University of California, San Diego School of Medicine, and Veterans Affairs San Diego Healthcare System researchers report discovering that the accumulation of amyloid, the abnormal protein linked to neurodegenerative conditions such as Alzheimer’s disease (AD), actually occurs faster among persons deemed to have “objectively-defined subtle cognitive difficulties” (Obj-SCD) than among those persons deemed “cognitively normal.” This offers the research community the prospect of a new early biomarker—all the result of the ongoing Alzheimer’s Disease Neuroimaging Initiative. 

TrialSite News breaks down this recent information generated from the University of California San Diego Health Newsroom.

What is the key finding reported?

The new findings suggest that Obj-SCD can be detected during the preclinical state of AD when amyloid plaques are accumulating in the brain—neurodegeneration is just starting—however, the symptoms of impairment on total scores of thinking and memory tests have not yet been recorded.

How does this San Diego-based finding modify the researchers’ perspective on AD?

Mark W. Bondi, PhD and senior research study author, notes that “The scientific community has long thought that amyloid drives the neurodegeneration and cognitive impairment associated with AD.” He continued, “These findings, in addition to other work in our lab, suggest that this is likely not the case for everyone and that sensitive neuropsychological measurement strategies capture subtle cognitive changes much earlier in the disease process than previously thought possible.”

What are the implications of this research finding?

The research findings have important implications on AD treatment targets and imply that cognitive changes are possibly occurring even before the significant build-up of amyloid. The researchers suspect that “we may have to focus more on treatment targets of pathologies other than amyloid, such as tau—those more highly associated with the thinking and memory challenges that impact people’s lives” noted Bondi.

The Study

This research effort—the Alzheimer’s Disease Neuroimaging Initiative (ADNI)—has been ongoing since 2003 and enrolled study participants to test whether regularly repeated brain imaging, combined with other biological markers and clinical assessments can measure the progression of Mild Cognitive Impairment (MCI) and early AD. The study has involved 747 people; 305 deemed cognitively normal, 153 with Obj-SCD, and 289 MCI. All underwent neuropsychological testing, and both PET and MRI scans.

Results

The team found that amyloid accumulation was faster in persons classified with Obj-SCD than in the cognitively normal group. Those classified as Obj-SCD also experienced selective thinning of the entorhinal cortex, a region of the brain impacted very early in Alzheimer’s disease and associated with memory, navigation, and perception of time. Persons with MCI had more amyloid in their brains at the start of the study, but they did not have a faster accumulation of amyloid compared to those with normal cognition. However, those with MCI had more widespread temporal lobe atrophy, including the hippocampus.

Challenging the Amyloid Hypothesis

The results here contribute to the movement questioning the amyloid hypothesis in regard to AD. Given a large number of clinical trials in which drugs targeted and successfully cleared amyloid from the brain, but did not impact the trajectory of cognitive decline. Hence the importance to identify those at risk for AD prior to any impairment and before or during the phase of accelerated amyloid accumulation represents a “clinical boon” reported the authors as it offers a path to monitor disease progress and a “window of opportunity” to execute on advancing preventative or treatment approaches.

In reality, there are limitations to both approaches, and some AD risk factors can be minimized—from the elimination of smoking to managing vascular risk factors such as hypertension or following a healthy diet with regular exercise. Although there are some medications approved to treat AD symptoms, not all of them work for patients, and there is no cure. Moreover, the current biomarker research represents a high cost and essentially inaccessible for clinical use.

What is ADNI?

The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is a longitudinal multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of AD. Since its launch, the landmark public-private partnership has made major contributions to AD research, enabling the sharing of data between researchers around the world. Launched in 2004 under the leadership of Dr. Michael W. Weiner, it was funded as a public-private partnership with $27 million contributed by 20 companies and two foundations through the Foundation for the National Institutes of Health and $40 million from the National Institute on Aging. The initial five-year study (ADNI-1) was extended by two years in 2009 by a Grand Opportunities grant (ADNI-GO), and in 2011 and 2016 by further competitive renewals of the ADNI-1 grant (ADNI-2) and ADNI-3).

ADNI Funders

Funding for this study came, in part, from the National Institutes of Health (grants R01 AG049810, K24 AG026431), the Alzheimer’s Association (AARF-17-528918), the U.S. Department of Veterans Affairs Clinical Sciences Research and Development Service (1IK2CX001865), and the Alzheimer’s Disease Neuroimaging Initiative, which is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering and AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada.

Lead Research/Investigator UCSD/VA San Diego Research Activities

Dr. Kelsey Thomas

Mark W. Bondi, PhD

Source: UC San Diego Health

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