We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer’s-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-β plaques and tauopathy. Given that the ‘oldest-old’ are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC.
For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer’s disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.
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Direct support for meeting logistics was provided via a NIA/NACC grant (supplemental to the parent NIH grant U01 AG016976 to W.A.K.). Support from the National Health and Medical Research Council of Australia (NHMRC) included NHMRC Senior Principal Research Fellowship (1079679) and other NHMRC grants (1132524, 1095127, 1037746) to G.H. Grant support from U.S. National Institutes of Health included grants P01 AG003949 (D.W.D.), R01 AG037491 (D.W.D.), P50 AG016574 (D.W.D.), R01 AG054449 (M.E.M.), P30 AG028303 (P.T.N. and G.A.J.), P30 AG012300 (C.L.W.), P30 AG049638 (T.J.M.), P30 AG010124 (J.Q.T.), P30 AG010161 (K.A., J.A.S., P.A.B.), P50 AG047366 (T.J.M.), P50 AG025688 (A.I.L.), P50 AG005131 (R.A.R.), R37 AG011378 (C.R.J.), R01 AG041851 (C.R.J.), R01 AG042210 (J.A.S.), R01 AG017917 (J.A.S.), R01 AG034374 (P.A.B.), UF1 AG053983 (T.J.M.), UF1 AG057707 (T.J.M.). UK grants included ARUK-PhD2014–19, and NIHR Senior Investigators award Ref: 534906 NF-SI-0616–10090 to co-author C.B. National Institute for Health Research, Senior Investigator Award, was awarded to C.B. for C.B. and S.H. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. S.H. is supported by the Addenbrooke’s Charitable Trust, the Paul G. Allen Family Foundation and Alzheimer’s Research, UK. S.R.K.H. is supported by Alzheimer’s Research, UK. See Appendix 1 for additional acknowledgments.
The NACC database is funded by NIA/NIH Grant U01 AG016976.
NACC data are contributed by the NIA-funded ADCs: P30 AG019610 (PI Eric Reiman, MD), P30 AG013846 (PI Neil Kowall, MD), P50 AG008702 (PI Scott Small, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P50 AG047266 (PI Todd Golde, MD, PhD), P30 AG010133 (PI Andrew Saykin, PsyD), P50 AG005146 (PI Marilyn Albert, PhD), P50 AG005134 (PI Bradley Hyman, MD, PhD), P50 AG016574 (PI Ronald Petersen, MD, PhD), P50 AG005138 (PI Mary Sano, PhD), P30 AG008051 (PI Thomas Wisniewski, MD), P30 AG013854 (PI M. Marsel Mesulam, MD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG010161 (PI David Bennett, MD), P50 AG047366 (PI Victor Henderson, MD, MS), P30 AG010129 (PI Charles DeCarli, MD), P50 AG016573 (PI Frank LaFerla, PhD), P50 AG005131 (PI James Brewer, MD, PhD), P50 AG023501 (PI Bruce Miller, MD), P30 AG035982 (PI Russell Swerdlow, MD), P30 AG028383 (PI Linda Van Eldik, PhD), P30 AG053760 (PI Henry Paulson, MD, PhD), P30 AG010124 (PI John Trojanowski, MD, PhD), P50 AG005133 (PI Oscar Lopez, MD), P50 AG005142 (PI Helena Chui, MD), P30 AG012300 (PI Roger Rosenberg, MD), P30 AG049638 (PI Suzanne Craft, PhD), P50 AG005136 (PI Thomas Grabowski, MD), P50 AG033514 (PI Sanjay Asthana, MD, FRCP), P50 AG005681 (PI John Morris, MD), P50 AG047270 (PI Stephen Strittmatter, MD, PhD).
Nelson, Peter T.; Dickson, Dennis W.; Trojanowski, John Q.; Jack, Clifford R.; Boyle, Patricia A.; Arfanakis, Konstantinos; Rademakers, Rosa; Alafuzoff, Irina; Attems, Johannes; Brayne, Carol; Coyle-Gilchrist, Ian T. S.; Chui, Helena C.; Fardo, David W.; Flanagan, Margaret E.; Halliday, Glenda; Hokkanen, Suvi R. K.; Hunter, Sally; Jicha, Gregory A.; Katsumata, Yuriko; Kawas, Claudia H.; Keene, C. Dirk; Kovacs, Gabor G.; Kukull, Walter A.; Levey, Allan I.; Makkinejad, Nazanin; Montine, Thomas J.; Murayama, Shigeo; Murray, Melissa E.; Nag, Sukriti; Rissman, Robert A.; Seeley, William W.; Sperling, Reisa A.; White, Charles L. III; Yu, Lei; and Schneider, Julie A., "Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE): Consensus Working Group Report" (2019). Sanders-Brown Center on Aging Faculty Publications. 112.