Skip to main content Accessibility help
×
Home
Hostname: page-component-55597f9d44-pgkvd Total loading time: 2.193 Render date: 2022-08-10T17:38:31.154Z Has data issue: true Feature Flags: { "shouldUseShareProductTool": true, "shouldUseHypothesis": true, "isUnsiloEnabled": true, "useRatesEcommerce": false, "useNewApi": true } hasContentIssue true

Section 7 - Funding and Financing Alzheimer’s Disease Drug Development

Published online by Cambridge University Press:  03 March 2022

Jeffrey Cummings
Affiliation:
University of Nevada, Las Vegas
Jefferson Kinney
Affiliation:
University of Nevada, Las Vegas
Howard Fillit
Affiliation:
Alzheimer’s Drug Discovery Foundation
Get access

Summary

Image of the first page of this content. For PDF version, please use the ‘Save PDF’ preceeding this image.'
Type
Chapter
Information
Alzheimer's Disease Drug Development
Research and Development Ecosystem
, pp. 465 - 543
Publisher: Cambridge University Press
Print publication year: 2022

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Alzheimer’s Association. 2021 Alzheimer’s disease facts and figures. Alzheimers Dement 2021; 17: 327406.CrossRefGoogle Scholar
PhRMA. Alzheimer’s medicines: setbacks and stepping stones. Available at: www.phrma.org/en/Alzheimer-s-Medicines-Setbacks-and-Stepping-Stones (accessed November 30, 2020).Google Scholar
Garde, D, Feuerstein, A. Why Biogen may be sitting on the most lucrative product in pharmaceutical history. Available at: www.statnews.com/2021/06/07/why-biogen-may-be-sitting-on-the-most-lucrative-product-in-pharmaceutical-history/ (accessed July 23, 2021).Google Scholar
Wong, CH, Siah, KW, Lo, AW. Estimation of clinical trial success rates and related parameters. Biostatistics 2019; 20: 273–86.Google ScholarPubMed
Wouters, OJ, McKee, M, Luyten, J. Estimated research and development investment needed to bring a new medicine to market, 2009–2018. JAMA 2020; 323: 844–53.CrossRefGoogle Scholar
Scott, TJ, O’Connor, AC, Link, AN, Beaulieu, TJ. Economic analysis of opportunities to accelerate Alzheimer’s disease research and development. Ann N Y Acad Sci 2014; 1313: 1734.CrossRefGoogle ScholarPubMed
Cummings, JL, Morstorf, T, Zhong, K. Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther 2014; 6: 37.CrossRefGoogle ScholarPubMed
Prasad, V, Mailankody, S. Research and development spending to bring a single cancer drug to market and revenues after approval. JAMA Intern Med 2017; 177: 1569–75.CrossRefGoogle Scholar
Cleary, EG, Beierlein, JM, Khanuja, NS, McNamee, LM, Ledley, FD. Contribution of NIH funding to new drug approvals 2010–2016. Proc Natl Acad Sci USA 2018; 115: 2329–34.Google Scholar
US Department of Health and Human Services. National Plan to Address Alzheimer’s Disease. 2012. Available at: https://aspe.hhs.gov/national-plan-address-alzheimers-disease (accessed December 23, 2020).Google Scholar
National Institutes of Health. Estimates of funding for various research, condition, and disease categories (RCDC). 2020. Available at: https://report.nih.gov/funding/categorical-spending#/ (accessed July 19, 2021).Google Scholar
Mariotto, AB, Enewold, L, Zhao, J, Zeruto, CA, Yabroff, KR. Medical care costs associated with cancer survivorship in the United States. Cancer Epidemiol Biomarkers Prev 2020; 29: 1304–12.CrossRefGoogle ScholarPubMed
Keller, K, Briggs, L, Riley, E. Alzheimer’s disease: a center for strategic philanthropy giving smarter guide. Available at: https://milkeninstitute.org/sites/default/files/reports-pdf/FINAL-Alz-GSG2_2.pdf (accessed December 23, 2020).Google Scholar
Finkbeiner, S. Bridging the valley of death of therapeutics for neurodegeneration. Nat Med 2010; 16: 1227–32.CrossRefGoogle ScholarPubMed
Angel Resource Institute. Halo report: annual report on angel investments. 2020. Available at: https://angelresourceinstitute.org/ (accessed December 30, 2020).Google Scholar
Castiglia, O. Biotech angels bedeviled by dilution. Available at: www.forbes.com/sites/mergermarket/2020/01/06/biotech-angels-bedeviled-by-dilution/?sh=512e619c6486 (accessed July 19, 2021).Google Scholar
Ford, D, Nelsen, B. The view beyond venture capital. Nat Biotechnol 2014; 32: 1523.CrossRefGoogle ScholarPubMed
Fleming, JJ. The decline of venture capital investment in early-stage life sciences poses a challenge to continued innovation. Health Aff 2015; 34: 271–6.CrossRefGoogle ScholarPubMed
National Venture Capital Association. NVCA and MedIC Coalition release patient capital 3.0: confronting the crisis and achieving the promise of venture-backed medical innovation. Available at: www.prweb.com/releases/2013/4/prweb10670100.htm (accessed December 30, 2020).Google Scholar
Thomas, D, Wessel, C. The state of innovation in highly prevalent chronic diseases. Volume IV: Alzheimer’s disease therapeutics. Available at: http://go.bio.org/rs/490-EHZ-999/images/BIO_HPCD4_ALZHEIMERS.pdf (accessed November 20, 2020).Google Scholar
PhRMA. 2020 PhRMA annual membership survey. Available at: https://phrma.org/Report/2020-PhRMA-Annual-Membership-Survey (accessed December 30, 2020).Google Scholar
Cole, MA, Seabrook, GR. On the horizon: the value and promise of the global pipeline of Alzheimer’s disease therapeutics. Alzheimers Dement (N Y) 2020; 6: e12009.Google ScholarPubMed
Fernandez, J-M, Stein, RM, Lo, AW. Commercializing biomedical research through securitization techniques. Nat Biotechnol 2012; 30: 964–75.CrossRefGoogle ScholarPubMed
Lo, AW, Ho, C, Cummings, J, Kosik, KS. Parallel discovery of Alzheimer’s therapeutics. Sci Transl Med 2014; 6: 241cm5.CrossRefGoogle ScholarPubMed
Cummings, J, Lee, G, Ritter, A, Sabbagh, M, Zhong, K. Alzheimer’s disease drug development pipeline: 2020. Alzheimers Dement (N Y) 2020; 6: e12050.Google ScholarPubMed
Fagnan, DE, Fernandez, J-M, Lo, AW, Stein, RM. Can financial engineering cure cancer? Am Econ Rev 2013; 103: 406–11.CrossRefGoogle Scholar
Al Idrus, A. Dementia Discovery Fund reels in $350 M for disease-modifying drugs. Available at: www.fiercebiotech.com/dementia-discovery-fund-reels-350m-for-disease-modifying-drugs (accessed January 1, 2021).Google Scholar
Kim, E, Lo, AW. Venture philanthropy: a case study of the Cystic Fibrosis Foundation. Available at: https://ssrn.com/abstract=3376673 (accessed January 1, 2021).Google Scholar
Lo, AW, Naraharisetti, SV. New financing methods in the biopharma industry: a case study of Royalty Pharma, Inc. J Invest Manag 2014; 12: 419.Google Scholar
Chaudhuri, SE, Lo, AW. Financially adaptive clinical trials via option pricing analysis. J Econom 2020; DOI: 10.1016/j.jeconom.2020.08.012.CrossRefGoogle Scholar
Eli Lilly. Lilly’s donanemab slows clinical decline of Alzheimer’s disease in positive Phase 2 trial. Jan 11, 2021. Available at: https://investor.lilly.com/news-releases/news-release-details/lillys-donanemab-slows-clinical-decline-alzheimers-disease (accessed January 18, 2021).Google Scholar
Kocahan, S, Zumrut, D. Mechanisms of Alzheimer’s disease pathogenesis and prevention: the brain, neural pathology, N-methyl-D-aspartate receptors, tau protein and other risk factors. Clin Psychopharmacol Neurosci 2017; 15: 18.CrossRefGoogle ScholarPubMed
Sevigny, J, Chiao, P, Bussière, T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 2016; 537: 50–6.CrossRefGoogle ScholarPubMed
Montazerhodjat, V, Chaudhuri, SE, Sargent, DJ, Lo, AW. Use of Bayesian decision analysis to minimize harm in patient-centered randomized clinical trials in oncology. JAMA Oncol 2017; 3: e170123.CrossRefGoogle ScholarPubMed
Chaudhuri, SE, Ho, MP, Irony, T, Sheldon, M, Lo, AW. Patient-centered clinical trials. Drug Discov Today 2018; 23: 395401.CrossRefGoogle ScholarPubMed
Isakov, L, Lo, AW, Montazerhodjat, V. Is the FDA too conservative or too aggressive? A Bayesian decision analysis of clinical trial design. J Econom 2019; 211: 11736.CrossRefGoogle Scholar
Chaudhuri, S, Lo, AW, Xiao, D, Xu, Q. Bayesian adaptive clinical trials for anti-infective therapeutics during epidemic outbreaks. Harvard Data Sci Rev 2020;DOI: https://doi.org/10.1162/99608f92.7656c213.CrossRefGoogle Scholar
Chaudhuri, SE, Lo, AW. Incorporating patient preferences via Bayesian decision analysis. Clin J Am Soc Nephrol 2021; 16: 639–41.CrossRefGoogle ScholarPubMed
Hauber, B, Mange, B, Zhou, M, et al. Parkinson’s patients’ tolerance for risk and willingness to wait for potential benefits of novel neurostimulation devices: a patient-centered threshold technique study. MDM Policy Pract 2021; 6: 2381468320978407.Google ScholarPubMed
Prince, MJ, Wimo, A, Guerchet, MM, et al. World Alzheimer Report 2015: the global impact of dementia: an analysis of prevalence, incidence, cost and trends. Available at: https://kclpure.kcl.ac.uk/portal/en/publications/world-alzheimer-report-2015--the-global-impact-of-dementia(ae525fda-1938-4892-8daa-a2222a672254)/export.html (accessed November 23, 2020).Google Scholar
Seyhan, AA. Lost in translation: the valley of death across preclinical and clinical divide – identification of problems and overcoming obstacles. Transl Med Commun 2019; 4: 18.CrossRefGoogle Scholar
DiMasi, JA, Grabowski, HG, Hansen, RW. Innovation in the pharmaceutical industry: new estimates of R&D costs. J Health Econ 2016; 47: 2033.CrossRefGoogle ScholarPubMed
Cummings, JL, Morstorf, T, Zhong, K. Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther 2014; 6: 37.CrossRefGoogle ScholarPubMed
Choi, DW, Armitage, R, Brady, LS, et al. Medicines for the mind: policy-based “pull” incentives for creating breakthrough CNS drugs. Neuron 2014; 84: 554–63.CrossRefGoogle ScholarPubMed
Finkbeiner, S. Bridging the valley of death of therapeutics for neurodegeneration. Nat Med 2010; 16: 1227–32.CrossRefGoogle ScholarPubMed
Cummings, J, Reiber, C, Kumar, P. The price of progress: funding and financing Alzheimer’s disease drug development. Alzheimers Dement (N Y) 2018; 4: 330–43.Google Scholar
Thomas, D, Wessel, C. The state of innovation in highly prevalent chronic diseases. Volume IV: Alzheimer’s disease therapeutics. Available at: http://go.bio.org/rs/490-EHZ-999/images/BIO_HPCD4_ALZHEIMERS.pdf (accessed November 23, 2020).Google Scholar
Cummings, J, Lee, G, Mortsdorf, T, Ritter, A, Zhong, K. Alzheimer’s disease drug development pipeline: 2017. Alzheimers Dement (N Y) 2017; 3: 367–84.Google ScholarPubMed
Hanson, SL, Nadig, L, Altevogt, BM, et al. Workshop on venture philanthropy strategies to support translational Research Planning Committee. In Venture Philanthropy Strategies to Support Translational Research: Workshop Summary. Washington, DC: National Academies Press; 2009: 59–68.Google Scholar
Lopez, JC, Suojanen, C. Harnessing venture philanthropy to accelerate medical progress. Nat Rev Drug Discov 2019; 18: 809–10.CrossRefGoogle ScholarPubMed
Esther Kim, AWL. Venture philanthropy: a case study of the Cystic Fibrosis Foundation, April 2019. Available at: https://ssrn.com/abstract=3376673 (accessed November 23, 2020).Google Scholar
Kerem, B, Rommens, JM, Buchanan, JA, et al. Identification of the cystic fibrosis gene: genetic analysis. Science 1989; 245: 1073–80.CrossRefGoogle ScholarPubMed
Riordan, JR, Rommens, JM, Kerem, B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989; 245: 1066–73.CrossRefGoogle ScholarPubMed
Rommens, JM, Iannuzzi, MC, Kerem, B, et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 1989; 245: 1059–65.CrossRefGoogle ScholarPubMed
Sloane, PA, Rowe, SM. Cystic fibrosis transmembrane conductance regulator protein repair as a therapeutic strategy in cystic fibrosis. Curr Opin Pulm Med 2010; 16: 591–7.Google ScholarPubMed
Senior, M. Foundation receives $3.3-billion windfall for Kalydeco. Nat Biotechnol 2015; 33: 89.CrossRefGoogle ScholarPubMed
Perkins, LM, Young, AQ, Giusti, K. One foundation’s strategy to accelerate drug discovery through genomics. Sci Transl Med 2011; 3: 78cm11.CrossRefGoogle ScholarPubMed
Ramsey, BW, Nepom, GT, Lonial, S. Academic, foundation, and industry collaboration in finding new therapies. N Engl J Med 2017; 376: 1762–9.CrossRefGoogle ScholarPubMed
Orelli, B. JDRF teams with VC PureTech to promote startups. Nat Biotechnol 2013; 31: 1065.CrossRefGoogle ScholarPubMed
Osherovich, L. Fast forward in MS. Science-Business eXchange 2009; 2: 858.CrossRefGoogle Scholar
Alzheimer’s Drug Discovery Foundation. 2018 Alzheimer’s clinical trials report. Available at: www.alzdiscovery.org/research-and-grants/clinical-trials-report/2018-report (accessed November 23, 2020).Google Scholar
Hara, Y, McKeehan, N, Fillit, HM. Translating the biology of aging into novel therapeutics for Alzheimer disease. Neurology 2019; 92: 8493.CrossRefGoogle ScholarPubMed
Lo, AW, Ho, C, Cummings, J, Kosik, KS. Parallel discovery of Alzheimer’s therapeutics. Sci Transl Med 2014; 6: 241cm245.CrossRefGoogle ScholarPubMed
Shineman, DW, Alam, J, Anderson, M, et al. Overcoming obstacles to repurposing for neurodegenerative disease. Ann Clin Transl Neurol 2014; 1: 512–18.CrossRefGoogle ScholarPubMed
Yang, L, Rieves, D, Ganley, C. Brain amyloid imaging: FDA approval of florbetapir F18 injection. N Engl J Med 2012; 367: 885–7.CrossRefGoogle ScholarPubMed
Honig, LS, Vellas, B, Woodward, M, et al. Trial of solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med 2018; 378: 321–30.CrossRefGoogle ScholarPubMed
Sevigny, J, Chiao, P, Bussiere, T, et al. The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. Nature 2016; 537: 50–6.CrossRefGoogle ScholarPubMed
Conley, AK, Blackford, J, Rook, J, et al. Functional activity of the muscarinic positive allosteric modulator VU319 during a Phase 1 single ascending dose study. Am J Geriatr Psychiatry 2020; 28: S114–15.CrossRefGoogle Scholar
Acadia Pharmaceuticals and Vanderbilt University. Acadia Pharmaceuticals and Vanderbilt University announce exclusive license agreement and research collaboration [press release]. Available at: www.businesswire.com/news/home/20200507005980/en/ACADIA-Pharmaceuticals-and-Vanderbilt-University-Announce-Exclusive-License-Agreement-and-Research-Collaboration (accessed November 23, 2020).Google Scholar
Shineman, DW, Basi, GS, Bizon, JL, et al. Accelerating drug discovery for Alzheimer’s disease: best practices for preclinical animal studies. Alzheimers Res Ther 2011; 3: 28.CrossRefGoogle ScholarPubMed
Lane, RF, Friedman, LG, Keith, C, et al. Optimizing the use of CROs by academia and small companies. Nat Rev Drug Discov 2013; 12: 487–8.CrossRefGoogle ScholarPubMed
Alzheimer’s Association. 2020 Alzheimer’s disease facts and figures. Alzheimers Dement 2020; 16: 391460.CrossRefGoogle Scholar
Alzheimer’s Disease International. World Alzheimer Report 2015: The Global Impact of Dementia. London: Alzheimer’s Disease International; 2015.Google Scholar
Jack, CR, Jr., Albert, MS, Knopman, DS, et al. Introduction to the recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7: 257–62.CrossRefGoogle Scholar
Petersen, RC, Lopez, O, Armstrong, MJ, et al. Practice guideline update summary: mild cognitive impairment. Neurology 2018; 90: 126–35.CrossRefGoogle ScholarPubMed
Ward, A, Tardiff, S, Dye, C, Arrighi, HM. Rate of conversion from prodromal Alzheimer’s disease to Alzheimer’s dementia: a systematic review of the literature. Dement Geriatr Cogn Disord Extra 2013; 3: 320–32.CrossRefGoogle ScholarPubMed
Mitchell, AJ, Shiri-Feshki, M. Rate of progression of mild cognitive impairment to dementia: meta-analysis of 41 robust inception cohort studies. Acta Psychiatr Scand 2009; 119: 252–65.CrossRefGoogle ScholarPubMed
Sperling, RA, Aisen, PS, Beckett, LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7: 280–92.CrossRefGoogle ScholarPubMed
Albert, MS, DeKosky, ST, Dickson, D, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7: 270–9.CrossRefGoogle Scholar
McKhann, GM, Knopman, DS, Chertkow, H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7: 263–9.CrossRefGoogle Scholar
Karlawish, J, Jack, CR, Jr., Rocca, WA, Snyder, HM, Carrillo, MC. Alzheimer’s disease: the next frontier – special report 2017. Alzheimers Dement 2017; 13: 374–80.CrossRefGoogle ScholarPubMed
Jack, CR, Jr., Bennett, DA, Blennow, K, et al. A/T/N: an unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology 2016; 87: 539–47.CrossRefGoogle ScholarPubMed
Jack, CR, Jr., Bennett, DA, Blennow, K, et al. NIA–AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement 2018; 14: 535–62.CrossRefGoogle Scholar
Alzheimer’s Association. The Tau Pipeline Enabling Program (T-PEP). Available at: www.alz.org/research/for_researchers/grants/types-of-grants/partnership_funding_programs/the_tau_pipeline_enabling_program_(t-pep)_(2) (accessed July 24, 2021).Google Scholar
Johnson, KA, Minoshima, S, Bohnen, NI, et al. Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer’s Association. J Nucl Med 2013; 54: 476–90.CrossRefGoogle Scholar
Mattsson, N, Andreasson, U, Persson, S, et al. CSF biomarker variability in the Alzheimer’s Association quality control program. Alzheimers Dement 2013; 9: 251–61.CrossRefGoogle ScholarPubMed
Carrillo, MC, Blennow, K, Soares, H, et al. Global standardization measurement of cerebral spinal fluid for Alzheimer’s disease: an update from the Alzheimer’s Association Global Biomarkers Consortium. Alzheimers Dement 2013; 9: 137–40.CrossRefGoogle ScholarPubMed
Shaw, LM, Arias, J, Blennow, K, et al. Appropriate use criteria for lumbar puncture and cerebrospinal fluid testing in the diagnosis of Alzheimer’s disease. Alzheimers Dement 2018; 14: 1505–21.Google ScholarPubMed
National Institute on Aging. Together we make the difference: national strategy for recruitment and participation in Alzheimer’s and related dementias clinical research. Available at: www.nia.nih.gov/research/recruitment-strategy (accessed July 20, 2021).Google Scholar
Super, N, Ahuja, R, Proff, K. Reducing the cost and risk of dementia. Available at: https://milkeninstitute.org/sites/default/files/reports-pdf/Reducing%20the%20Cost%20and%20Risk%20of%20Dementia%20Full%20Report-FINAL-for-posting_0.pdf (accessed November 25, 2020).Google Scholar
Alzheimer’s Association. 2020 Alzheimer’s disease facts and figures. Alzheimers Dement 2020; 16: 391460.CrossRefGoogle Scholar
PhRMA. Research. Alzheimer’s medicines: setbacks and stepping stones. Available at: www.phrma.org/en/Alzheimer-s-Medicines-Setbacks-and-Stepping-Stones (accessed November 25, 2020).Google Scholar
Research!America. U.S. Investments in Medical and Health Reserach and Development, 2013–2017. Available at: www.researchamerica.org/sites/default/files/Policy_Advocacy/2013-2017InvestmentReportFall2018.pdf (accessed November 25, 2020).Google Scholar
Milken, M. Giving pledge letter 2010. Available at: https://givingpledge.org/Pledger.aspx?id=245 (accessed November 25, 2020).Google Scholar
Alzheimer’s Impact Movement. Alzheimer’s and dementia research. Available at: https://alzimpact.org/issues/research#:~:text=Today%2C%20funding%20for%20Alzheimer’s%20and,increase%20for%20fiscal%20year%202020 (accessed November 25, 2020).Google Scholar
Losak, A. New coalition of philanthropists including Bill Gates, Leonard Lauder commit more than $30 million. Available at: www.alzdiscovery.org/news-room/announcements/new-coalition-of-philanthropists-including-bill-gates-and-leonard-lauder-co (accessed November 25, 2020).Google Scholar
The Giving Pledge. Giving pledge. 2020. Available at: https://givingpledge.org/PledgerList.aspx (accessed November 25, 2020).Google Scholar
Charette, MF, Oh, YS, Maric-Bilkan, C, et al. Shifting demographics among research project grant awardees at the National Heart, Lung, and Blood Institute (NHLBI). PloS One 2016; 11: e0168511.CrossRefGoogle Scholar
Blau, DM, Weinberg, BA. Why the US science and engineering workforce is aging rapidly. PNAS 2017; 114: 3879–84.CrossRefGoogle ScholarPubMed
National Institutes of Health. NIH professional judgment budget for Alzheimer’s disease and related dementias for fiscal year 2022. Available at: www.nia.nih.gov/sites/default/files/2020-07/bypass-budget-report-FY-2022.pdf (accessed January 18, 2021).Google Scholar
Kelley, AS, McGarry, K, Gorges, R, Skinner, JS. The burden of health care costs for patients with dementia in the last 5 years of life. Ann Intern Med 2015; 163: 729–36.CrossRefGoogle ScholarPubMed
Refolo, L. From mouse to medicine: improving preclinical research in Alzheimer’s disease. Available at: www.nia.nih.gov/research/blog/2017/02/mouse-medicine-improving-preclinical-research-alzheimers-disease (accessed January 18, 2021).Google Scholar
Petanceska, S, Ryan, L, Silverberg, N, Buckholtzet, N. Commentary on ‘‘A roadmap for the prevention of dementia II. Leon Thal Symposium 2008.’’ Alzheimer’s disease translational research programs at the National Institute on Aging. Alzheimers Dement 2009; 5: 130–2.CrossRefGoogle Scholar
Buckholtz, NS, Ryan, LM, Petanceska, S, Refolo, LM. NIA commentary: translational issues in Alzheimer’s disease drug development. Neuropsychopharmacol Rev 2012; 37: 284–6.CrossRefGoogle ScholarPubMed
Weninger, S, Carrillo, MC, Dunn, B, et al. Collaboration for Alzheimer’s prevention: principles to guide data and sample sharing in preclinical Alzheimer’s disease trials. Alzheimers Dement 2016; 12: 631–2.CrossRefGoogle ScholarPubMed
Ryan, L, Petanceska, S. Raising the bar on data and biosample sharing from AD/ADRD clinical trials. Available at: www.nia.nih.gov/research/blog/2020/12/raising-bar-data-and-biosample-sharing-ad-adrd-clinical-trials (accessed January 18, 2021).Google Scholar
Sperling, RA, Jack, CR Jr., Aisen, PS. Testing the right target and right drug at the right stage. Sci Transl Med 2011; 3: 111cm33.CrossRefGoogle ScholarPubMed
Petanceska, S, Refolo, L. Open science delivers a wealth of AD/ADRD research data to a portal near you. Available at: www.nia.nih.gov/research/blog/2020/11/open-science-delivers-wealth-ad-adrd-research-data-portal-near-you (accessed January 18, 2021).Google Scholar
Greenwood, AK, Montgomery, KS, Kaueret, N, et al. The AD knowledge portal: a repository for multi-omic data on Alzheimer’s disease and aging. Curr Protoc Hum Genet 2020; 108: e105.Google ScholarPubMed
Oblak, AL, Forner, S, Territo, PR, et al. Model Organism Development and Evaluation for Late-Onset Alzheimer’s Disease: MODEL-AD. Alzheimers Dement 2020; 6: e12110.Google ScholarPubMed
Sukoff Rizzo, SJ, Masters, A, Onoset, KD, et al. Improving preclinical to clinical translation in Alzheimer’s disease research. Alzheimers Dement 2020; 6: e12038.Google ScholarPubMed
Weiner, MW, Veitch, DP, Aisen, PS, et al. Recent publications from the Alzheimer’s Disease Neuroimaging Initiative: reviewing progress toward improved AD clinical trials. Alzheimers Dement 2017; 13: e185.Google Scholar
Sperling, RA, Donohue, MC, Raman, R, et al. Association of factors with elevated amyloid burden in clinically normal older individuals. JAMA Neurol 2020; 77: 735–45.CrossRefGoogle ScholarPubMed
Bernard, M. Announcing NIA’s new crop of research concepts! Available at: www.nia.nih.gov/research/blog/2020/09/announcing-nias-new-crop-research-concepts (accessed January 18, 2021).Google Scholar
Institute of Medicine. Sharing Clinical Trial Data: Maximizing Benefits, Minimizing Risk. Washington, DC: The National Academies Press; 2015.Google Scholar
Patterson, C. World Alzheimer Report 2018. The state of the art of dementia research: new frontiers. Available at: www.alz.co.uk/research/WorldAlzheimerReport2018.pdf (accessed January 29, 2021).Google Scholar
Heron, M. Deaths: leading causes for 2016. Available at: www.cdc.gov/nchs/data/nvsr/nvsr67/nvsr67_06.pdf (accessed January 29, 2021).Google Scholar
Grabrucker, A, Vaida, B, Bockmann, J, Boeckers, TM. Synaptogenesis of hippocampal neurons in primary cell culture. Cell Tissue Res 2009; 338: 333–41.CrossRefGoogle ScholarPubMed
Ramakers, GJA, Kloosterman, F, van Hulten, P, van Pelt, J, Corner, MA. Activity-dependent regulation of neuronal network excitability. In Neural Circuits and Networks, Torre, V, Nicholls, J (eds.). Berlin: Springer; 1998: 141–51.Google Scholar
Banker, G, Goslin, K. Types of nerve cell cultures, their advantages, and limitations. In Culturing Nerve Cells, Banker, G, Goslin, K (eds.). Cambridge, MA: MIT Press; 1998: 1136.Google Scholar
Opitz, T, De Lima, AD, Voigt, T. Spontaneous development of synchronous oscillatory activity during maturation of cortical networks in vitro. J Neurophysiol 2002; 88: 2196–206.CrossRefGoogle ScholarPubMed
Torre, V, Nicholls, J (eds.). Neural Circuits and Networks. Heidelberg: Springer; 1998.CrossRefGoogle Scholar
LaBarbera, KM, Limegrover, CM, Rehak, C, et al. Modeling the mature CNS: a predictive screening platform for neurodegenerative disease drug discovery. J Neurosci Methods 2021; 358: 109180.CrossRefGoogle ScholarPubMed
Kamenetz, F, Tomita, T, Hsieh, H, et al. APP processing and synaptic function. Neuron 2003; 37: 925–37.CrossRefGoogle ScholarPubMed
Lacor, PN, Buniel, MC, Chang, L, et al. Synaptic targeting by Alzheimer’s-related amyloid β oligomers. J Neurosci 2004; 24: 10191–200.CrossRefGoogle ScholarPubMed
Reed, MN, Hofmeister, JJ, Jungbauer, L, et al. Cognitive effects of cell-derived and synthetically derived Aβ oligomers. Neurobiol Aging 2011; 32: 1784–94.CrossRefGoogle ScholarPubMed
Hsieh, H, Boehm, J, Sato, C, et al. AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron 2006; 52: 831–43.CrossRefGoogle ScholarPubMed
Hong, H-S, Maezawa, I, Yao, N, et al. Combining the rapid MTT formazan exocytosis assay and the MC65 protection assay led to the discovery of carbazole analogs as small molecule inhibitors of Abeta oligomer-induced cytotoxicity. Brain Res 2007; 1130: 223–34.CrossRefGoogle Scholar
Kreutzmann, P, Wolf, G, Kupsch, K. Minocycline recovers MTT-formazan exocytosis impaired by amyloid beta peptide. Cell Mol Neurobiol 2010; 30: 979–84.CrossRefGoogle ScholarPubMed
Liu, Y, Schubert, D. Cytotoxic amyloid peptides inhibit cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction by enhancing MTT formazan exocytosis. J Neurochem 1997; 69: 2285–93.Google ScholarPubMed
Izzo, NJ, Staniszewski, A, To, L, et al. Alzheimer’s therapeutics targeting amyloid beta 1–42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits. PLoS One 2014; 9: e111898.CrossRefGoogle ScholarPubMed
Izzo, NNJ, Xu, J, Zeng, C, et al. Alzheimer’s therapeutics targeting amyloid beta 1–42 oligomers II: sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity. PLoS One 2014; 9: e111899.CrossRefGoogle ScholarPubMed
Izzo, NJ, Yuede, CM, LaBarbera, KM, et al. Preclinical and clinical biomarker studies of CT1812: a novel approach to Alzheimer’s disease modification. Alzheimers Dement 2021;DOI: https://doi.org/10.1002/alz.12302.CrossRefGoogle Scholar
Rishton, GM, Look, G, Ni, Z-J, et al. Negative allosteric modulators of the sigma-2 receptor: discovery of investigational drug CT1812 for Alzheimer’s Disease. ACS Med Chem Lett; DOI: https://doi.org/10.1021/acsmedchemlett.1c00048.CrossRefGoogle Scholar
Rishton, GM. Reactive compounds and in vitro false positives in HTS. Drug Discov Today 1997; 2: 382–4.CrossRefGoogle Scholar
Rishton, GM. Nonleadlikeness and leadlikeness in biochemical screening. Drug Discov Today 2003; 8: 8696.CrossRefGoogle ScholarPubMed
Rishton, GM. Aggregator compounds confound amyloid fibrillization assay. Nat Chem Biol 2008; 4: 159–60.CrossRefGoogle ScholarPubMed
Arai, H, Beierle, K, Fullenwider, C, Kaj, Z. Chemically conditioned extracts of ginger oil: leadlike “alkaloidal” compounds derived from natural extracts via reductive amination. American Chemical Society Western Regional Meeting, Anaheim, CA, Jan 22, 2006. Available at: http://acs.confex.com/acs/werm05/techprogram/S2455.HTM.Google Scholar
Grundman, M, Morgan, R, Lickliter, JD, et al. A Phase 1 clinical trial of the sigma-2 receptor complex allosteric antagonist CT1812, a novel therapeutic candidate for Alzheimer’s disease. Alzheimers Dement (N Y) 2019; 5: 20–6.Google ScholarPubMed
Limegrover, CS, LeVine, H, Izzo, NJ, et al. Alzheimer’s protection effect of A673 T mutation may be driven by lower Aβ oligomer binding affinity. J Neurochem 2021; 157: 1316–30.CrossRefGoogle Scholar
Masliah, E, Terry, RD, Alford, M, DeTeresa, R, Hansen, L. Cortical and subcortical patterns of synaptophysinlike immunoreactivity in Alzheimer’s disease. Am J Pathol 1991; 138: 235–46.Google ScholarPubMed
DeKosky, ST, Scheff, SW. Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 1990; 27: 457–64.CrossRefGoogle ScholarPubMed
Scheff, SW, Price, DA. Synaptic pathology in Alzheimer’s disease: a review of ultrastructural studies. Neurobiol Aging 2003; 24: 1029–46.CrossRefGoogle ScholarPubMed
Colom-Cadena, M, Spires-Jones, T, Zetterberg, H, et al. The clinical promise of biomarkers of synapse damage or loss in Alzheimer’s disease. Alzheimers Res Ther 2020; 12: 21.CrossRefGoogle ScholarPubMed
Riad, A, Zeng, C, Weng, C-CC, et al. Sigma-2 receptor/TMEM97 and PGRMC-1 increase the rate of internalization of LDL by LDL receptor through the formation of a ternary complex. Sci Rep 2018; 8: 16845.CrossRefGoogle ScholarPubMed
Riad, A, Lengyel-Zhand, Z, Zeng, C, et al. The sigma-2 receptor/TMEM97, PGRMC1, and LDL receptor complex are responsible for the cellular uptake of Aβ42 and its protein aggregates. Mol Neurobiol 2020; 57: 3803–13.CrossRefGoogle ScholarPubMed
Xu, J, Zeng, C, Chu, W, et al. Identification of the PGRMC1 protein complex as the putative sigma-2 receptor binding site. Nat Commun 2011; 2: 380.CrossRefGoogle ScholarPubMed
Alon, A, Schmidt, HR, Wood, MD, et al. Identification of the gene that codes for the σ 2 receptor. Proc Natl Acad Sci USA 2017; 114: 7160–5.CrossRefGoogle Scholar
Behrends, C, Sowa, ME, Gygi, SP, Harper, JW. Network organization of the human autophagy system. Nature 2010; 466: 6876.CrossRefGoogle ScholarPubMed
Mir, SU, Schwarze, SR, Jin, L, et al. Progesterone receptor membrane component 1/sigma-2 receptor associates with MAP1LC3B and promotes autophagy. Autophagy 2013; 9: 1566–78.CrossRefGoogle ScholarPubMed
Ahmed, IS, Rohe, HJ, Twist, KE, Craven, RJ. PGRMC1 (progesterone receptor membrane component 1) associates with epidermal growth factor receptor and regulates erlotinib sensitivity. J Biol Chem 2010; 285: 24775–82.CrossRefGoogle ScholarPubMed
Thomas, P, Pang, Y, Dong, J. Enhancement of cell surface expression and receptor functions of membrane progestin receptor α (mPRα) by progesterone receptor membrane component 1 (PGRMC1): evidence for a role of PGRMC1 as an adaptor protein for steroid receptors. Endocrinology 2014; 155: 1107–19.CrossRefGoogle ScholarPubMed
Zhang, M, Robitaille, M, Showalter, AD, et al. Progesterone receptor membrane component 1 is a functional part of the GLP-1 receptor complex in pancreatic beta cells. Mol Cell Proteomics 2014; 1: 3049–62.Google Scholar
Runko, E, Kaprielian, Z. Caenorhabditis elegans VEM-1, a novel membrane protein, regulates the guidance of ventral nerve cord-associated axons. J Neurosci 2004; 24: 9015–26.CrossRefGoogle ScholarPubMed
Hampton, KK, Anderson, K, Frazier, H, Thibault, O, Craven, RJ. Insulin receptor plasma membrane levels increased by the progesterone receptor membrane component 1. Mol Pharmacol 2018; 94: 665–73.CrossRefGoogle ScholarPubMed
Mansouri, MR, Schuster, J, Badhai, J, et al. Alterations in the expression, structure and function of progesterone receptor membrane component-1 (PGRMC1) in premature ovarian failure. Hum Mol Genet 2008; 17: 3776–83.CrossRefGoogle Scholar
Sanchez-Pulido, L, Ponting, CP. TM6SF2 and MAC30, new enzyme homologs in sterol metabolism and common metabolic disease. Front Genet 2014; 5: 19.CrossRefGoogle ScholarPubMed
Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 300205:11/20/2019. Available at: https://omim.org/.Google Scholar
Ebrahimi-Fakhari, D, Wahlster, L, Bartz, F, et al. Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann–Pick type C1 disease cells. Hum Mol Genet 2015; 25: 3588–99.Google Scholar
Intlekofer, KA, Clements, K, Woods, H, et al. Progesterone receptor membrane component 1 inhibits tumor necrosis factor alpha induction of gene expression in neural cells. PLoS One 2019; 14: e0215389.CrossRefGoogle ScholarPubMed
Rohe, HJ, Ahmed, IS, Twist, KE, Craven, RJ. PGRMC1 (progesterone receptor membrane component 1): a targetable protein with multiple functions in steroid signaling, P450 activation and drug binding. Pharmacol Ther 2009; 121: 14–19.CrossRefGoogle ScholarPubMed
Suchanek, M, Radzikowska, A, Thiele, C. Photo-leucine and photo-methionine allow identification of protein–protein interactions in living cells. Nat Methods 2005; 2: 261–7.CrossRefGoogle ScholarPubMed
Hughes, AL, Powell, DW, Bard, M, et al. Dap1/PGRMC1 binds and regulates cytochrome P450 enzymes. Cell Metab 2007; 5: 143–9.CrossRefGoogle ScholarPubMed
Limegrover, CS, Yurko, R, Izzo, NJ, et al. Sigma-2 receptor antagonists rescue neuronal dysfunction induced by Parkinson’s patient brain-derived α-synuclein. J Neurosci Res 2021; 99: 1161–76.CrossRefGoogle ScholarPubMed
Izzo, NJ, Colom-Cadena, M, Riad, AA, et al. Proceedings from the Fourth International Symposium on Sigma-2 Receptors: Role in Health and Disease. eNeuro 2020; 7: 17. Available at: http://eneuro.org/lookup/doi/10.1523/ENEURO.0317-20.2020.CrossRefGoogle ScholarPubMed
Frautschy, SA, Cole, GM. Why pleiotropic interventions are needed for Alzheimer’s disease. Mol Neurobiol 2010; 41: 392409.CrossRefGoogle ScholarPubMed
Cummings, JL, Morstorf, T, Zhong, K. Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther 2014; 6: 37.CrossRefGoogle ScholarPubMed
Sabbagh, JJ, Kinney, JW, Cummings, J. Animal systems in the development of treatments for Alzheimer’s disease: challenges, methods, and implications. Neurobiol Aging 2013; 34: 169–83.CrossRefGoogle ScholarPubMed
Windisch, M. We can treat Alzheimer’s disease successfully in mice but not in men: failure in translation? A perspective. Neurodegen Dis 2014; 13: 147–50.CrossRefGoogle Scholar
Lo, AW, Ho, C, Cummings, J, Kosik, KS. Parallel discovery of Alzheimer’s therapeutics. Sci Transl Med 2014; 6: 241cm245.CrossRefGoogle ScholarPubMed
Deb, A, Thornton, JD, Sambamoorthi, U, Innes, K. Direct and indirect cost of managing Alzheimer’s disease and related dementias in the United States. Expert Rev Pharmacoecon Outcomes Res 2017; 17: 189202.CrossRefGoogle ScholarPubMed
Hurd, MD, Martorell, P, Delavande, A, Mullen, KJ, Langa, KM. Monetary costs of dementia in the United States. N Engl J Med 2013; 368: 1326–34.CrossRefGoogle ScholarPubMed
US Department of Health and Human Services, Office of the Assistant Secretary for Planning and Evaluation. National plans to address Alzheimer’s disease. 2012. Available at: https://aspe.hhs.gov/napa-national-plans (accessed December 7, 2021).Google Scholar
Ghazarian, A, Haim, T, Sauma, S, Katiyar, P. National Institute on Aging seed funding enables Alzheimer’s disease startups to reach key value inflection points. Alzheimers Dement 2021;DOI: https://doi.org/10.1002/alz.12392.CrossRefGoogle Scholar
Mauricio, R, Benn, C, Davis, J, et al. Therapeutics for dementia: tackling gaps in developing life-changing treatments for dementia. Alzheimers Dement (N Y) 2019; 5: 241–53.Google ScholarPubMed
Scott, TJ, O’Connor, AC, Link, AN, Beaulieu, TJ. Economic analysis of opportunities to accelerate Alzheimer’s disease research and development. Ann N Y Acad Sci 2014; 1313: 1734.CrossRefGoogle ScholarPubMed
Cummings, J, Reiber, C, Kumar, P. The price of progress: funding and financing Alzheimer’s disease drug development. Alzheimers Dement (N Y) 2018; 4: 33043.CrossRefGoogle Scholar
US Small Business Administration. Birth and history of the SBIR program. Available at: www.sbir.gov/birth-and-history-of-the-sbir-program (accessed November 10, 2021).Google Scholar
Onken, J, Miklos, AC, Dorsey, TF, et al. Using database linkages to measure innovation, commercialization, and survival of small businesses. Eval Program Plann 2019; 77: 101710.CrossRefGoogle ScholarPubMed
US Small Business Administration. About SBA. Available at: www.sba.gov/about-sba (accessed November 3, 2020).Google Scholar
US Small Business Administration. Performance benchmark requirements for Phase I. Available at: www.sbir.gov/performance-benchmarks (accessed November 10, 2020).Google Scholar
National Science Board. Science and Engineering Indicators. 2018: research and development – US trends and international comparisons. Available at: www.nsf.gov/statistics/2018/nsb20181/ (accessed November 10, 2020).Google Scholar
Jefferson, RS. How the largest public funder of biomedical research in the world spends your money. Available at: www.forbes.com/sites/robinseatonjefferson/2018/12/21/how-the-largest-public-funder-of-biomedical-research-in-the-world-spends-your-money/?sh=69d3d48f27b9 (accessed November 23, 2020).Google Scholar
NIH Research Portfolio Online Reporting Tools (RePORT). Small business research (SBIR/STTR). Available at: https://report.nih.gov/nihdatabook/category/8 (accessed November 23, 2020).Google Scholar
National Institutes of Health. Intellectual property and iEdison invention report requirements. Available at: https://sbir.nih.gov/policy/invention-reporting (accessed December 2, 2020).Google Scholar
Ben-Menachem, G, Ferguson, SM, Balakrishnan, K. Doing business with the NIH. Nat Biotechnol 2006; 24: 1720.Google ScholarPubMed
National Institutes of Health. Advancing research on Alzheimer’s disease (AD) and Alzheimer’s-disease-related dementias (ADRD) (R41/R42). Available at: https://grants.nih.gov/grants/guide/pa-files/PAs-17-065.html (accessed November 10, 2020).Google Scholar
National Institutes of Health. Advancing research on Alzheimer’s disease (AD) and Alzheimer’s-disease-related dementias (ADRD) (R43/R44). Available at: https://grants.nih.gov/grants/guide/pa-files/PAs-17-064.html (accessed November 10, 2020).Google Scholar
Cole, MA, Seabrook, GR. On the horizon: the value and promise of the global pipeline of Alzheimer’s disease therapeutics. Alzheimers Dement (N Y) 2020; 6: e12009.Google ScholarPubMed
Bakker, A, Krauss, GL, Albert, MA, et al. Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron 2012; 74: 467–74.CrossRefGoogle ScholarPubMed
Cognition Therapeutics. Cognition Therapeutics receives $75.8 million NIA grant for 540-patient Phase 2 study of CT1812 in collaboration with the Alzheimer’s Clinical Trials Consortium. Available at: https://cogrx.com/cognition-receives-nia-grant-for-actc-study/ (accessed December 2, 2020).Google Scholar
Businesswire. Tetra Therapeutics and Shionogi announce expanded alliance. Available at: www.businesswire.com/news/home/20200306005082/en/Tetra-Therapeutics-Shionogi-Announce-Expanded-Alliance (accessed December 2, 2021).Google Scholar
Canaria, CA, Portilla, L, Weingarten, M. I-Corps at NIH: entrepreneurial training program creating successful small businesses. Clin Transl Sci 2019; 12: 324–8.CrossRefGoogle ScholarPubMed
Cummings, J, Lee, G, Ritter, A, Sabbagh, M, Zhong, K. Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement (N Y) 2019; 5: 272–93.Google ScholarPubMed

Save book to Kindle

To save this book to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×