Observational Study

. 2023 Nov;19 Suppl 9(Suppl 9):S98-S114.

doi: 10.1002/alz.13453. Epub 2023 Sep 10.

Amyloid and tau-PET in early-onset AD: Baseline data from the Longitudinal Early-onset Alzheimer's Disease Study (LEADS)

Hanna Cho^{1

2

3}, Nidhi S Mundada¹, Liana G Apostolova^{4

5

6}, Maria C Carrillo⁷, Ranjani Shankar¹, Alinda N Amuiri¹, Ehud Zeltzer¹, Charles C Windon¹, David N Soleimani-Meigooni¹, Jeremy A Tanner¹, Courtney Lawhn Heath⁸, Orit H Lesman-Segev^{1

9}, Paul Aisen¹⁰, Ani Eloyan¹¹, Hye Sun Lee¹², Dustin B Hammers⁴, Kala Kirby⁴, Jeffrey L Dage⁴, Anne Fagan¹³, Tatiana Foroud⁶, Lea T Grinberg^{1

14}, Clifford R Jack¹⁵, Joel Kramer¹, Walter A Kukull¹⁶, Melissa E Murray¹⁷, Kelly Nudelman⁶, Arthur Toga¹⁸, Prashanthi Vemuri¹⁵, Alireza Atri¹⁹, Gregory S Day²⁰, Ranjan Duara²¹, Neill R Graff-Radford²⁰, Lawrence S Honig²², David T Jones^{15

23}, Joseph Masdeu²⁴, Mario Mendez²⁵, Erik Musiek¹³, Chiadi U Onyike²⁶, Meghan Riddle²⁷, Emily J Rogalski²⁸, Stephen Salloway²⁷, Sharon Sha²⁹, Raymond Scott Turner³⁰, Thomas S Wingo³¹, David A Wolk³², Robert Koeppe³³, Leonardo Iaccarino¹, Bradford C Dickerson³⁴, Renaud La Joie¹, Gil D Rabinovici^{1

8}; LEADS Consortium⁴

Affiliations

¹ Memory and Aging Center, UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, California, USA.
² Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
³ Global Brain Health Institute, University of California, San Francisco, California, USA.
⁴ Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
⁵ Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine Indianapolis, Indianapolis, Indiana, USA.
⁶ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
⁷ Medical & Scientific Relations Division, Alzheimer's Association, Chicago, Illinois, USA.
⁸ Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA.
⁹ Department of Diagnostic Imaging, Sheba Medical Center, Tel HaShomer, Israel.
¹⁰ Alzheimer's Therapeutic Research Institute, University of Southern California, San Diego, California, USA.
¹¹ Department of Biostatistics, Center for Statistical Sciences, Brown University, Rhode Island, USA.
¹² Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, Republic of Korea.
¹³ Department of Neurology, Washington University in St. Louis, St. Louis, Missouri, USA.
¹⁴ Department of Pathology, University of California - San Francisco, San Francisco, California, USA.
¹⁵ Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.
¹⁶ Department of Epidemiology, University of Washington, Seattle, Washington, USA.
¹⁷ Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
¹⁸ Laboratory of Neuro Imaging, USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, Los Angeles, California, USA.
¹⁹ Banner Sun Health Research Institute, Sun City, Arizona, USA.
²⁰ Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
²¹ Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami, Florida, USA.
²² Taub Institute and Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA.
²³ Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
²⁴ Nantz National Alzheimer Center, Houston Methodist and Weill Cornell Medicine, Houston, Texas, USA.
²⁵ Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
²⁶ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²⁷ Department of Neurology, Alpert Medical School, Brown University, Rhode Island, USA.
²⁸ Department of Psychiatry and Behavioral Sciences, Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
²⁹ Department of Neurology & Neurological Sciences, Stanford University, Palo Alto, California, USA.
³⁰ Department of Neurology, Georgetown University, Washington, USA.
³¹ Department of Neurology and Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
³² Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³³ Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor, Michigan, USA.
³⁴ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

PMID: 37690109
PMCID: PMC10807231
DOI: 10.1002/alz.13453

Observational Study

Amyloid and tau-PET in early-onset AD: Baseline data from the Longitudinal Early-onset Alzheimer's Disease Study (LEADS)

Hanna Cho et al. Alzheimers Dement. 2023 Nov.

. 2023 Nov;19 Suppl 9(Suppl 9):S98-S114.

doi: 10.1002/alz.13453. Epub 2023 Sep 10.

Authors

Affiliations

¹ Memory and Aging Center, UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, California, USA.
² Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
³ Global Brain Health Institute, University of California, San Francisco, California, USA.
⁴ Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
⁵ Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine Indianapolis, Indianapolis, Indiana, USA.
⁶ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
⁷ Medical & Scientific Relations Division, Alzheimer's Association, Chicago, Illinois, USA.
⁸ Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA.
⁹ Department of Diagnostic Imaging, Sheba Medical Center, Tel HaShomer, Israel.
¹⁰ Alzheimer's Therapeutic Research Institute, University of Southern California, San Diego, California, USA.
¹¹ Department of Biostatistics, Center for Statistical Sciences, Brown University, Rhode Island, USA.
¹² Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, Republic of Korea.
¹³ Department of Neurology, Washington University in St. Louis, St. Louis, Missouri, USA.
¹⁴ Department of Pathology, University of California - San Francisco, San Francisco, California, USA.
¹⁵ Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.
¹⁶ Department of Epidemiology, University of Washington, Seattle, Washington, USA.
¹⁷ Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
¹⁸ Laboratory of Neuro Imaging, USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, Los Angeles, California, USA.
¹⁹ Banner Sun Health Research Institute, Sun City, Arizona, USA.
²⁰ Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
²¹ Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami, Florida, USA.
²² Taub Institute and Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA.
²³ Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
²⁴ Nantz National Alzheimer Center, Houston Methodist and Weill Cornell Medicine, Houston, Texas, USA.
²⁵ Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
²⁶ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²⁷ Department of Neurology, Alpert Medical School, Brown University, Rhode Island, USA.
²⁸ Department of Psychiatry and Behavioral Sciences, Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
²⁹ Department of Neurology & Neurological Sciences, Stanford University, Palo Alto, California, USA.
³⁰ Department of Neurology, Georgetown University, Washington, USA.
³¹ Department of Neurology and Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
³² Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³³ Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor, Michigan, USA.
³⁴ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

PMID: 37690109
PMCID: PMC10807231
DOI: 10.1002/alz.13453

Abstract

Introduction: We aimed to describe baseline amyloid-beta (Aβ) and tau-positron emission tomograrphy (PET) from Longitudinal Early-onset Alzheimer's Disease Study (LEADS), a prospective multi-site observational study of sporadic early-onset Alzheimer's disease (EOAD).

Methods: We analyzed baseline [18F]Florbetaben (Aβ) and [18F]Flortaucipir (tau)-PET from cognitively impaired participants with a clinical diagnosis of mild cognitive impairment (MCI) or AD dementia aged < 65 years. Florbetaben scans were used to distinguish cognitively impaired participants with EOAD (Aβ+) from EOnonAD (Aβ-) based on the combination of visual read by expert reader and image quantification.

Results: 243/321 (75.7%) of participants were assigned to the EOAD group based on amyloid-PET; 231 (95.1%) of them were tau-PET positive (A+T+). Tau-PET signal was elevated across cortical regions with a parietal-predominant pattern, and higher burden was observed in younger and female EOAD participants.

Discussion: LEADS data emphasizes the importance of biomarkers to enhance diagnostic accuracy in EOAD. The advanced tau-PET binding at baseline might have implications for therapeutic strategies in patients with EOAD.

Highlights: 72% of patients with clinical EOAD were positive on both amyloid- and tau-PET. Amyloid-positive patients with EOAD had high tau-PET signal across cortical regions. In EOAD, tau-PET mediated the relationship between amyloid-PET and MMSE. Among EOAD patients, younger onset and female sex were associated with higher tau-PET.

Keywords: Alzheimer's disease; EOAD; LEADS; amyloid-PET; atypical AD; centiloids; early-onset; sex differences; tau-PET.

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Conflict of interest statement

CONFLICT OF INTEREST STATEMENT

Dr. Cho has nothing to disclose. Ms. Mundada has nothing to disclose. Dr. Apostolova served as a paid consultant for Biogen and Two Labs, serves on a DSMB for IQVIA, and receives research support from the NIH, the Alzheimer’s Association, Roche, Life Molecular Imaging, and Eli Lilly. Dr. Carrillo has nothing to disclose. Ms. Shankar has nothing to disclose. Ms. Amuiri has nothing to disclose. Dr. Zeltzer has nothing to disclose. Dr. Windon has nothing to disclose. Dr. Soleimani-Meigooni has nothing to disclose. Dr. Tanner has nothing to disclose. Dr. Lawhn Heath has nothing to disclose. Dr. Lesman-Segev has nothing to disclose. Dr. Aisen reports grants from NIA, FNIH, the Alzheimer’s Association, Janssen, Lilly, and Eisai, and personal fees from Merck, Roche, Biogen, Lundbeck, ImmunoBrain Checkpoint, and Samus. Dr. Eloyan has nothing to disclose. Dr. Lee has nothing to disclose. Dr. Hammers has nothing to disclose. Ms. Kirby has nothing to disclose. Dr. Dage has nothing to disclose. Dr. Fagan has received research support from Biogen, Fujirebio, and Roche Diagnostics. She is a member of the scientific advisory boards for Roche Diagnostics, Genentech, and AbbVie and consults for Araclon/Griffols, DiademRes, and Otsuka Pharmaceuticals. Dr. Foroud has nothing to disclose. Dr. Grinberg has nothing to disclose. Dr. Jack serves on an independent data monitoring board for Roche and has consulted for and served as a speaker for Eisai, but he receives no personal compensation from any commercial entity. He receives research support from the NIH and the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic. Dr. Kramer has nothing to disclose. Dr. Kukull is supported by the NIA. Dr. Murray served as a paid consultant for AVID Radiopharmaceuticals and receives research support from the NIH, the Alzheimer’s Association, and the state of Florida. Dr. Nudelman has nothing to disclose. Dr. Toga has nothing to disclose. Dr. Vemuri has nothing to disclose. Dr. Atri has nothing to disclose. Dr. Day is supported by the NIA; he serves as a topic editor on dementia for DynaMed Plus (EBSCO Industries, Inc), is the clinical director for the Anti-NMDA Receptor Encephalitis Foundation and holds stocks in ANI Pharmaceuticals. Dr. Duara has nothing to disclose. Dr. Graff-Radford receives research support from Lilly, AbbVie, and Biogen. Dr. Honig has nothing to disclose. Dr. Jones has nothing to disclose. Dr. Masdeu served on the speaker’s bureau and consulted for Biogen. He received research support from the NIH, Avanir, Abbvie, Biogen, Eli Lilly, Esai, and Novartis. Dr. Mendez receives grant support from NIA and has received support from Biogen. Dr. Musiek received research funding from Eisai Pharmaceuticals Inc. Dr. Onyike has nothing to disclose. Dr. Rogalski has nothing to disclose. Dr. Salloway received consultation fees and research support from Biogen, Eisai, Lilly, Genentech, and Roche. Dr. Sha has nothing to disclose. Dr. Turner has nothing to disclose. Dr. Wingo has nothing to disclose. Dr. Wolk received grants from Eli Lilly/Avid Radiopharmaceuticals, Merck, and Biogen, and consulted for Merck, Janssen, and GE Healthcare. Dr. Koeppe has nothing to disclose. Dr. Iaccarino is currently a full-time employee of Eli Lilly and Company / Avid Radiopharmaceuticals and a minor shareholder of Eli Lilly and Company. His contribution to the work presented in this manuscript was performed while he was affiliated with the University of California San Francisco. Dr. Dickerson receives research support from the NIH and the Alzheimer’s Drug Discovery Foundation. He consulted for Arkuda, Axovant, Lilly, Biogen, Merck, Novartis, and Wave LifeSciences. He is editor for Neuroimage: Clinical and Cortex. He receives royalties from Oxford University Press and Cambridge University Press. Dr. La Joie is an Associate Editor for Alzheimer’s Research & Therapy. Dr. Rabinovici receives research funding from Avid Radiopharmaceuticals, GE Healthcare, Life Molecular Imaging, Genentech. He has received consulting fees from Alector, Eli Lilly, Genentech, Roche, Merck. He receives fees for serving on a DSMB for Johnson & Johnson. He is an Associate Editor for JAMA Neurology The authors have no conflicts of interest to declare supporting information.

Figures

**FIGURE 1**
Study flow and amyloid-PET screening. (A) Flowchart of patient selection and cohort assignment. (B) PET-only quantification performed for amyloid-PET screening (dashed line indicate the SUVR_PET-only threshold of 1.18). CI, cognitively impaired; CN, cognitively normal; EOAD, early-onset Alzheimer’s disease; EOnonAD, early-onset non-Alzheimer’s disease; FBB, 18F-Florbetaben; FTP, 18F-Flortaucipir; PET, positron emission tomography

**FIGURE 2**
Summary metrics of amyloid- and tau-PET across groups. Distribution of Centiloid (A) and temporal FTP-SUVR (B) values across the three groups. (C) The association between Centiloid and temporal FTP-SUVR, with summary metrics for linear, quadratic, and cubic models. The red dotted line shows a data-driven smooth regression line using the locally estimated scatterplot smoothing (LOESS) method. Dotted lines indicate pre-determined positivity thresholds of 25 Centiloid for amyloid-PET (A and C) and 1.27 temporal meta-ROI FTP-SUVR (B and C). See Figure S2 for tau-PET analyses using global cortical SUVR instead of temporal SUVR. FTP, 18F-Flortaucipir; PET, positron emission tomography; ROI, region of interest; SUVR, standardized uptake value ratio

**FIGURE 3**
Summary metrics of amyloid- and tau-PET in the EOAD group, Association between amyloid- and tau-PET and age (A), sex (B), and MMSE (C) in the EOAD group. The rightmost part of panel C shows the result of a mediation analysis; numbers indicate point estimates ± standard error. Mediation model was repeated using the MOCA or CDR-SB scores as alternative dependent variables. Full path values are −0.035 ± 0.012 for MMSE (p = 0.005, n = 240), −0.044 ± 0.016 for MOCA (p = 0.006, n = 182) and 0.009 ± 0.004 for CDR-SB (p = 0.057, n = 225). See Figure S2 for tau-PET analyses using global cortical SUVR instead of temporal SUVR. CDR-SB, Clinical Dementia Rating sum of boxes; EOAD, early-onset Alzheimer’s disease; MOCA, Montreal Cognitive Assessment; MMSE, Mini-Mental State Examination; PET, positron emission tomography

**FIGURE 4**
Regional distribution of amyloid- and tau-PET signal in the EOAD group. Regional distribution of amyloid- (A) and tau (B)-PET signal in all groups. Mean SUVR values were extracted from 68 cortical ROIs from the Desikan-Killiany atlas. The right panel shows group differences between EOAD and CN groups, quantified as Cohen’s d effect sizes (all 68 ROIs are different with Bonferroni-corrected p < 0.05). All pairwise group comparisons are described in detail in Table S1. CN, cognitively normal; EOAD, early-onset Alzheimer’s disease; PET, positron emission tomography; ROI, region of interest; SUVR, standardized uptake value ratio

**FIGURE 5**
Association between regional PET SUVR and age, sex, and MMSE in the EOAD group. Regional analyses between PET SUVR, extracted from 68 cortical ROIs from the Desikan-Killiany atlas (left column: amyloid-PET with Florbetaben; right column: tau-PET with Flortaucipir), and age (A), sex (B), and MMSE (C). The right most panel shows the distribution of effect sizes (correlation coefficients for A and C, Cohen’s d for B) in all 68 ROIs. Details on the statistical measures are available in Table S2. EOAD, early-onset Alzheimer’s disease; MMSE, Mini-Mental State Examination; PET, positron emission tomography; ROI, region of interest; SUVR, standardized uptake value ratio

**FIGURE 6**
Clinical phenotypes in clinically impaired participants: exploratory analyses. (A) Proportion of cases that were assigned to the EOAD versus EOnonAD groups based on the amyloid-PET screening (see Figure 1a). (B) Summary metrics of amyloid and tau PET for each clinical phenotype in the EOAD group (n = 196 amnestic, 18 PCA, 13 PPA, 16 other non-amnestic cases); see Figure S3 for demographic and clinical information, and Figure S3 for tau-PET analyses using global cortical SUVR instead of temporal SUVR. Groups were compared using Welch’s analysis of variance (“pANOVA”) and using an analysis of covariance controlling for age and sex (“pANCOVA”). (C) Regional distribution of amyloid (Florbetaben, top) and tau (Flortaucipir, bottom) PET in each clinical phenotype in the EOAD group (same Ns as in panel B). See Table S4 and Figure S3 for statistical comparisons. EOAD, early-onset Alzheimer’s disease; EOnonAD, early-onset non-Alzheimer’s disease; PCA, posterior cortical atrophy; PET, positron emission tomography; PPA, primary progressive aphasia; SUVR, standardized uptake value ratio

See this image and copyright information in PMC

References

1. Zhu XC, Tan L, Wang HF, et al. Rate of early onset Alzheimer’s disease: a systematic review and meta-analysis. Ann Transl Med. 2015;3:38. doi: 10.3978/j.issn.2305-5839.2015.01.19 - DOI - PMC - PubMed
1. Sirkis DW, Bonham LW, Johnson TP, La Joie R, Yokoyama JS. Dissecting the clinical heterogeneity of early-onset Alzheimer’s disease. Mol Psychiatry. 2022;27:2674–2688. doi: 10.1038/s41380-022-01531-9 - DOI - PMC - PubMed
1. Szigeti K, Doody RS. Should EOAD patients be included in clinical trials? Alzheimers Res Ther. 2011;3:4. doi: 10.1186/alzrt63 - DOI - PMC - PubMed
1. Apostolova LG, Aisen P, Eloyan A, et al. The Longitudinal Early-onset Alzheimer’s Disease Study (LEADS): framework and methodology. Alzheimers Dement. 2021;17:2043–2055. doi: 10.1002/alz.12350 - DOI - PMC - PubMed
1. Swartz JR, Miller BL, Lesser IM, et al. Behavioral phenomenology in Alzheimer’s disease, frontotemporal dementia, and late-life depression: a retrospective analysis. J Geriatr Psychiatry Neurol. 1997;10:67–74. doi: 10.1177/089198879701000206 - DOI - PubMed

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Amyloid and tau-PET in early-onset AD: Baseline data from the Longitudinal Early-onset Alzheimer's Disease Study (LEADS)

Affiliations

Amyloid and tau-PET in early-onset AD: Baseline data from the Longitudinal Early-onset Alzheimer's Disease Study (LEADS)

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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Grants and funding

LinkOut - more resources

Full Text Sources

Medical