The Current Landscape of Prevention Trials in Dementia

Patterson C. World Alzheimer report. Alzheimers Dis Int. 2018. Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256:184–5. https://doi.org/10.1126/science.1566067. Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov. 2011;10:698–712. https://doi.org/10.1038/nrd3505. Blessed G, Tomlinson BE, Roth M. The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. Br J Psychiatry J Ment Sci. 1968;114:797–811. https://doi.org/10.1192/bjp.114.512.797. Brookmeyer R, Evans DA, Hebert L, Langa KM, Heeringa SG, Plassman BL, et al. National estimates of the prevalence of Alzheimer’s disease in the United States. Alzheimers Dement J Alzheimers Assoc. 2011;7:61–73. https://doi.org/10.1016/j.jalz.2010.11.007. Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet Lond Engl. 2020;396:413–46. https://doi.org/10.1016/S0140-6736(20)30367-6. Raz L, Knoefel J, Bhaskar K. The neuropathology and cerebrovascular mechanisms of dementia. J Cereb Blood Flow Metab. 2016;36:172–86. https://doi.org/10.1038/jcbfm.2015.164. Oliver DMA, Reddy PH. Small molecules as therapeutic drugs for Alzheimer’s disease. Mol Cell Neurosci. 2019;96:47–62. https://doi.org/10.1016/j.mcn.2019.03.001. Norton S, Matthews FE, Barnes DE, Yaffe K, Brayne C. Potential for primary prevention of Alzheimer’s disease: an analysis of population-based data. Lancet Neurol. 2014;13:788–94. https://doi.org/10.1016/S1474-4422(14)70136-X. Lin FR, Niparko JK, Ferrucci L. Hearing loss prevalence in the United States. Arch Intern Med. 2011;171:1851–3. https://doi.org/10.1001/archinternmed.2011.506. Loughrey DG, Kelly ME, Kelley GA, Brennan S, Lawlor BA. Association of age-related hearing loss with cognitive function, cognitive impairment, and dementia: a systematic review and meta-analysis. JAMA Otolaryngol- Head Neck Surg. 2018;144:115–26. https://doi.org/10.1001/jamaoto.2017.2513. Ray J, Popli G, Fell G. Association of cognition and age-related hearing impairment in the English longitudinal study of ageing. JAMA Otolaryngol- Head Neck Surg. 2018;144:876–82. https://doi.org/10.1001/jamaoto.2018.1656. Peters R, Ee N, Peters J, Booth A, Mudway I, Anstey KJ. Air pollution and dementia: a systematic review. J Alzheimers Dis JAD. 2019;70:S145–63. https://doi.org/10.3233/JAD-180631. Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW. A protein factor essential for microtubule assembly. Proc Natl Acad Sci U S A. 1975;72:1858–62. https://doi.org/10.1073/pnas.72.5.1858. Alonso AC, Grundke-Iqbal I, Iqbal K. Alzheimer’s disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nat Med. 1996;2:783–7. https://doi.org/10.1038/nm0796-783. Mandelkow E-M, Stamer K, Vogel R, Thies E, Mandelkow E. Clogging of axons by tau, inhibition of axonal traffic and starvation of synapses. Neurobiol Aging. 2003;24:1079–85. https://doi.org/10.1016/j.neurobiolaging.2003.04.007. Wang X, Wang W, Li L, Perry G, Lee H, Zhu X. Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochim Biophys Acta. 2014;1842:1240–7. https://doi.org/10.1016/j.bbadis.2013.10.015. Praticò D, Clark CM, Liun F, Rokach J, Lee VY-M, Trojanowski JQ. Increase of brain oxidative stress in mild cognitive impairment: a possible predictor of Alzheimer disease. Arch Neurol. 2002;59:972–6. https://doi.org/10.1001/archneur.59.6.972. Van Cauwenberghe C, Van Broeckhoven C, Sleegers K. The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet Med. 2016;18:421–30. https://doi.org/10.1038/gim.2015.117. Ryman DC, Acosta-Baena N, Aisen PS, Bird T, Danek A, Fox NC, et al. Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology. 2014;83:253–60. https://doi.org/10.1212/WNL.0000000000000596. Bateman RJ, Xiong C, Benzinger TLS, Fagan AM, Goate A, Fox NC, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012;367:795–804. https://doi.org/10.1056/NEJMoa1202753. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261:921–3. https://doi.org/10.1126/science.8346443. Polvikoski T, Sulkava R, Haltia M, Kainulainen K, Vuorio A, Verkkoniemi A, et al. Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein. N Engl J Med. 1995;333:1242–7. https://doi.org/10.1056/NEJM199511093331902. Grupe A, Abraham R, Li Y, Rowland C, Hollingworth P, Morgan A, et al. Evidence for novel susceptibility genes for late-onset Alzheimer’s disease from a genome-wide association study of putative functional variants. Hum Mol Genet. 2007;16:865–73. https://doi.org/10.1093/hmg/ddm031. Malhotra AK, Kestler LJ, Mazzanti C, Bates JA, Goldberg T, Goldman D. A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. Am J Psychiatry. 2002;159:652–4. https://doi.org/10.1176/appi.ajp.159.4.652. Ulrich JD, Ulland TK, Colonna M, Holtzman DM. Elucidating the role of TREM2 in Alzheimer’s disease. Neuron. 2017;94:237–48. https://doi.org/10.1016/j.neuron.2017.02.042. Cruchaga C, Nowotny P, Kauwe JSK, Ridge PG, Mayo K, Bertelsen S, et al. Association and expression analyses with single-nucleotide polymorphisms in TOMM40 in Alzheimer disease. Arch Neurol. 2011;68:1013–9. https://doi.org/10.1001/archneurol.2011.155. Chiba-Falek O, Gottschalk WK, Lutz MW. The effects of the TOMM40 poly-T alleles on Alzheimer’s disease phenotypes. Alzheimers Dement J Alzheimers Assoc. 2018;14:692–8. https://doi.org/10.1016/j.jalz.2018.01.015. Roses A, Sundseth S, Saunders A, Gottschalk W, Burns D, Lutz M. Understanding the genetics of APOE and TOMM40 and role of mitochondrial structure and function in clinical pharmacology of Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc. 2016;12:687–94. https://doi.org/10.1016/j.jalz.2016.03.015. Tiraboschi P, Hansen LA, Alford M, Sabbagh MN, Schoos B, Masliah E, et al. Cholinergic dysfunction in diseases with Lewy bodies. Neurology. 2000;54:407–11. https://doi.org/10.1212/wnl.54.2.407. Piggott MA, Marshall EF, Thomas N, Lloyd S, Court JA, Jaros E, et al. Striatal dopaminergic markers in dementia with Lewy bodies, Alzheimer’s and Parkinson’s diseases: rostrocaudal distribution. Brain J Neurol. 1999;122(Pt 8):1449–68. https://doi.org/10.1093/brain/122.8.1449. Huang L-K, Chao S-P, Hu C-J. Clinical trials of new drugs for Alzheimer disease. J Biomed Sci. 2020;27:18. https://doi.org/10.1186/s12929-019-0609-7. Winblad B, Kilander L, Eriksson S, Minthon L, Båtsman S, Wetterholm A-L, et al. Donepezil in patients with severe Alzheimer’s disease: double-blind, parallel-group, placebo-controlled study. Lancet Lond Engl. 2006;367:1057–65. https://doi.org/10.1016/S0140-6736(06)68350-5. Seltzer B, Zolnouni P, Nunez M, Goldman R, Kumar D, Ieni J, et al. Efficacy of donepezil in early-stage Alzheimer disease: a randomized placebo-controlled trial. Arch Neurol. 2004;61:1852–6. https://doi.org/10.1001/archneur.61.12.1852. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999;56:303–8. https://doi.org/10.1001/archneur.56.3.303. Kryscio RJ, Abner EL, Schmitt FA, Goodman PJ, Mendiondo M, Caban-Holt A, et al. A randomized controlled Alzheimer’s disease prevention trial’s evolution into an exposure trial: the PREADViSE Trial. J Nutr Health Aging. 2013;17:72–5. https://doi.org/10.1007/s12603-012-0083-3. Peters R, Beckett N, Forette F, Tuomilehto J, Clarke R, Ritchie C, et al. Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial. Lancet Neurol. 2008;7:683–9. https://doi.org/10.1016/S1474-4422(08)70143-1. Alzheimer’s Disease Anti-inflammatory Prevention Trial Research Group. Results of a follow-up study to the randomized Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT). Alzheimers Dement J Alzheimers Assoc. 2013;9:714–23. https://doi.org/10.1016/j.jalz.2012.11.012. Craig MC, Maki PM, Murphy DGM. The Women’s Health Initiative Memory Study: findings and implications for treatment. Lancet Neurol. 2005;4:190–4. https://doi.org/10.1016/S1474-4422(05)01016-1. Schneider LS. Prevention therapeutics of dementia. Alzheimers Dement J Alzheimers Assoc. 2008;4:S122-130. https://doi.org/10.1016/j.jalz.2007.11.005. DeKosky ST, Williamson JD, Fitzpatrick AL, Kronmal RA, Ives DG, Saxton JA, et al. Ginkgo biloba for prevention of dementia: a randomized controlled trial. JAMA. 2008;300:2253–62. https://doi.org/10.1001/jama.2008.683. Bridi R, Crossetti FP, Steffen VM, Henriques AT. The antioxidant activity of standardized extract of Ginkgo biloba (EGb 761) in rats. Phytother Res PTR. 2001;15:449–51. https://doi.org/10.1002/ptr.814. ADAPT Research Group, Martin BK, Szekely C, Brandt J, Piantadosi S, Breitner JCS, et al. Cognitive function over time in the Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT): results of a randomized, controlled trial of naproxen and celecoxib. Arch Neurol. 2008;65:896–905. https://doi.org/10.1001/archneur.2008.65.7.nct70006. Vellas B, Coley N, Ousset PJ, Berrut G, Dartigues JF, Dubois B, et al. GuidAge Study Group. Long-term use of standardised Ginkgo biloba extract for the prevention of Alzheimer’s disease (GuidAge): a randomised placebo-controlled trial. Lancet Neurol. 2012;11(10):851–9. https://doi.org/10.1016/S1474-442(12)70206-5. Salloway S, Farlow M, McDade E, Clifford DB, Wang G, Llibre-Guerra JJ, Hitchcock JM, Mills SL, Santacruz AM, Aschenbrenner AJ, Hassenstab J, et al. Dominantly inherited alzheimer Network-trials unit. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat Med. 2021;27(7):1187–96. https://doi.org/10.1038/s41591-021-01369-8. Rinne JO, Brooks DJ, Rossor MN, Fox NC, Bullock R, Klunk WE, et al. 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol. 2010;9:363–72. https://doi.org/10.1016/S1474-4422(10)70043-0. Sperling RA, Jack CR, Black SE, Frosch MP, Greenberg SM, Hyman BT, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 2011;7:367–85. https://doi.org/10.1016/j.jalz.2011.05.2351. Honig LS, Vellas B, Woodward M, Boada M, Bullock R, Borrie M, et al. Trial of solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med. 2018;378:321–30. https://doi.org/10.1056/NEJMoa1705971. Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005;352(23):2379–88. https://doi.org/10.1056/NEJMoa050151. Gilman S, Koller M, Black RS, Jenkins L, Griffith SG, Fox NC, et al. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology. 2005;64:1553–62. https://doi.org/10.1212/01.WNL.0000159740.16984.3C. Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370:322–33. https://doi.org/10.1056/NEJMoa1304839. Mintun MA, Lo AC, Duggan Evans C, Wessels AM, Ardayfio PA, Andersen SW, et al. Donanemab in early Alzheimer’s disease. N Engl J Med. 2021;384:1691–704. https://doi.org/10.1056/NEJMoa2100708. Andrieu S, Guyonnet S, Coley N, Cantet C, Bonnefoy M, Bordes S, et al. Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial. Lancet Neurol. 2017;16:377–89. https://doi.org/10.1016/S1474-4422(17)30040-6. Chandler MJ, Lacritz LH, Hynan LS, Barnard HD, Allen G, Deschner M, et al. A total score for the CERAD neuropsychological battery. Neurology. 2005;65:102–6. https://doi.org/10.1212/01.wnl.0000167607.63000.38. Rossetti HC, Munro Cullum C, Hynan LS, Lacritz L. The CERAD Neuropsychological Battery total score and the progression of Alzheimer’s disease. Alzheimer Dis Assoc Disord. 2010;24:138–42. https://doi.org/10.1097/WAD.0b013e3181b76415. Ngandu T, Lehtisalo J, Solomon A, Levälahti E, Ahtiluoto S, Antikainen R, et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet Lond Engl. 2015;385:2255–63. https://doi.org/10.1016/S0140-6736(15)60461-5. SPRINT Research Group, Wright JT, Williamson JD, Whelton PK, Snyder JK, Sink KM, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373:2103–16. https://doi.org/10.1056/NEJMoa1511939. SPRINT MIND Investigators for the SPRINT Research Group, Williamson JD, Pajewski NM, Auchus AP, Bryan RN, Chelune G, et al. Effect of intensive vs standard blood pressure control on probable dementia: a randomized clinical trial. JAMA. 2019;321:553–61. https://doi.org/10.1001/jama.2018.21442. World Health Organitzation. Risk reduction of cognitive decline and dementia. 2019. https://www.who.int/publications-detail-redirect/risk-reduction-of-cognitive-decline-and-dementia. Accessed 28 Jan 2022. Suzuki T, Shimada H, Makizako H, Doi T, Yoshida D, Tsutsumimoto K, et al. Effects of multicomponent exercise on cognitive function in older adults with amnestic mild cognitive impairment: a randomized controlled trial. BMC Neurol. 2012;12:128. https://doi.org/10.1186/1471-2377-12-128. Nagamatsu LS, Handy TC, Hsu CL, Voss M, Liu-Ambrose T. Resistance training promotes cognitive and functional brain plasticity in seniors with probable mild cognitive impairment. Arch Intern Med. 2012;172:666–8. https://doi.org/10.1001/archinternmed.2012.379. Petersen RC, Lopez O, Armstrong MJ, Getchius TSD, Ganguli M, Gloss D, et al. Practice guideline update summary: mild cognitive impairment: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90:126–35. https://doi.org/10.1212/WNL.0000000000004826. Tarumi T, Rossetti H, Thomas BP, Harris T, Tseng BY, Turner M, et al. Exercise training in amnestic mild cognitive impairment: a one-year randomized controlled trial. J Alzheimers Dis JAD. 2019;71:421–33. https://doi.org/10.3233/JAD-181175. Sink KM, Espeland MA, Castro CM, Church T, Cohen R, Dodson JA, et al. Effect of a 24-Month physical activity intervention vs health education on cognitive outcomes in sedentary older adults: the LIFE randomized trial. JAMA. 2015;314:781–90. https://doi.org/10.1001/jama.2015.9617. Stuckenschneider T, Sanders ML, Devenney KE, Aaronson JA, Abeln V, Claassen JAHR, et al. NeuroExercise: the effect of a 12-month exercise intervention on cognition in mild cognitive impairment—a multicenter randomized controlled trial. Front Aging Neurosci. 2021;12. Kivipelto M, Solomon A, Ahtiluoto S, Ngandu T, Lehtisalo J, Antikainen R, et al. The Finnish geriatric intervention study to prevent cognitive impairment and disability (FINGER): study design and progress. Alzheimers Dement J Alzheimers Assoc. 2013;9:657–65. https://doi.org/10.1016/j.jalz.2012.09.012. van Charante EPM, Richard E, Eurelings LS, van Dalen J-W, Ligthart SA, van Bussel EF, et al. Effectiveness of a 6-year multidomain vascular care intervention to prevent dementia (preDIVA): a cluster-randomised controlled trial. Lancet Lond Engl. 2016;388:797–805. https://doi.org/10.1016/S0140-6736(16)30950-3. Richard E, van Charante EPM, Hoevenaar-Blom MP, Coley N, Barbera M, van der Groep A, et al. Healthy ageing through internet counselling in the elderly (HATICE): a multinational, randomised controlled trial. Lancet Digit Health. 2019;1:e424–34. https://doi.org/10.1016/S2589-7500(19)30153-0. Kivipelto M, Mangialasche F, Snyder HM, Allegri R, Andrieu S, Arai H, et al. World-Wide FINGERS Network: a global approach to risk reduction and prevention of dementia. Alzheimers Dement. 2020;16:1078–94. https://doi.org/10.1002/alz.12123. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH, 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 J Alzheimers Assoc. 2011;7:263–9. https://doi.org/10.1016/j.jalz.2011.03.005. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, 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 J Alzheimers Assoc. 2011;7:270–9. https://doi.org/10.1016/j.jalz.2011.03.008. Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K, et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol. 2014;13:614–29. https://doi.org/10.1016/S1474-4422(14)70090-0. Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc. 2018;14:535–62. https://doi.org/10.1016/j.jalz.2018.02.018. Center for Drug Evaluation and Research. Alzheimer’s disease: developing drugs for treatment guidance for industry. US Food Drug Adm. 2020. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/alzheimers-disease-developing-drugs-treatment-guidance-industy. Accessed 21 Feb 2018. Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, et al. Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol. 2010;9:1118–27. https://doi.org/10.1016/S1474-4422(10)70223-4. Schneider LS, Goldberg TE. Composite cognitive and functional measures for early stage Alzheimer’s disease trials. Alzheimers Dement Diagn Assess Dis Monit. 2020;12:e12017. https://doi.org/10.1002/dad2.12017. Burns DK, Chiang C, Welsh-Bohmer KA, Brannan SK, Culp M, O’Neil J, et al. The TOMMORROW study: design of an Alzheimer’s disease delay-of-onset clinical trial. Alzheimers Dement Transl Res Clin Interv. 2019;5:661–70. https://doi.org/10.1016/j.trci.2019.09.010. Dubois B, Hampel H, Feldman HH, Scheltens P, Aisen P, Andrieu S, et al. Preclinical Alzheimer’s disease: definition, natural history, and diagnostic criteria. Alzheimers Dement J Alzheimers Assoc. 2016;12:292–323. https://doi.org/10.1016/j.jalz.2016.02.002. Ioannidis JPA. Why Most Published research findings are false. PLoS Med. 2005;2:e124. https://doi.org/10.1371/journal.pmed.0020124. Burns DK, Alexander RC, Welsh-Bohmer KA, Culp M, Chiang C, O’Neil J, et al. Safety and efficacy of pioglitazone for the delay of cognitive impairment in people at risk of Alzheimer’s disease (TOMMORROW): a prognostic biomarker study and a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2021;20:537–47. https://doi.org/10.1016/S1474-4422(21)00043-0. Fishman E. Risk of developing dementia at older ages in the United States. Demography. 2017;54:1897–919. https://doi.org/10.1007/s13524-017-0598-7. Mueller SG, Weiner MW, Thal LJ, Petersen RC, Jack C, Jagust W, et al. The Alzheimer’s disease neuroimaging initiative. Neuroimaging Clin N Am. 2005;15(869–77):xi–xii. https://doi.org/10.1016/j.nic.2005.09.008. Hofman A, Breteler MMB, van Duijn CM, Krestin GP, Pols HA, Stricker BHCh, et al. The Rotterdam Study: objectives and design update. Eur J Epidemiol. 2007;22:819–29. https://doi.org/10.1007/s10654-007-9199-x. Brookmeyer R, Abdalla N. Estimation of lifetime risks of Alzheimer’s disease dementia using biomarkers for preclinical disease. Alzheimers Dement J Alzheimers Assoc. 2018;14:981–8. https://doi.org/10.1016/j.jalz.2018.03.005. Maitournam A, Simon R. On the efficiency of targeted clinical trials. Stat Med. 2005;24:329–39. https://doi.org/10.1002/sim.1975. Moher D, Glasziou P, Chalmers I, Nasser M, Bossuyt PMM, Korevaar DA, et al. Increasing value and reducing waste in biomedical research: who’s listening? The Lancet. 2016;387:1573–86. https://doi.org/10.1016/S0140-6736(15)00307-4. McLeod C, Norman R, Litton E, Saville BR, Webb S, Snelling TL. Choosing primary endpoints for clinical trials of health care interventions. Contemp Clin Trials Commun. 2019;16:100486. https://doi.org/10.1016/j.conctc.2019.100486. Grill JD, Galvin JE. Facilitating Alzheimer disease research recruitment. Alzheimer Dis Assoc Disord. 2014;28:1–8. https://doi.org/10.1097/WAD.0000000000000016. Raman R, Quiroz YT, Langford O, Choi J, Ritchie M, Baumgartner M, et al. Disparities by race and ethnicity among adults recruited for a preclinical Alzheimer disease trial. JAMA Netw Open. 2021;4:e2114364. https://doi.org/10.1001/jamanetworkopen.2021.14364. Anderson TS, Ayanian JZ, Souza J, Landon BE. Representativeness of participants eligible to be enrolled in clinical trials of aducanumab for Alzheimer disease compared with medicare beneficiaries with Alzheimer disease and mild cognitive impairment. JAMA. 2021;326:1627–9. https://doi.org/10.1001/jama.2021.15286. Schneider LS, Olin JT, Lyness SA, Chui HC. Eligibility of Alzheimer’s disease clinic patients for clinical trials. J Am Geriatr Soc. 1997;45:923–8. https://doi.org/10.1111/j.1532-5415.1997.tb02960.x. Bell SA, Cohen HR, Lee S, Kim H, Ciarleglio A, Andrews H, et al. Development of novel measures for Alzheimer’s disease prevention trials (NoMAD). Contemp Clin Trials. 2021;106:106425. https://doi.org/10.1016/j.cct.2021.106425.