PET evidence of preclinical cerebellar amyloid plaque deposition in autosomal dominant Alzheimer's disease-causing Presenilin-1 E280A mutation carriers

Valentina Ghisays, Francisco Lopera, Dhruman D Goradia, Hillary D Protas, Michael H Malek-Ahmadi, Yinghua Chen, Vivek Devadas, Ji Luo, Wendy Lee, Ana Baena, Yamile Bocanegra, Edmarie Guzmán-Vélez, Enmanuelle Pardilla-Delgado, Clara Vila-Castelar, Joshua T Fox-Fuller, Nan Hu, David Clayton, Ronald G Thomas, Sergio Alvarez, Alejandro Espinosa, Natalia Acosta-Baena, Margarita M Giraldo, Silvia Rios-Romenets, Jessica B Langbaum, Kewei Chen, Yi Su, Pierre N Tariot, Yakeel T Quiroz, Eric M Reiman, API ADAD Colombia Trial Group, Valentina Ghisays, Francisco Lopera, Dhruman D Goradia, Hillary D Protas, Michael H Malek-Ahmadi, Yinghua Chen, Vivek Devadas, Ji Luo, Wendy Lee, Ana Baena, Yamile Bocanegra, Edmarie Guzmán-Vélez, Enmanuelle Pardilla-Delgado, Clara Vila-Castelar, Joshua T Fox-Fuller, Nan Hu, David Clayton, Ronald G Thomas, Sergio Alvarez, Alejandro Espinosa, Natalia Acosta-Baena, Margarita M Giraldo, Silvia Rios-Romenets, Jessica B Langbaum, Kewei Chen, Yi Su, Pierre N Tariot, Yakeel T Quiroz, Eric M Reiman, API ADAD Colombia Trial Group

Abstract

Background: In contrast to sporadic Alzheimer's disease, autosomal dominant Alzheimer's disease (ADAD) is associated with greater neuropathological evidence of cerebellar amyloid plaque (Aβ) deposition. In this study, we used positron emission tomography (PET) measurements of fibrillar Aβ burden to characterize the presence and age at onset of cerebellar Aβ deposition in cognitively unimpaired (CU) Presenilin-1 (PSEN1) E280A mutation carriers from the world's largest extended family with ADAD.

Methods: 18F florbetapir and 11C Pittsburgh compound B (PiB) PET data from two independent studies - API ADAD Colombia Trial (NCT01998841) and Colombia-Boston (COLBOS) longitudinal biomarker study were included. The tracers were selected independently by the respective sponsors prior to the start of each study and used exclusively throughout. Template-based cerebellar Aβ-SUVR (standard-uptake value ratios) using a known-to-be-spared pons reference region (cerebellar SUVR_pons), to a) compare 28-56-year-old CU carriers and non-carriers; b) estimate the age at which cerebellar SUVR_pons began to differ significantly in carrier and non-carrier groups; and c) characterize in carriers associations with age, cortical SUVR_pons, delayed recall memory, and API ADAD composite score.

Results: Florbetapir and PiB cerebellar SUVR_pons were significantly higher in carriers than non-carriers (p < 0.0001). Cerebellar SUVR_pons began to distinguish carriers from non-carriers at age 34, 10 years before the carriers' estimated age at mild cognitive impairment onset. Florbetapir and PiB cerebellar SUVR_pons in carriers were positively correlated with age (r = 0.44 & 0.69, p < 0.001), cortical SUVR_pons (r = 0.55 & 0.69, p < 0.001), and negatively correlated with delayed recall memory (r = -0.21 & -0.50, p < 0.05, unadjusted for cortical SUVR_pons) and API ADAD composite (r = -0.25, p < 0.01, unadjusted for cortical SUVR_pons in florbetapir API ADAD cohort).

Conclusion: This PET study provides evidence of cerebellar Aβ plaque deposition in CU carriers starting about a decade before the clinical onset of ADAD. Additional studies are needed to clarify the impact of using a cerebellar versus pons reference region on the power to detect and track ADAD changes, even in preclinical stages of this disorder.

Keywords: Amyloid; Autosomal dominant Alzheimer’s disease; Brain imaging; Cerebellum; PET; Pons.

Conflict of interest statement

V.G., D.D.G., H.D.P., M.H.M-A., Y.C., V.D., J.L., W.L., C. T. B., A.B., Y.B., E.G.V., E.P.D., C.V.C., J.T.F-F., and S.A. report no disclosures. J.B.L. is a consultant to Alector. N.H., and D.C. are full-time employees of Genentech, Inc., a member of the Roche Group. R.G.T. obtained research support from NIH (U01 AG010483) and consultant fees from Toyama and vTv. Y.T.Q. was supported by grants from the NIA/NIH, Alzheimer’s Association, and Massachusetts General Hospital Executive Committee on Research (ECOR). S.R.R. received grant and contract support from the NIA, Roche/Genentech, and an anonymous international foundation to help conduct the API ADAD Trial in Colombia. F.L reports participation in other projects financed by NIH, Roche, Comité para el Desarrollo de la Investigación (CODI- U de A), and COLCIENCIAS. K.C. and Y.S are consultants for Green Valley Pharmaceuticals. P.N.T. received personal compensation for consulting, serving on scientific advisory board, speaking, or other activities with AbbVie, Acadia, AC Immune, Acadia, Auspex, Axsome, BioExcel, Boehringer Ingelheim, Chase Pharmaceuticals, Corium, Cotexyme, Eisai, GliaCure, INSYS Therapeutics, Pfizer, T3D, AstraZeneca, Avanir, Biogen, Brain Test, Inc., Eli Lilly, H. Lundbeck A/S, Merck and Company, Otsuka & Astex, Roche and Syneos; is listed on a patent application from the University of Rochester; holds stock and/or stock options in Adamas; received research support from AbbVie, AstraZeneca, Avanir, Biogen, Cortexyme, Eli Lilly, H. Lundbeck A/S, Merck and Company, Roche, Amgen, Avid, Functional Neuromodulation, GE Healthcare, Genentech, Novartis, Takeda, and Targacept. E.M.R. is a scientific advisor to Alkahest, Alzheon, Aural Analytics, Biogen, Denali, Green Valley, MagQ, Takeda & United Neuroscience, and Roche/Roche Diagnostics (expenses only). He is a principal investigator of prevention trials that include research agreements with Genentech/Roche and Novartis/Amgen, PET studies that include research agreements with Avid/Lilly, and several NIH and foundation supported research studies. He is the inventor of a patent owned by Banner Health in which biomarkers are used to accelerate the evaluation of AD prevention therapies. He is also the co-founder of ALZPath, a startup company that is intended to help develop and support the use of blood-based biomarkers for Alzheimer’s disease and related disorders in research, drug development and clinical settings. E.M.R., F.L., and P.N.T are principal investigators of the Alzheimer’s Prevention Initiative (API) Autosomal Dominant AD Trial.

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Figures

Fig. 1
Fig. 1
Relationships between cerebellar Aβ PET SUVRs and age in preclinical cognitively unimpaired PSEN1 E280A carriers and non-carriers. Cerebellar SUVR_pons and age associations with LOESS (95% CIs) (left) and unpaired t-test (right). Age estimates (AAO), means, and p-values are reported. Abbreviations: Aβ, amyloid beta; AAO, average age of biomarker onset; LOESS, non-parametric local regression; SUVR, standard uptake value ratio; CIs, confidence intervals.
Fig. 2
Fig. 2
a-b. Cortical Aβ PET SUVRs and CERAD delayed recall associations with cerebellar Aβ PET SUVRs in PSEN1 E280A carriers Linear-fitted curves (95% CIs) and Pearson r correlations for (a) cortical SUVR_pons and (b) CERAD delayed recall in cognitively unimpaired carriers. *Pearson r correlations and p-values unadjusted for cortical SUVR_pons are reported for delayed recall correlations, similar findings were seen with CERAD total recall. Abbreviations: Aβ, amyloid beta; SUVR, standard uptake value ratio; CERAD, consortium to establish a registry for Alzheimer’s Disease; CIs, confidence intervals. Fig. 2c. Cerebellar Aβ PET SUVR associations with API ADAD composite score in PSEN1 E280A carriers Linear-fitted curves with 95% CIs and Pearson r correlations for (c) API ADAD composite cognitive score in cognitively unimpaired carriers. *Pearson r correlation and p-value unadjusted for cortical SUVR_pons are reported. Abbreviations: Aβ, amyloid beta; API, Alzheimer’s Prevention Initiative; SUVR, standard uptake value ratio; CIs, confidence intervals.

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