14 Oct 2022

The Alzheimer’s Disease Neuroimaging Initiative, now 18 years old, was instrumental in transforming researchers’ conceptions of AD by revealing the decades-long, preclinical buildup of amyloid plaques in the brain. This landmark study continues with ADNI4, which began last month. Funded for five years and $147 million by the National Institute on Aging, the newest iteration will focus on underrepresented minorities. In the October 9 Alzheimer’s & Dementia, ADNI researchers led by principal investigator Michael Weiner at the University of California, San Francisco, described the study design. They plan to use online recruitment and remote screening to enroll 500 new participants. At least half will come from diverse populations. Weiner hopes that ADNI4 could pave the way for more inclusive AD clinical trials. “To my knowledge, no clinical trial has achieved anything close to this [diversity] before,” Weiner told Alzforum.

The ADNI biomarker study began in 2004 with the goal of identifying the best outcome measures for clinical trials (Mar 2005 conference news). As amyloid imaging revealed how early in the disease plaques formed, follow-up studies ADNI-GO and ADNI2 shifted to examine prognostic biomarkers (Oct 2010 news). ADNI3, which kicked off in 2016 and was extended one year to 2022 due to the COVID pandemic, added tau PET imaging. More than 2,000 people have participated in these studies to date. The publicly available dataset has proven a treasure trove for the field, with nearly 5,000 papers published using ADNI data.

ADNI4 will be the first iteration of the study to emphasize broader participant selection. The majority of ADNI participants, like those in most AD studies, have been white, non-Hispanic, and highly educated. Both the AD field and the U.S. federal government are trying to improve diversification in clinical trial recruitment, with the Food and Drug Administration recently releasing a draft guidance for AD trials (Apr 2022 news). ADNI researchers will reach out to underrepresented groups, including those with less than a high school education, via digital platforms and social media.

ADNI4 will screen up to 20,000 people online using digital cognitive tests, such as the Everyday Cognition (ECog) questionnaire (Farias et al., 2008) and speech analysis software from U.K. start-up Novoic Ltd. Outreach will focus on areas of the country with large populations of underrepresented groups who live near one of the 60 ADNI clinical sites. Up to 4,000 people with signs of cognitive decline on these tests will be asked to donate blood locally for AD biomarker screening. Samples will be sent to C2N Diagnostics in St. Louis, and the ADNI biomarker core at the University of Pennsylvania, Philadelphia, for analysis of the Aβ42/40 ratio and p-tau isoforms, as well as APOE genotyping.

The goal is to refer 500 participants to ADNI clinical sites. Of these, 20 percent will be amyloid-negative controls, 20 percent amyloid-positive but cognitively healthy, 40 percent amyloid-positive MCI, and 20 percent AD dementia. For new participants, exclusion criteria will be relaxed to allow people with heart conditions or other co-morbidities to join the study. Researchers will perform additional MRI scans to assess the extent of cerebrovascular disease. In addition, ADNI researchers expect to roll over at least 500 current ADNI participants, for a total cohort of about 1,000.

All participants will undergo tau PET imaging with either flortaucipir, MK-6240, or PI-2620 every two years. Participants will also get amyloid scans every two years with either florbetapir, florbetaben, or the investigational tracer NAV-4694, but FDG-PET will be discontinued. The study will continue to measure fluid biomarkers and track people with cognitive and clinical tests. Meanwhile, the 3,500 people who were not selected for clinical follow-up will be invited to retake the online cognitive tests every six months, providing more data on rates of decline in community cohorts.—Madolyn Bowman Rogers

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References

News Citations

1. Sorrento: ADNI Imagines the Future of AD Imaging 24 Mar 2005
2. Research Brief: Announcing ADNI2—Funding for Five More Years 29 Oct 2010
3. Diversity: FDA Guidance and New Data on Incidence/Biomarkers by Race 29 Apr 2022

Paper Citations

1. Farias ST, Mungas D, Reed BR, Cahn-Weiner D, Jagust W, Baynes K, Decarli C. The measurement of everyday cognition (ECog): scale development and psychometric properties. Neuropsychology. 2008 Jul;22(4):531-44. PubMed.

Further Reading

News

1. Davos Alzheimer’s Consortium to Link Global Cohorts 24 Sep 2021
2. In the United States, Racial Disparities in Dementia Risk Persist 3 Dec 2020
3. Largest Alzheimer GWAS in African Americans Finds New Variants 22 Oct 2020
4. Do African-Americans Have More, or Different, Alzheimer’s Disease? Too Little Data to Tell 26 Oct 2018