The Alzheimer's Disease Neuroimaging Initiative 3: Continued innovation for clinical trial improvement

Weiner, Michael W.; Veitch, Dallas P.; Aisen, Paul S.; Beckett, Laurel A.; Cairns, Nigel J.; Green, Robert C.; Harvey, Danielle; Jack, Clifford R.; Jagust, William J.; Morris, John C.; Petersen, Ronald C.; Salazar, Jennifer; Saykin, Andrew J.; Shaw, Leslie M.; Toga, Arthur W.; Trojanowski, John Q.

doi:10.1016/j.jalz.2016.10.006

Cited by 312 publications

(294 citation statements)

References 83 publications

(71 reference statements)

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“…ADNI-3, a national biomarker study, is directly comparing an athome computerized cognitive self-test measure vs. standard paper and pencil tests as well as pathological markers of AD progression in a sample of 1200 subjects ranging from normal to MCI to mild AD dementia. 11 …”

Section: Mobile Cognitive Outcomesmentioning

confidence: 99%

“…One of the exceptions has been ADNI, which has made data sharing a priority from day 1 and led to >800 publications. 11 Today, many AD-related informatics algorithms are trained using ADNI data, but there is no equivalent public resource for replication or validation. Further, databases created over the past two decades for AD trials may lack contemporary features, such as a patient portal, integrated sensor and smart phone data, patient engagement tools, and secure data sharing.…”

Section: Cloud-based Analytic Platforms and Trial Network For Mobilementioning

confidence: 99%

“…The Brain Health Registry (BHR) at USCF is pioneering a broad-based internet-based approach for recruiting and monitoring individuals at risk for AD. 11 The registry is currently being used for pilot validation studies of mobile cognitive tests, and ultimately, all subjects enrolled in a large national biomarker trial (ADNI-3) will be given the option to participate in BHR. 11 The Dominant Inherited Alzheimer's Network (DIAN) and the Alzheimer's Prevention Initiative (API) registries have successfully recruited subjects with specified genetic mutations.…”

Section: Introductionmentioning

confidence: 99%

“…11 The registry is currently being used for pilot validation studies of mobile cognitive tests, and ultimately, all subjects enrolled in a large national biomarker trial (ADNI-3) will be given the option to participate in BHR. 11 The Dominant Inherited Alzheimer's Network (DIAN) and the Alzheimer's Prevention Initiative (API) registries have successfully recruited subjects with specified genetic mutations. The Human Cognition Project (with >40 million subjects of all ages from 180 countries) provides a model for the kind of global brain laboratory that can be harnessed using mobile tools.…”

Section: Introductionmentioning

confidence: 99%

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Mobile and pervasive computing technologies and the future of Alzheimer’s clinical trials

2018

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The rapid growth of mobile phones, automated speech recognizing personal assistants, and internet access among the elderly provides new opportunities for incorporating such technologies into clinical research and personalized medical care. Alzheimer's disease is a good test case given the need for early detection, the high rate of clinical trial failures, the need to more efficiently recruit patients for trials, and the need for sensitive and ecologically valid trial outcomes.

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Section: Mobile Cognitive Outcomesmentioning

confidence: 99%

Section: Cloud-based Analytic Platforms and Trial Network For Mobilementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mobile and pervasive computing technologies and the future of Alzheimer’s clinical trials

2018

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“…A performance-based functional assessment, the Financial Capacity Instrument–Short Form, has been used in practice to detect functional impairment in preclinical AD [42]. This instrument has also been incorporated by ADNI-3 [43]. Second, the alternative IADL total score derived by summing the 3-level individual item scores had a bigger effect size than the IADL total score derived by counting the number of items patients needed help, suggesting that measuring each individual functional domain more quantitatively can also increase the power.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal Modeling of Functional Decline Associated with Pathologic Alzheimer’s Disease in Older Persons without Cognitive Impairment

Wang

Schultz

Novak

et al. 2018

JAD

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Background: Therapeutic research on Alzheimer’s disease (AD) has moved to intercepting the disease at the preclinical phase. Most drugs in late development have focused on the amyloid hypothesis. Objective: To understand the magnitude of amyloid-related functional decline and to identify the functional domains sensitive to decline in a preclinical AD population. Methods: Data were from the Religious Orders Study and the Rush Memory and Aging Project. Cognitive decline was measured by a modified version of the Alzheimer’s Disease Cooperative Study Preclinical Alzheimer Cognitive Composite. The trajectories of functional decline, as measured by the instrumental and basic activities of daily living, were longitudinally modeled in 484 participants without cognitive impairment at baseline and having both a final clinical and a postmortem neuropathology assessment of AD. Results: Individuals with different final clinical diagnoses had different trajectories of cognitive and functional decline. Individuals with AD dementia, minor cognitive impairment, and no cognitive impairment had the most, intermediate, and least declines. While individuals with pathologic AD had significantly more cognitive decline over time than those without, the magnitude of difference in functional decline between these 2 groups was small. Functional domains such as handling finance and handling medications were more sensitive to decline. Conclusion: Demonstrating the functional benefit of an amyloid-targeting drug represents a significant challenge as elderly people experience functional decline due to a wide range of reasons with limited manifestation attributable to AD neuropathology. More sensitive functional scales focusing on the functional domains sensitive to decline in preclinical AD are needed.

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ApoE4 and Connectivity-Mediated Spreading of Tau Pathology at Lower Amyloid Levels

Steward,

Biel,

Dewenter

et al. 2023

JAMA Neurol

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ImportanceFor the Alzheimer disease (AD) therapies to effectively attenuate clinical progression, it may be critical to intervene before the onset of amyloid-associated tau spreading, which drives neurodegeneration and cognitive decline. Time points at which amyloid-associated tau spreading accelerates may depend on individual risk factors, such as apolipoprotein E ε4 (ApoE4) carriership, which is linked to faster disease progression; however, the association of ApoE4 with amyloid-related tau spreading is unclear.ObjectiveTo assess if ApoE4 carriers show accelerated amyloid-related tau spreading and propose amyloid positron emission tomography (PET) thresholds at which tau spreading accelerates in ApoE4 carriers vs noncarriers.Design, Setting, and ParticipantsThis cohort study including combined ApoE genotyping, amyloid PET, and longitudinal tau PET from 2 independent samples: the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 237; collected from April 2015 to August 2022) and Avid-A05 (n = 130; collected from December 2013 to July 2017) with a mean (SD) tau PET follow-up time of 1.9 (0.96) years in ADNI and 1.4 (0.23) years in Avid-A05. ADNI is an observational multicenter Alzheimer disease neuroimaging initiative and Avid-A05 an observational clinical trial. Participants classified as cognitively normal (152 in ADNI and 77 in Avid-A05) or mildly cognitively impaired (107 in ADNI and 53 in Avid-A05) were selected based on ApoE genotyping, amyloid-PET, and longitudinal tau PET data availability. Participants with ApoE ε2/ε4 genotype or classified as having dementia were excluded. Resting-state functional magnetic resonance imaging connectivity templates were based on 42 healthy participants in ADNI.Main Outcomes and MeasuresMediation of amyloid PET on the association between ApoE4 status and subsequent tau PET increase through Braak stage regions and interaction between ApoE4 status and amyloid PET with annual tau PET increase through Braak stage regions and connectivity-based spreading stages (tau epicenter connectivity ranked regions).ResultsThe mean (SD) age was 73.9 (7.35) years among the 237 ADNI participants and 70.2 (9.7) years among the 130 Avid-A05 participants. A total of 107 individuals in ADNI (45.1%) and 45 in Avid-A05 (34.6%) were ApoE4 carriers. Across both samples, we found that higher amyloid PET–mediated ApoE4-related tau PET increased globally (ADNI b, 0.15; 95% CI, 0.05-0.28; P = .001 and Avid-A05 b, 0.33; 95% CI, 0.14-0.54; P &lt; .001) and in earlier Braak regions. Further, we found a significant association between ApoE4 status by amyloid PET interaction and annual tau PET increases consistently through early Braak- and connectivity-based stages where amyloid-related tau accumulation was accelerated in ApoE4carriers vs noncarriers at lower centiloid thresholds, corrected for age and sex.Conclusions and RelevanceThe findings in this study indicate that amyloid-related tau accumulation was accelerated in ApoE4 carriers at lower amyloid levels, suggesting that ApoE4 may facilitate earlier amyloid-driven tau spreading across connected brain regions. Possible therapeutic implications might be further investigated to determine when best to prevent tau spreading and thus cognitive decline depending on ApoE4 status.

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The Alzheimer's Disease Neuroimaging Initiative 3: Continued innovation for clinical trial improvement

Cited by 312 publications

References 83 publications

Mobile and pervasive computing technologies and the future of Alzheimer’s clinical trials

Mobile and pervasive computing technologies and the future of Alzheimer’s clinical trials

Longitudinal Modeling of Functional Decline Associated with Pathologic Alzheimer’s Disease in Older Persons without Cognitive Impairment

ApoE4 and Connectivity-Mediated Spreading of Tau Pathology at Lower Amyloid Levels

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