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Plasma Insulin-like Growth Factor Binding Protein 2 Is Associated with Cognitive Outcomes

Article In Brief

Investigators reported an association between plasma insulin-like growth factor binding protein 2 (IGFBP-2) levels and structural MRI brain measures, cognitive performance, as well as incident dementia and AD-dementia. The authors proposed that IGFBP-2 could offer potential utility as a circulating biomarker for predicting dementia risk.

Researchers have identified a novel biomarker for incident dementia, supporting increasing evidence that suggests metabolic dysfunction and insulin resistance in the brain are integrally involved in adverse cognitive outcomes.

“The insulin-like growth factor (IGF) signaling system is known to play a role in neuroregeneration, neuronal survival and proliferation, and cerebral metabolic function,” the study's authors reported in the September issue of Annals of Clinical and Translational Neurology.

The research sheds light on the “complex biological pathways underpinning the development of dementia,” with the aim of advancing earlier detection and pinpointing possible therapeutic targets for subsequent inquiry.

For the study, the investigators extracted data from the Framingham Heart Study Offspring, a large, prospective community-based cohort of cognitively healthy adults, followed for more than four decades. Participants agreed to a periodic examination every four years for assessment of vascular risk factors, cognitive performance decline, stroke, and dementia.

The researchers opted to focus on insulin-like growth factor binding protein 2 (IGFBP-2) because it is the most prominent IGF-binding protein in the brain. Heightened levels of IGFBP-2 are believed to decrease the bioavailability of IGF-I and IGF-II in the brain and hinder IGF signaling, which inhibits the neuroprotective effects of IGF-I and IGF-II. While in circulation, IGF-I and IGF-II generally attach to one of six known IGF-binding proteins.

In prior small studies, elevated plasma and cerebrospinal fluid IGFBP-2 levels were cross-sectionally associated with hippocampal atrophy and Alzheimer's disease (AD). However, it remained to be seen whether plasma IGFBP-2 levels could foretell cognitive decline, such as dementia, over a longer follow-up period.

“There have been a number of trials in Alzheimer's disease, which haven't shown the most promising results to date,” Emer McGrath, MD, PhD, the study's corresponding author and associate neurologist at Brigham and Women's Hospital and Harvard Medical School, told Neurology Today.

“Biomarkers can provide additional insight into other physiological pathways leading to dementia and may lead us to rethink our approach to targeted therapies,” Dr. McGrath said.

In this study, the researchers sought to determine the association between plasma IGFBP-2 levels and structural MRI brain measures, cognitive performance, as well as incident dementia and AD-dementia.

The authors proposed that IGFBP-2 could offer potential utility as a circulating biomarker for predicting dementia risk, a surrogate marker for future clinical trials, and a possible therapeutic target, although these results require replication.

Study Design, Findings

For the analysis, researchers included 1,596 cohort subjects aged 60 years or older who had had plasma IGFBP-2 recorded in their primary analysis for incident dementia. Most were dementia-free at baseline. Using hazards models, they linked plasma IGFBP-2 with subsequent risk of incident dementia and AD. Secondary outcomes included MRI brain measures and cognitive performance.

During a median follow-up of 11.8 years, 131 participants experienced incident dementia; 98 of them were diagnosed with AD. In multivariable analysis, the highest tertile of IGFBP-2, compared with the lowest tertile, was associated with an elevated risk of incident all-cause dementia (hazard ratio [HR] 2.89, 95% CI 1.63-5.13) and AD (HR 3.63, 95% CI 1.76-7.50).

The analysis factored in age, sex, education, time from blood draw to neuropsychological testing, systolic blood pressure, use of antihypertensive medication, prevalent diabetes mellitus, prevalent cardiovascular disease, and body mass index.

The researchers observed cross-sectional associations between higher circulating IGFBP2 levels and worse performance on abstract reasoning tests but not with MRI-based outcomes. After adding plasma IGFBP-2 levels to a traditional dementia prediction model, 32 percent of individuals with dementia were properly assigned a higher predicted risk, while 8 percent of those without dementia were correctly assigned a lower predicted risk.

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“Biomarkers can provide additional insight into other physiological pathways leading to dementia and may lead us to rethink our approach to targeted therapies.”—DR. EMER MCGRATH

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“Biochemical and molecular pathologies are emerging as promising approaches for evaluating peripheral blood to noninvasively detect significant abnormalities in insulin and IGF signaling mechanisms present in dementia and probably other neurodegenerative diseases.”—DR. SUZANNE DE LA MONTE

The team found an association between elevated circulating IGFBP-2 levels and heightened risk of both all-cause dementia and AD. Including IGFBP-2 plasma levels in a traditional risk factors model resulted in improvement in dementia risk classification. “Manipulation of insulin-like growth factor signaling via IGFBP-2 may be a promising therapeutic target for dementia,” the investigators suggested.

Expert Commentary

The study reinforces the need for research to elucidate the nature and causes of brain metabolic dysfunction in the early or preclinical stages of AD, said Suzanne M. de la Monte, MD, MPH, a neuropathologist and professor of pathology, neurosurgery, and neurology at the Warren Alpert Medical School of Brown University.

“Biochemical and molecular pathologies are emerging as promising approaches for evaluating peripheral blood to noninvasively detect significant abnormalities in insulin and IGF signaling mechanisms present in dementia and probably other neurodegenerative diseases,” said Dr. de la Monte, who is also chief of pathology and laboratory medicine at Providence VA Medical Center.

However, other evidence points to adverse effects on a wide spectrum of insulin-related polypeptides in both the brain and periphery—not simply metabolic dysregulation within the insulin/IGF signaling networks—as potential targets for diagnostic and therapeutic purposes in AD, Dr. de la Monte added.

“What the authors do not address is whether the same or similar abnormalities simultaneously exist in the central nervous system and periphery,” she noted. In an unrelated study, Dr. de la Monte and her colleagues “demonstrated that a number of insulin/IGF-metabolic markers were aberrantly expressed in cerebrospinal fluid and peripheral blood in early AD, but the responses in each compartment were non-identical. That raises questions about whether the central nervous system and systemic diseases are actually related or if one drives the other.”

The Framingham Offspring cohort study also left open the question of whether the source of IGFBP-2 originates in the central nervous system or from peripheral tissues. Furthermore, the trends identified in the study neither inform about an individual's specific risk nor provide cut-off diagnostic values. “In fact, the inter-group differences were not large,” Dr. de la Monte said. “This will be challenging in terms of detecting clear differences between Alzheimer's disease and controls.”

Before such research can be applicable to neurology practice, “it is quite likely that a group of markers will be needed to improve diagnostic accuracy and also to better define therapeutic strategies,” she said. “The study was about predicting cognitive decline rather than determining a particular level of IGFBP-2 that diagnostically marked Alzheimer's disease or another form of dementia.”

Adam L. Boxer, MD, PhD, endowed professor in memory and aging in the department of neurology at the University of California, San Francisco, said he found the study compelling. However, “the results need to be replicated in another cohort and compared with established biomarkers that are predictive of cognitive decline, such as cerebrospinal fluid and plasma Abeta and pTau, and ideally amyloid (and potentially tau) PET imaging to better understand their implications,” said Dr. Boxer, who also directs the Neurosciences Clinical Research Unit and the Alzheimer's Disease and Frontotemporal Degeneration Clinical Trials Program.

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“While insulin growth factor signaling could potentially be a therapeutic target, there are many additional considerations both relevant to the current study and unrelated to the study that would need to be taken into consideration before gauging how promising a therapeutic target this might be.”—DR. ADAM L. BOXER

“While insulin growth factor signaling could potentially be a therapeutic target, there are many additional considerations both relevant to the current study and unrelated to the study that would need to be taken into consideration before gauging how promising a therapeutic target this might be,” Dr. Boxer said.

The authors acknowledged the study's limitations, including reliance on clinical criteria rather than biomarker-based data (such as CSF amyloid-beta-42 or amyloid PET) for dementia diagnosis and subtyping. They also pointed out that the Framingham Offspring cohort is mainly comprised of white people, which may restrict the generalizability of the findings to more diverse groups.

Nonetheless, a Framingham data-based study involving nearly 1,600 participants followed for almost 12 years is worthy of serious consideration for future research, said Jeffrey M. Burns, MD, MS, professor and neurocognitive division chief at the University of Kansas Medical Center in Kansas City, KS.

“Although it would be difficult to draw clinically relevant conclusions from this study alone, the research can be interpreted as part of a bigger picture that underscores the concept of targeting metabolic processes, which tend to be overlooked as a risk factor for cognitive decline,” said Dr. Burns, who is also co-director of the university's Alzheimer's Disease Center.

The study, he noted, is “another solid piece of evidence that insulin signaling and metabolism are areas that deserve more intense focus.”

The National Heart, Lung, and Blood Institute provided funding for the Framingham Heart Study. This research received support from the Alzheimer's Association Clinician Scientist Fellowship, grants from the National Institute on Aging, and grants from the National Institute of Neurological Disorders and Stroke.

Disclosures

Drs. McGrath and de la Monte had no disclosures. Dr. Boxer has served as a consultant for Abbvie, Alector, Amgen, Arkuda, Arvinas, Asceneuron, Ionis, Lundbeck, Novartis, Passage BIO, Samumed, Third Rock, Toyama and UCB. He also has received research support from Avid, Biogen, BMS, C2N, Cortice, Eli Lilly, Forum, Genentech, Janssen, Novartis, Pfizer, Roche and TauRx.

Link Up for More Information

• McGrath ER, Himali JJ, Leby D, et al. Circulating IGFBP-2: A novel biomarker for incident dementia https://onlinelibrary.wiley.com/doi/abs/10.1002/acn3.50854. Ann Clin Transl Neurol 2019; 6(9):1659–1670.
    • de la Monte SM, Tong M, Daiello LA, Ott BR. Early-stage Alzheimer's disease is associated with simultaneous systemic and central nervous system dysregulation of insulin-linked metabolic pathways https://content.iospress.com/articles/journal-of-alzheimers-disease/jad180906. J Alzheimers Dis 2019;68(2):657–668.