Understanding Alzheimer’s—How Multi-omics Can Discover Insights Into Disease Progression and Therapies

Posted In: Blog, Omics
Understanding-Alzheimers

Introduction—The Global State of Research into Alzheimer’s Disease

There are currently an estimated 55 million people living with dementia in the world and every 3 seconds another person in the world develops it. As the world population is forecast to age, the numbers are predicted to almost triple by 2050. The most common form of dementia is Alzheimer’s disease (AD) which accounts for 60 to 70% of dementia (See Dementia Facts and Figures). In the US, AD is officially listed as the 6th leading cause of death. It is also an important cause of disability.1

“The number of people living with dementia is predicted to almost triple by 2050.”

The awareness and knowledge of AD have greatly increased since it was originally described in 1906 by the German physician, Alois Alzheimer. In 2019, AD research funding in the US reached an all-time high of $2.8 billion, and in 2021, aducanumab, a monoclonal antibody that targets the amyloid plaque present in the brains of people with the disease, received accelerated approval by the FDA (See Milestones). As of August 2022, 394 interventional studies registered at ClinicalTrials.gov are actively recruiting patients. Tested therapies include anti-plaque agents, neurotransmitter modification, anti-neuroinflammation, neuroprotection interventions, cognitive enhancement, and behavioral psychological symptoms relief.2 However, one aspect that remains understudied is the basis of racial and ethnic disparities in the diagnosis of AD. To this end, researchers were awarded a $45 million grant from the National Institute on Aging to study the biological differences in multi-ethnic populations with AD.

Alzheimer’s and the Genotype—An Overview into the Biomarkers and Findings at the Genomic Level for Alzheimer’s Disease

AD can be described as a non-linear, genetics-driven pathophysiological process underlain by highly heterogeneous biological and clinical alterations and temporal disease progression.3 From the genetic point of view, although most AD forms have no apparent familial aggregation, AD has a heritability level of ~70%. In addition to mutations in APP, PSEN1, and PSEN2 genes, responsible for almost all cases of early-onset dominantly-inherited AD, more than 600 genes have been implicated as susceptibility factors for AD with APOE being the most important risk factor for the late-onset AD. Carriers of the APOEe4 allele in hetero-/homozygosis are at a 3 to 4/12 to 15 times higher risk of developing AD than individuals carrying APOEe3.4

Alzheimer’s and the Phenotype—An Overview into the Application of Metabolomics to Uncover Insights into Alzheimer’s Disease

The genetic heterogeneity of AD causes clinical phenotype heterogeneity regarding cognitive, neurological, and behavioral symptoms. To untangle such complexity, holistic approaches are needed such as the Omics sciences. Metabolomics, the newest omics platform, possesses great potential for the diagnosis and prognosis of AD as an individual’s metabolome reflects all genetic, transcriptional, and protein alterations and includes influence from the environment. Metabolomic research so far has confirmed the intricacy of dynamic changes associated with AD progression.5 Further definition of metabolite-level alterations in AD should provide insights into disease mechanisms, reveal sex-specific and ethnicity-related changes, advance the development of biomarker panels, aid the choice of individualized therapies, and monitor therapy efficacy.

“The definition of metabolite-level alterations in AD should provide insights into disease mechanisms, reveal sex-specific and ethnicity-related changes, advance the development of biomarker panels, and aid the choice of individualized therapies and monitoring their efficacy.”

Metabolon’s Contribution to Alzheimer’s Disease Research

Metabolon’s pipeline deciphers thousands of discrete chemical signals from genetic and non-genetic factors to reveal metabolic networks underlying disease. One of our strongest clinical applications is the study of AD. The company has been cited in 85 publications containing the keyword “Alzheimer’s disease” from 49 organizations. For example, researchers6 explored the potential usefulness of rapamycin as a pharmacological intervention for extending longevity through a comprehensive approach that included metabolomics. Could rapamycin prevent AD in E4FAD mice that express human APOe4 allele and overexpress amyloid beta? The results indicate that rapamycin can restore brain functions and reduce AD risk in young, asymptomatic mice suggesting the possibility that rapamycin could be used to prevent AD in asymptomatic APOe4 carriers.6 In another study, researchers7 determined the neuroprotective and pharmacological properties of CAD-31, a curcumin-derived AD drug candidate, and assayed its therapeutic efficacy in the APPswe/PS1ΔE9 mouse model of AD. CAD-31, endowed with neuroprotective properties, was able to prevent toxic events associated with age-related neurodegeneration.7

Taken together, research into AD is a thriving field of biomedical science. Future work should include metabolomic approaches, which have the potential to bring new clues into the biology and provide new targets in the treatment of AD.

References

1. Alzheimer’s Association. 2022 Alzheimer’s Disease Facts and Figures; 2022.

2. Huang LK, Chao SP, Hu CJ. Clinical trials of new drugs for Alzheimer disease. J Biomed Sci. 2020;27(1):18.

3. Hampel H, Nistico R, Seyfried NT, et al. Omics sciences for systems biology in Alzheimer’s disease: State-of-the-art of the evidence. Ageing Res Rev. 2021;69:101346.

4. Knopman DS, Amieva H, Petersen RC, et al. Alzheimer disease. Nat Rev Dis Primers. 2021;7(1):33.

5. Wilkins JM, Trushina E. Application of Metabolomics in Alzheimer’s Disease. Front Neurol. 2017;8:719.

6. Lin AL, Parikh I, Yanckello LM, et al. APOE genotype-dependent pharmacogenetic responses to rapamycin for preventing Alzheimer’s disease. Neurobiol Dis. 2020;139:104834.

7. Daugherty D, Goldberg J, Fischer W, Dargusch R, Maher P, Schubert D. A novel Alzheimer’s disease drug candidate targeting inflammation and fatty acid metabolism. Alzheimers Res Ther. 2017;9(1):50.

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