The purpose of this review is to understand how the downregulation of brain-derived neurotrophic factor (BDNF) may elevate the accumulation of beta-amyloid protein and impact the pathology of Alzheimer’s Disease (AD). This review also identifies possible treatments that can increase BDNF levels to prevent cognitive impairment and the relationship between BDNF and other AD-related genes like apolipoprotein (APOE). Single nucleotide polymorphisms (SNPs) in the BDNF gene may lead to its loss-of-function and subsequent deteriorating effects on cognition. The lack of BDNF expression has a damaging effect because of its beneficial neurotrophic supply, prevention of beta-amyloid production, and inhibition of beta-amyloid’s neurotoxicity. When genotyping different AD patients, a correlation between BDNF, APOE, and AD were found. The combined treatment of cerebrolysin and donepezil can be used in AD patients to increase BDNF levels and improve cognition. There is a promising connection between BDNF and carriers of the E4 allele of APOE, as increasing BDNF levels will increase neurotrophic supply, which could help with preventing AD.
Alzheimer’s Disease (AD) was discovered in 1906 when Dr. Alois Alzheimer recognized the unusual brain tissue of one of his female patients, Auguste Deter, who exhibited delusional qualities and cognitive/memory impairment . Even though AD was the cause of 121,404 deaths in 2017 and is the 6th leading cause of death in the U.S., the amount of AD research is small compared to cancer research and other diseases . The symptoms that we associate with AD now are very similar to Deter’s: memory loss, confusion, difficulty completing familiar tasks, and inability to understand basic images and words . Current researchers have discovered that the accumulation of proteins like beta-amyloid and tau in neural tissue has been the root cause of the disease, but exactly how they are formed and what exact genes play into AD pathology is still unknown. There are many genes associated with AD such as the amyloid precursor protein (APP), apolipoprotein (APOE), and phospholipase D3 (PLD3) . One particular gene called the brain-derived neurotrophic factor (BDNF) gene has shown promise alongside the APOE for potential avenues of further exploration of AD pathology.
Studies conducted with pluripotent stem cells and clustered regularly interspaced short palindromic repeats (CRISPR) have allowed us to get more insight, showcasing a strong correlation between some genes and late-onset AD . For instance, the apolipoprotein (APOE) gene, which functions in the transport of brain cholesterol and promotion of lipoprotein clearance from circulation, has been heavily studied recently. It has three alleles: E2, E3, and E4. The E2 allele is considered protective and has a worldwide frequency of 4.2%, while E3 is the most common allele with a frequency of 77.9%. Finally, the E4 allele has been found to be the strongest risk factor associated with AD with a 13.7% worldwide frequency but a ~40% frequency with patients who have AD. Since identifying the risk of the development of AD-related to APOE4, researchers have studied a lot about the gene’s function, structure, and sequence. All three alleles have one or two different amino acid substitutions . Between E2 and E3, out of the 299 amino acids, they have a single amino acid difference at 158 where E3 has arginine while E2 has cysteine. Between E3 and E4, the amino acid difference lies in position 112 where E3 has cysteine and E4 has arginine. Between E2 and E4, there is a double amino acid difference in 158 and 112 where E2 has cysteine in both locations, while E4 has arginine . Infants that carry the APOE4 gene have been found to have less gray matter than normal infants. Less gray matter typically translates to limited communication between neurons and other cells .
BDNF’s Role in APOE
Recently, there has been interest in identifying factors related to the APOE gene to further understand risk factors for AD. One study found that the brain-derived neurotrophic factor (BDNF) gene was significantly downregulated in APOE4 genotypes that expressed increased AD pathology. Using cDNA sequence, northern blot analysis, and in situ hybridization, BDNF mRNA had the highest concentration in the hippocampus, followed by the cerebral cortex . Despite being heavily concentrated in those areas, BDNF is widespread across the nervous system, found in the spinal cord, superior colliculus, primary sensory neurons, and retinal ganglion cells. When analyzing the adult mouse, the BDNF gene was most prevalent in the central nervous system. Additionally, when BDNF levels were compared to nerve growth factor (NGF), another neurotrophic factor, BDNF mRNA showed significantly higher levels of expression, despite BDNF and NGF mRNA’s striking similarities in regional and cellular localization . There was a strong association between a SNP, the E6K or the Glu6Lys, in the BDNF gene which may have caused the loss-of-function. However, additional research should be performed to support this finding . The downregulation of the BDNF gene worsened the AD pathology. Thus, it can be inferred that increasing the BDNF levels could alleviate some of the symptoms and cognitive decline associated with AD.
A possible reason why the downregulation of BDNF exacerbates AD pathology is because BDNF’s neurotrophic supply improves cognition in patients. This means that lower BDNF levels will thus lead to lower cognition. Another possibility is how BDNF prevents the generation of beta-amyloid, the protein that builds up the brain causing AD, through an innate process called the non-amyloidogenic pathway . It is also possible that BDNF inhibits and lessens the neurotoxicity of beta-amyloid thus attenuating AD pathology like the previous possibility . BDNF deficiency is caused by a variety of factors, such as metal dyshomeostasis, shortage in NGF support, malfunctional Aβ monomers, and toxic Aβ oligomers. These factors could all attribute to AD pathology .
Yu-Hui Liu et al. performed another study to determine the relationship between APOE4 and BDNF levels under the assumption that they are both important factors related to the development of AD . In this experiment, 120 normal patients and 110 patients with AD were examined for their BDNF levels and the APOE4 gene. By using restriction fragment length polymorphism (RFLP) to genotype ApoE and enzyme-linked immunosorbent assay (ELISA) to detect the serum BDNF levels, they found that those carrying one or more copies of the APOE4 gene had the lowest BDNF levels compared to those without any copies of the APOE4 gene and the normal patients. Additionally, there was no significant difference in BDNF levels between those who carried one or two copies of APOE4 . The association between APOE4, BDNF, and AD was further explored through a series of tests and statistical analyses. Through the use of a regression model where APOE E4 was the independent variable and AD was the dependent variable, an association between the two factors (AD and carrying APOE E4) was found. The second analysis used BDNF as the independent variable which indicated a relationship between BDNF and APOE E4 carriers with AD. Using different tests on AD patients, the researchers found that patients with AD tended to score lower on the mini-mental state examinations (MMSE). The MMSE is a test used to evaluate cognitive function by analyzing aspects such as memory, attention, and orientation. AD patients also had higher clinical dementia rating (CDR), higher activities of daily living (ADL), and higher prevention of disability scores (POD). These different tests were then used in a univariate general linear model which showed that carrying the APOE E4 gene tended to affect ADL scores but not CDR and POD. However, the interaction between APOE E4 carriers and BDNF levels were further analyzed and found to affect MMSE scores. This interaction implies the possibility of APOE regulating BDNF which may correlate with the overall development of AD . BDNF supplies the brain with neurotrophic support, and consequently, a deficiency in BDNF will directly negatively impact brain integrity. The final conclusion reached was that APOE4 may impact BDNF metabolism, but an experiment with a larger sample size needs to be conducted in order to confirm this hypothesis.
Increasing BDNF Levels as Treatment
After recognizing that low BDNF levels are correlated to a higher risk of AD, researchers then began efforts to increase BDNF levels in patients. Anton Alvarez et al. performed an experiment comparing the use of cerebrolysin, donepezil, and combined therapy with both cerebrolysin and donepezil on patients carrying the APOE4 gene. Their goal was to determine if these treatments would alleviate the AD pathology by increasing BDNF levels. They hypothesized that cerebrolysin would indeed increase BDNF levels because cerebrolysin decreases glycogen synthase kinase 3-beta (GSK3beta), which tends to lead to increased BDNF levels. Within 16 weeks, the patients treated with cerebrolysin exhibited higher BDNF levels and less cognitive decline. Furthermore, the combined therapy showed even greater success than cerebrolysin alone. From this experiment, the researchers concluded the following statements: cerebrolysin produces higher BDNF levels in APOE4 carriers, the combined treatment allowed donepezil to draw out the increased BDNF levels that cerebrolysin induced, and better cognitive improvement in APOE4 patients was correlated with higher BDNF levels .
Regardless of the potential of targeting BDNF in treatments, there are limitations. BDNF levels can be affected by many factors such as smoking, exercise, body weight, and diet [13-16]. These different factors make it difficult to be able to draw a clear correlation between APOE4 and BDNF. Furthermore, because BDNF can be altered in many other neurodegenerative diseases, such as Parkinson’s Disease, it can't be considered a specific biomarker for AD .
Future advances in the prevention of AD are focused on alternative ways to increase BDNF levels. Beta-amyloid, the core cause of the plaques in AD patients, is known to regulate neurotransmitter release. Because of this, it is categorized under the group of factors that can alter neurocognitive effects with the NGF and the BDNF . Because beta-amyloid is activated by the phosphatidyl-inositol-3-kinase pathway (PI3K/AKT), they can also stimulate the cyclic AMP response element-binding protein (CREB) which then releases BDNF.  Additionally, because of NGF’s ability to activate BDNF through phosphorylation of CREB, copper and zinc metal ions can increase BDNF levels. This could be another avenue of future research. Because of its similarity to that of the cerebrolysin treatment in increasing BDNF levels, using zinc and copper ions may also alleviate AD pathology by diminishing cognitive decline .
Low BDNF levels have been demonstrated to be related to the development of AD, specifically for patients carrying the APOE4 gene. A significant amount of research has been performed to characterize the BDNF gene and determine its relationship to AD. Combined therapy with cerebrolysin and donepezil was noted to positively affect cognition by increasing BDNF levels. As a result, future research avenues for the prevention of AD are focused on additional ways to increase BDNF levels. As of now, the benefits of BDNF are highlighted by its ability to strengthen different aspects of brain function.
Hi! My name is Katherine and I'm a rising junior from Arizona. Neuroscience and biology are the two fields in science that I'm really interested in and hope to study in college. I also like writing poetry and playing volleyball.