Dr. Alfred Fonteh is an Associate Professor of Neuroscience and Head of the Biomarker and Neuro-disease Mechanism Lab (BNML) in the Department of Neurosciences at HMRI. His research focuses on lipid and protein biomarkers that predict the development of Alzheimer’s disease (AD) in an otherwise cognitively healthy population. The overall objective for early AD detection is to design interventions to prevent disease progression. Since the brain loses a third of its mass in AD and lipids are a significant component of the brain, the BNML aims to detect early changes in urine or blood lipids that isolate participants who will develop AD from those who do not. Dr. Fonteh’s research also examines the proteins that change lipids to understand the underlying mechanisms for AD progression. In addition to AD, the BNML characterizes lipid disorders in migraine.
The BNML also provides analytical support for the other neuroscience labs for measuring enzyme activities, peptides, sodium and other cation changes, and cerebrospinal fluid amyloid/tau measures for the fluid biomarker classification of AD participants in the ongoing HMRI aging cohort. Finally, Dr. Fonteh’s lab prepares cerebrospinal fluid, plasma, urine, and blood cells and archives these biospecimens as part of the HMRI Aging Biorepository, comprising over 20,000 samples collected in the past 20 years.
Dr. Fonteh earned his BS in biochemistry with chemistry from Queen Mary College, University of London, and his MS in medicinal chemistry from the Loughborough University of Technology. He completed his PhD in biochemistry at the Faculty of Medicine (School of Pharmacy) of the University of London. His research focuses on the interactions of drugs with membrane lipids, receptors, and enzymes. His interest in lipid signaling pathways led him to pursue postdoctoral studies at the Johns Hopkins University Asthma and Allergy Center, Baltimore, Maryland. His desire to use state-of-the-art technology to characterize lipids critical to human diseases enabled him to work at Wake Forest University School of Medicine in Winston-Salem, North Carolina, initially as a Research Associate, then as an Instructor of Internal Medicine, and subsequently as an Assistant Professor (1997-2001). Dr. Fonteh joined HMRI in 2001 and has served as a Senior Principal Biochemist, Research Director, and Associate Professor of Neurosciences. Several foundations and the NIH have supported his work, and he has been a major contributor to program projects and multiple RO1 grants.
Amyloid and changes in tau variants in the cerebrospinal fluid (CSF) and blood precede the clinical symptoms of AD by decades. However, treatments targeting these fluid biomarkers have not yielded clinical success. These negative outcomes suggest that scientists must look beyond amyloid/tau to prevent or treat AD. Dr. Fonteh’s approach is to examine lipid changes that will yield diagnostic profiles and disease mechanisms and thus can be targeted through lifestyle modifications or specific enzyme inhibitors. Lipids provide structural and functional roles in the brain, and oxidative stress or inflammation generates signaling lipids that disrupt neuronal function. Dr. Fonteh’s previous studies showed a lipid disorder in the CSF of AD participants, and the current practice uses CSF amyloid/tau or brain amyloid PET for AD classification. However, these methods are invasive or very expensive. Dr. Fonteh’s approach examines biomarkers in urine and blood as less invasive substitutes that can be widely applied to an aging population. Dr. Fonteh collaborates with the neurosciences clinical team at HMRI and colleagues at USC and Caltech. The BNML uses state-of-the-art mass spectrometry, ion chromatography, liquid and gas chromatography, high sensitivity chemiluminescence detection of biomarkers, and high-performance thin-layered chromatography to isolate and quantify AD biomarkers. Dr. Fonteh’s group has discovered urine biomarkers that differentiate cognitively healthy senior participants into healthy and preclinical AD subgroups using these multivariate platforms. This discovery is significant since the urine test is non-invasive and can be applied to a general population for epidemiological and clinical studies.
Another focus of Dr. Fonteh’s lab is lipid metabolic dysfunction in migraines. Migraine is one of the leading causes of disability worldwide and is associated with psychiatric, cardiovascular, gastrointestinal, and allergic comorbidities. However, a common link between migraines and all these comorbidities is unknown. Dr. Fonteh proposes that lipids that play a role in energy regulation, vascular function, inflammation, and pain signaling are altered in migraine, and these lipid changes are the common link with its comorbidities. Dr. Fonteh collaborates with Dr. Cowan’s group at Stanford and has published several papers linking lipid metabolism to migraine pathology.
Dr. Fonteh’s contributions to science
A. Metabolic changes in Alzheimer’s Disease: Dr. Fonteh’s work at HMRI has focused on the importance of lipid metabolism to Alzheimer’s Disease, emphasizing biomarkers and disease mechanisms. Early work examined dipeptides and neurotransmitter changes in CSF, plasma, and urine and found a decrease in the levels of an anti-oxidant dipeptide and an increase in oxidative molecules in the plasma of AD participants (1, 2). Another study showed increased oxidatively-derived lipid products in AD urine, and subsequent studies showed a decrease in omega-3 fatty acids in CSF and serum from AD participants and an increase in CSF molecules that disturb the blood-brain barrier (3-6)
1. Fonteh AN, Harrington RJ, Tsai A, Liao P, and Harrington MG. Free amino acid and dipeptide changes in the body fluids from Alzheimer’s disease subjects. Amino Acids. 2007;32(2):213-24.
2. Fonteh AN, Harrington RJ, Huhmer AF, Biringer RG, Riggins JN, and Harrington MG. Identification of disease markers in human cerebrospinal fluid using lipidomic and proteomic methods. Dis Markers. 2006;22(1-2):39-64.
3. Fonteh AN, Chiang J, Cipolla M, Hale J, Diallo F, Chirino A, Arakaki X, and Harrington MG. Alterations in cerebrospinal fluid glycerophospholipids and phospholipase A2 activity in Alzheimer’s disease. J Lipid Res. 2013;54(10):2884-97.
4. Fonteh AN, Cipolla M, Chiang J, Arakaki X, and Harrington MG. Human cerebrospinal fluid fatty acid levels differ between supernatant fluid and brain-derived nanoparticle fractions, and are altered in Alzheimer’s disease. PLoS One. 2014;9(6):e100519.
5. Fonteh AN, Ormseth C, Chiang J, Cipolla M, Arakaki X, and Harrington MG. Sphingolipid metabolism correlates with cerebrospinal fluid Beta-amyloid levels in Alzheimer’s disease. PLoS One. 2015;10(5):e0125597.
6. Yassine HN, Feng Q, Azizkhanian I, Rawat V, Castor K, Fonteh AN, Harrington MG, Zheng L, Reed BR, DeCarli C, et al. Association of Serum Docosahexaenoic Acid With Cerebral Amyloidosis. JAMA Neurol. 2016;73(10):1208-16.
B. Energy and oxidative biomarkers in AD diagnosis: Dr. Fonteh’s recent studies indicate that lipid oxidation is a potential AD mechanism and targets novel therapies (1). Dr. Fonteh applied modern analytical tools to show that urine lipid metabolites linked with energy are decreased in AD. At the same time, lipid metabolites associated with oxidative damage are higher in AD compared with cognitively healthy participants (2). These studies have been validated in a second cohort from the HMRI studies. Thus, urine lipid biomarkers offer a non-invasive approach to diagnosing AD, and our studies have determined the importance of lipid-based mechanisms and potential enzyme targets for AD (3-6).
1. Chew H, Solomon VA, and Fonteh AN. Involvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies. Front Physiol. 2020;11(598.
2. Castor KJ, Shenoi S, Edminster SP, Tran T, King KS, Chui H, Pogoda JM, *Fonteh AN, and Harrington MG. Urine dicarboxylic acids change in pre-symptomatic Alzheimer’s disease and reflect loss of energy capacity and hippocampal volume. PLoS One. 2020;15(4):e0231765.
3. Klosinski LP, Yao J, Yin F, Fonteh AN, Harrington MG, Christensen TA, Trushina E, and Brinton RD. White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer’s Disease. EBioMedicine. 2015;2(12):1888-904.
4. Solomon V, Hafez M, Xian H, Harrington MG, *Fonteh A*, and Yassine HN. An Association Between Saturated Fatty Acid-Containing Phosphatidylcholine in Cerebrospinal Fluid with Tau Phosphorylation. J Alzheimers Dis. 2022;87(2):609-17.
5. Wang S, Li B, Solomon V, Fonteh A, Rapoport SI, Bennett DA, Arvanitakis Z, Chui HC, Sullivan PM, and Yassine HN. Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4. Mol Neurodegener. 2022;17(1):42
6. Bruce KD, Yassine HN, and Fonteh AN. Editorial: Lipid Metabolism and Transport in CNS Health and Disease. Front Physiol. 2021;12(768417.
C. In migraine research, Dr. Fonteh’s group has discovered an enzyme that is increased in the CSF of migraine patients and links migraine with its comorbidities (1-3). In addition, the lab recently showed that plasma lipolysis, or the breakdown of lipids, is increased in chronic migraine (15). These studies expose novel migraine mechanisms and potential drug targets.
1. Fonteh AN, Chung R, Sharma TL, Fisher RD, Pogoda JM, Cowan R, and Harrington MG. Cerebrospinal fluid phospholipase C activity increases in migraine. Cephalalgia. 2011;31(4):456-62.
2. Fonteh AN, Pogoda JM, Chung R, Cowan RP, and Harrington MG. Phospholipase C activity increases in cerebrospinal fluid from migraineurs in proportion to the number of comorbid conditions: a case-control study. J Headache Pain. 2013;14(60.
3. Castor K, Dawlaty J, Arakaki X, Gross N, Woldeamanuel YW, Harrington MG, Cowan RP, and Fonteh AN. Plasma Lipolysis and Changes in Plasma and Cerebrospinal Fluid Signaling Lipids Reveal Abnormal Lipid Metabolism in Chronic Migraine. Front Mol Neurosci. 2021;14(691733.