Dementia Research Leadership Fellowship NT113567 (H.A.D.K.), Addenbrooke’s Charitable Trust (H.A.D.K., S.H.), Addenbrooke’s Charitable Trust grant 900108 (S.H.), Paul G. Allen Foundation (S.H.), ARUK NSG (S.H.), Alzheimer’s Society 554 (AS-PG-2019b-024) (S.H., J.F.). The Cambridge Brain Bank Laboratory is supported by the National Institute for Health Research, Cambridge Biomedical Research Centre. APOE genotyping from the National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD), which receives government support under a cooperative agreement grant (U24AG021886) awarded by the National Institute on Aging (NIA), were used in this study.

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Authors and Affiliations

  1. University of Kentucky, Rm 311 Sanders-Brown Center on Aging, Lexington, KY, USA

    Peter T. Nelson, Erin L. Abner, Jing Di & Janna H. Neltner

  2. University of Cambridge, Cambridge, UK

    Carol Brayne, Jane Fleming, Suvi R. K. Hokkanen, Sally Hunter & Richard Merrick

  3. Northwestern University Medical Center, Chicago, IL, USA

    Margaret E. Flanagan & Rudolph J. Castellani

  4. Rush University Medical Center, Chicago, IL, USA

    Sonal Agrawal, Alifiya Kapasi, Sukriti Nag & Julie A. Schneider

  5. Newcastle University, Newcastle upon Tyne, UK

    Johannes Attems, Fiona E. Matthews & Tuomo Polvikoski

  6. University of California, Irvine, CA, USA

    Maria M. Corrada & Claudia H. Kawas

  7. Houston Methodist Hospital, Houston, TX, USA

    Matthew D. Cykowski

  8. Mayo Clinic, Jacksonville, FL, USA

    Dennis W. Dickson, Naomi Kouri, Sydney A. Labuzan, Billie J. Matchett & Melissa E. Murray

  9. University of California, Davis, CA, USA

    Brittany N. Dugger

  10. Duke University, Durham, NC, USA

    John F. Ervin & Shih-Hsiu J. Wang

  11. Mayo Clinic, Rochester, MN, USA

    Jonathan Graff-Radford, David S. Knopman, Aivi T. Nguyen, Ronald C. Petersen & R. Ross Reichard

  12. University of California, San Francisco, CA, USA

    Lea T. Grinberg

  13. University of Sao Paulo Medical School, Sao Paulo, Brazil

    Lea T. Grinberg, Renata E. P. Leite, Roberta D. Rodriguez & Claudia K. Suemoto

  14. University of South Australia, Adelaide, SA, Australia

    Hannah A. D. Keage

  15. University of Washington, Seattle, WA, USA

    C. Dirk Keene & Caitlin S. Latimer

  16. University of Helsinki and Helsinki University Hospital, Helsinki, Finland

    Mia Kero & Liisa Myllykangas

  17. Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON, Canada

    Gabor G. Kovacs

  18. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

    Gabor G. Kovacs

  19. Laboratory Medicine Program, University Health Network, Toronto, ON, Canada

    Gabor G. Kovacs

  20. Institute of Neurology, Medical University of Vienna, Vienna, Austria

    Gabor G. Kovacs

  21. Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA

    Eric B. Larson

  22. Stanford University, Stanford, CA, USA

    Thomas J. Montine

  23. Emory University, Atlanta, GA, USA

    Ruth S. Nelson

  24. Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK

    Stephen B. Wharton

  25. Pacific Health Research and Education Institute, Honolulu, HI, USA

    Lon White

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Correspondence to Peter T. Nelson.

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Conflict of interest

Authors D.W.D., G.G.K., and P.T.N. are members of the Editorial Board of Acta Neuropathologica and J.A. is Editor in Chief of Acta Neuropathologica, but none of the coauthors were involved in the Editorial handling of this article.

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Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 Information on included cohorts (DOCX 70 KB)

Supplementary file2 Data that were requested from each cohort–blank data templates (XLSX 12 KB)

Supplementary file3 Numbers of participants included on each figure and table from each cohort (XLSX 10 KB)

401_2022_2444_MOESM4_ESM.xlsx

Supplementary file4 Digital neuropathology to assess inter-rater reliability of Braak NFT stage diagnoses in a sample of LATE-NC+/ADNC- cases with cognitive impairment (XLSX 12 KB)

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Nelson, P.T., Brayne, C., Flanagan, M.E. et al. Frequency of LATE neuropathologic change across the spectrum of Alzheimer’s disease neuropathology: combined data from 13 community-based or population-based autopsy cohorts. Acta Neuropathol 144, 27–44 (2022). https://doi.org/10.1007/s00401-022-02444-1

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