The Genetics of Alzheimer’s Disease


    The human genome is complex, unique to each individual, and is the primary driving force behind every biological function and dysfunction. This week’s blog will discuss the genetic underpinnings creating variable risk factors for Alzheimer’s disease (AD), a well-researched topic but infrequently understood. With growing access to commercial genomic testing through companies like 23andMe, understanding the role that genetics play in AD and other diseases is more important than ever. The ability to understand one’s risk of developing AD may allow for the expansion of preventative medical practices to slow or stop disease progression before symptom onset.

    Initial AD genetic research was motivated by the observation that those suffering from the disease were found to have significant accumulation of amyloid beta (Aβ) plaques in the hippocampus, amygdala, and cerebral cortex. As we now know, the location of these plaques correlate well to the symptoms associated with AD such as impaired memory function, reduced emotional regulation, and dysfunctional executive functioning. 

    So how exactly do genetics drive Aβ production and AD pathology? The first mutation identified in inducing AD symptoms was found at the transcriptional site for β-amyloid precursor protein (βAPP) on chromosome 21. It was discovered because trisomy 21, more commonly known as Down’s Syndrome, is associated with deposition of Aβ plaques in young adulthood and drives development of the AD-associated symptoms. This research led to the discovery of 5 βAPP mutations associated with familial AD, however, these mutations cause only about 1% of familial AD cases in total, and are characterized by early onset. Despite this, these discoveries provided insights into the mechanism of Aβ deposition which are present in all AD cases. Furthermore, it led to the discovery of the Apolipoprotein E (ApoE) gene. Research into this gene suggests that a certain allele, a specific form of the ApoE gene known as E4, increases the likelihood of developing late onset AD in a much larger population. Inheritance of one copy of the E4 allele confers significantly increased risk, earlier onset of AD pathology, and higher density of Aβ aggregation. Two copies of E4 increase this risk even more. The E2 allele, on the other hand, provides resistance to Aβ deposition. It is important to mention that not all E4 carriers develop AD and not all AD patients have an E4 allele meaning that there are other risk factors at play, but genetics are a strong associative risk factor.

    βAPP mutations account for a small percentage of early onset AD cases and ApoE4 accounts for a significant percentage of late onset cases, but not all, indicating the presence of other risk factors. The next discovery in AD genetics came in the form of presenilin genes 1 and 2. There are 25 known missense mutations of presenilin 1 and 2 mutations of presenilin 2, all of which correlate with early onset familial AD. A missense mutation refers to the change of a single nucleotide in DNA which then codes for a different amino acid, which are protein building blocks. Imagine one of these presenilin proteins as a house made of bricks, and the missense mutation as a cinderblock where a brick should be, this single change throws the entire balance of the “house” off and in the case of proteins, changes their function. The specific function of presenilin proteins are only weakly understood but cell and animal models suggest that Aβ peptides consisting of 42 residues (Aβ42) have increased aggregation when present with presenilin mutations. Aβ peptides consisting of 40 residues (Aβ40), however, seem to be unaffected by presenilin mutations. Aβ42 peptides normally have increased aggregative properties in comparison to Aβ40, but this activity can be exacerbated by presenilin mutations possibly inducing AD. As with ApoE genes, these mutations do not account for all cases of AD but are clearly playing a powerful role in amyloid protein aggregation and disease manifestation. 

    The gene which codes for microtubule associated protein tau (MAPT) has also been implicated in AD pathology due to the presence of neurofibrillary tangles (NFTs), or aggregates of tau proteins. Tau proteins under normal conditions can be spliced by cellular mechanisms in different ways resulting in 6 different similar but functionally different forms of the protein. Two of these forms, named 3R and 4R, are present more abundantly in AD brains suggesting that these may be the pathological forms. Overexpression of 3R tau proteins alone tends to cause Pick’s disease (a subset of frontotemporal dementia) and overexpression of primarily 4R isoforms can cause corticobasal degeneration or progressive supranuclear palsy. However, the specific isoform tau takes is not the only factor in inducing AD. It seems that, through a different cellular mechanism, tau proteins can become hyperphosphorylated which increases the likelihood of aggregation and impedes clearance of these aggregates once created. 

    There are clearly numerous factors at play in the pathogenesis of AD, all of which seem to interact with each other to increase or minimize risk of developing the disease. While many of these mutations are well understood, there is clearly more to discover with regards to the underlying mechanisms promoting aggregation of these proteins and specifically, how to reverse these mechanisms to allow for dissociation and clearance of Aβ and NFT aggregates.  If you or someone you know has a family history of AD it might be worth getting genetic testing to identify your risk and start taking preventative measures, whether in the form of better sleep habits, dietary changes, implementation of supplements, exercise, or something else! There are numerous other genes not discussed here which are also hypothesized to play a role in AD pathology, so if you’re inspired to learn more, I encourage you to visit for more information about these lesser known genes. 

Selkoe, D. J. Amyloid β-Protein and the Genetics of Alzheimer’s Disease [Internet]. The Journal of Biological Chemistry. 1996. Available from:
Tanzi, R. E. The Genetics of Alzheimer Disease [Internet]. Cold Spring Harbor Perspectives in Medicine. 2012. Available from:

LMTM, Tau, and Alzheimer’s: A New Clinical Approach

Many followers of this blog, and those who have participated in our clinical trials, have heard the terms beta-amyloid (Aβ) plaques and tau neurofibrillary tangles time and time again. Both Aβ and tau are protein biomarkers associated with cognitive decline in Alzheimer’s disease (AD). For a long time, the scientific community has focused primarily on reducing Aβ production and aggregation as a means of preventing further decline and attempting to clear Aβ plaques in the brain to alleviate symptoms. Unfortunately, many of these studies have failed to show strong therapeutic potential across all sub-groups of AD patients resulting in the termination of many trials focusing on this method of disease modification. As such, there has been a slow shift from the “amyloid hypothesis”, suggesting that Aβ plaques are the predominant cause of AD, to an interest in the role that tau plays in the disease. A clinical trial aimed at reducing the production and aggregation of tau neurofibrillary tangles through the use of an oral agent, Leuco-Methylthioninium (LMTM), will be recruiting for participants at our clinic soon so I am using this week’s blog to provide information for anyone who might be interested.

The Aβ plaques and tau tangles associated with AD are misfolded proteins, indicating a change in protein shape, also resulting in functional changes. Tau, short for microtubule-associated protein tau, is vital for stabilization of microtubules (a structure critical for all neurons). However, once a tau protein becomes misfolded, either as product of genetics, transcriptional errors, or even physical trauma as seen in CTE or “punch drunk syndrome”, it becomes prionic. This essentially means that the misfolded tau protein can interact with correctly folded tau proteins and change their shape into that of the pathogenic form. Once this cascade begins, misfolded proteins bind together forming aggregates, or neurofibrillary tangles, which negatively impact neuronal function and induce cell death.

In cell models, LMTM administration reduces aggregation of improperly folded tau and promotes disaggregation of pre-existing neurofibrillary tangles. In transgenic mouse models, genetically modified to present with neurofibrillary tangles, LMTM facilitates clearance of neurofibrillary tangles and improves cognitive and motor learning capabilities. Previous trials in humans show variable efficacy for participants with MCI and early AD. Using cognitive assessments as a measure of AD progression, one LMTM trial showed significant improvement in cognition, MRI atrophy rates, and glucose uptake. In fact, the average brain atrophy rate for participants enrolled was typical of mild AD but after 9 months of treatment with LMTM, the atrophy rate decreased similar to that of normal elderly controls. LMTM and its previous trials show great potential for slowing or halting the progression of AD pathology, both cognitively and functionally.

TauRx, the company behind LMTM, has successfully completed two trials in humans with promising results. In the first trial, researchers found no differences between the treatment and control study groups, however, they did indicate a sub-group with improvement. Namely, those not receiving any other AD treatment and using LMTM as a monotherapy appeared to benefit compared to participants taking currently approved AD drugs with LMTM. This encouraged further research into LMTM as a monotherapy to confirm efficacy. In their second trial, as expected, those receiving LMTM at 100 mg/day as their only AD treatment scored better on cognitive assessments than those not using it as a monotherapy. Even the 4 mg dosage group, originally designed as a control, experienced a noticeable benefit if given as a monotherapy. As such, the next trial which we are participating in will focus on LMTM as a monotherapy and will analyze the efficacy of smaller doses (8-16 mg/day).

The dosing phase of the TauRx trial for LMTM treatment will take place over 52 weeks with approximately 7 in-clinic visits. It is a double-blind trial, meaning that neither participants nor researchers will know who is on active drug or placebo during this period. However, if the trial shows potential after these 7 visits, it will transition to an Open Label Extension trial, in which all participants receive active drug and will involve 3 more visits. Furthermore, because the trial is aiming to test LMTM as a monotherapy, the use of AchEIs (e.g. donepezil, galantamine, and rivastigmine) or memantine will need to be discontinued during the screening phase in all participants. It is important to note that all participants will require a study partner, someone who can provide an external perspective on the participant’s cognition and daily function, at each visit. In order to get enrollment in this trial started, potential participants should contact us to undergo a phone memory screen and answer a few questions regarding medication and medical history to confirm basic eligibility.

We, here at the Center for Cognitive Health, are very excited for the possible therapeutic benefits of LMTM in AD, a disease in which there is no current disease modifying drug, so if you, or a loved one, are suffering from AD or MCI and are interested in receiving potentially beneficial treatment while progressing the scientific understanding of AD, we would love to hear from you! You can reach out to the studies coordinator, Tyler Leecing, at (503)-548-0908 or You can also find more information about our currently recruiting trials and clinic on our website,, and more about TauRx at

Barbier, P., Zejneli, O., Martinho, M., Lasorsa, A., Belle, V., Smet-Nocca, C., Tsvetkov, P. O., et al. Role of Tau as a Microtubule-Associated Protein: Structural and Functional Aspects [Internet]. Aging Neuroscience. 2019. Available from:
Wilcock, G. K., Gauthier, S., Frisoni, G.B., Jia, J., Hardlund, J. K., Moebius, H. J., Bentham, P., et al. Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer’s Disease: Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial [Internet]. Journal of Alzheimer’s Disease. 2018. Available from:
Elaine Goodman. LMTM [Internet]. Article from Alzheimer’s News Today. Available from:

Photobiomodulation: Lighting Up the Brain

     There are, to date, few methods of non-invasive brain stimulation (NIBS) that show therapeutic potential for neurological dysfunction. The most commonly used forms of NIBS are transcranial magnetic stimulation (TMS), which uses a magnet to generate electrical currents thereby increasing activity in the targeted system of the brain, and transcranial direct current stimulation (tDCS), which uses electrodes to directly translate external electrical currents into the brain. Both of these NIBS techniques require multiple sessions of stimulation administered by a technician which make them, in the long run, relatively costly. However, a significantly cheaper and novel method of NIBS, termed transcranial photobiomodulation (tPBM), is currently undergoing research to determine efficacy. The device itself, branded as Vielight, is commercially available, user friendly, and safe. In this blog we will delve into the potential implications of this technology while analyzing the currently available research on Vielight.

     So what exactly is photobiomodulation? 

     It involves administration of pulsing, low-level red and near-infrared (NIR) light on specific locations in the brain to stimulate neural tissue. The Vielight Neuro Gamma model uses LED lights to deliver 40 Hz pulses of NIR transcranially and intranasally to neural structures associated with the default mode network (DMN), a system associated with introspection when the mind is not actively engaging in actions requiring attention. Activation of the DMN is associated with the brain being in an alpha state meaning that one is in a state of “resting wakefulness”. Previous research suggests that increasing alpha wave activity in the brain aids in inhibition of irrelevant cortical areas and integration of activity in relevant areas, essentially streamlining cognition and creating greater functional connectivity between these areas. This has implications for pathological presentations that involve the DMN such as those associated with Alzheimer’s disease (AD), dementia, schizophrenia, autism, anxiety, and depression. Unfortunately, research has not yet delved into its use for any specific disorders but rather, was used on healthy participants to determine the safety and efficacy for impacting cognition.

     In the study, twenty adults were recruited and attended two study visits each. During one visit they received active tPBM stimulation from the Vielight Neuro Gamma model and during the other they received sham stimulation (placebo), double-blinded to avoid researcher bias and to ensure that any detected changes were not a placebo effect. Participants also received pre- and post-stimulation EEGs to measure neural activity. Interestingly, after both active and sham stimulation sessions, the EEG showed an increase in power for all frequency bands (corresponding to different frequencies of neural firing) in comparison to baseline, but differential increases in the higher frequency bands. Specifically, in the active stimulation condition, participants experienced significant power increases of higher frequency bands (alpha, beta, and gamma) and smaller power increases of lower frequency bands (delta and theta).

     Conditions such as AD present with decreased power of high frequency activity and increased power of low frequency bands. If these abnormal ranges of activity are the cause of cognitive decline, then using tPBM to generate more high frequency activity should, in theory, alleviate some of the symptoms. To confirm this, however, will require pre-clinical and clinical trials on participants with dysfunction of the DMN

     We now know what tPBM is and what it does, but how exactly does it work? The specifics behind the neurophysiology are much less well understood than those associated with tDCS or TMS, but there are certain cellular mechanisms that appear to be impacted by NIR light stimulation. The most well studied are mitochondria, after PBM, ATP production increases as well as transcription of genes for protein synthesis, cell proliferation, anti-inflammatory, and antioxidant responses. In layman’s terms, PBM has the potential to maintain the function of neurons while also promoting growth of new neurites such as dendritic spines for enhanced neuronal communication and, as was seen in a rat model study, even the growth of entirely new neurons after ischemic stroke. This study does mention that there is little evidence that tPBM directly impacts neural activity but through the mechanisms mentioned above it may promote maintenance of functional connectivity through neurite growth as well as maintenance of the activity of individual neurons through transcriptional modulation and ATP production.

     In summation, the therapeutic potential of tPBM through Vielight’s relatively cheap, easily accessible, and portable technology is exciting in terms of possibly enhancing cognition for those with AD or dementia, as well as other disorders of the DMN, in the comfort of your own home. However, it is important to address the fact that this is an extremely new method of NIBS that, as of yet, has not been well studied for disease models in human participants. As such, if purchasing a tPBM system is a financial stretch, it is likely worth waiting for further research to confirm its purported therapeutic effects. On the bright side, for this pilot study none of the participants experienced any adverse effects or even abnormal sensations meaning that further research should be easily approved and, hopefully, within the next year or two we will have concrete proof of any effectiveness of tPBM.

Zomorrodi, R., Loheswaran, G., Pushparaj, A., & Lim, L. Pulsed Near Infrared Transcranial and Intranasal Photobiomodulation Significantly Modulates Neural Oscillations: a pilot exploratory study [Internet]. Nature. 2018. Available from:
Quiroga, R. Q., & Kreiman, G. Measuring sparseness in the brain: Comment on Bowers (2009) [Internet]. Psychological Review. 2010. Available from:

Sex Differences in Alzheimer’s Risk and Pathology

    Many facets of our lives are profoundly impacted by our underlying genetic makeup from birth. One particularly impactful genetic difference involves the X and Y chromosomes which, aside from assigning one’s biological sex, also play a crucial role in regulation and expression of other genes. The interaction between sex chromosomes and the apolipoprotein E (APOE) gene, which is commonly correlated to one’s risk of developing Alzheimer’s disease (AD), is well studied both in terms of relative risk as well as particular pathological presentations between males and females. This is especially important because certain sub-groups of AD patients often respond differently to various treatments. In the future, these mild differences in clinical manifestations may provide insights into specific treatments or preventative measures that are more effective in sex-based sub-groups. This week we will be delving into this research.

    One study determined that females were roughly twice as likely as men to develop AD, but that men had shorter lifespans after onset of the disease. These two data points alone outline the significant differences in both risk and expression of the disease amongst males and females. Specifically, in a group of 2611 participants followed for 20 years, it was determined that a 65 year old man without a current AD diagnosis had a 6.3% chance of developing AD later in life. This same study found that a 65 year old woman without a current AD diagnosis had a 12% chance of developing the disease. Once a diagnosis is suspected, several epidemiological studies have suggested that females experience neurodegeneration and onset of symptoms more quickly but also have longer lifespans with the disorder. One possible explanation for this is that, due to the faster onset/progression, women tend to be diagnosed earlier making their post-diagnosis lifespan appear longer, while men who may already be suffering from AD but are mostly asymptomatic are diagnosed later, shortening their post-diagnosis lifespan. However, one review study focusing on mortality associated with all dementing disorders found that men had shorter lifespans regardless of age at diagnosis. All of these acute differences raise the question, what is the difference between males and females when it comes to AD?

    Part of the differences, as we discussed earlier, come down to genetics. One study found that while women are generally more likely to develop AD, men with the APOE ɛ4 allele (a specific variant of the APOE gene) have higher relative risk than women with the APOE ɛ4 allele. Furthermore, they determined that the APOE ɛ2 allele, which is uncommon in the general population but has been hypothesized to confer some resistance to development of AD, only provided this reduced risk in women. However, the study involved very few males with the ɛ2 allele, which may have confounded protection in that population. Men have higher incidence rates of vascular disease and women more commonly take anti-hypertensive drugs. Vascular disorders have been hypothesized to advance the progression of dementia, while regular administration of anti-hypertensive drugs seem to reduce the risk associated with the APOE ɛ4 allele. This may be another confounding variable in the relative risks associated with sex, but even so it suggests that lifestyle differences, such as doctor visits and taking one’s medication may also play a role in the development of AD. You can change your lifestyle but you cannot change your genetics.

   Yet another possible differential between the sexes involves hormone secretion. Mouse models lacking estrogen receptors result in up-regulated estrogen levels, possibly playing a powerful role in neuroprotection. Estradiol, the predominant estrogen produced during reproductive years in females, administered to females prior to a prolonged period of reduced hormone secretion like menopause provided neuroprotective effects. However, if administered after a prolonged reduction in hormone secretion (hypogonadism), estradiol was incapable of producing the same effects, leading us to the “healthy cell hypothesis”. It proposes that normal hormonal secretion promotes healthy cell aging while a period of reduced secretion diminishes the neuroprotective effects of hormones. In animal models, estrogens like estradiol promote turnover of thin spines in neurons which are synaptic structures associated with higher cognitive functioning, particularly of the prefrontal cortex which plays a critical role in executive function. Maintenance of normal hormone levels is crucial because during periods of hypogonadism the cells become “less healthy” and may no longer benefit from the normal protective effects. Among women who develop AD, those that had more lifetime exposure to estrogens developed AD at a later age. This has created interest in the possibility of hormone therapy during the onset of menopause as a possible preventative treatment for AD. 

   Unfortunately, one clinical trial testing the effects of estradiol and estrogen/ medroxyprogesterone supplementation on cerebrovascular events in aging women found hormone replacement to increase risk for breast cancer, stroke, and coronary heart disease, meaning that, as of now, this may not be a safe option for prevention of dementia. Males, on the other hand, experience much less marked decreases in hormone production in the late stages of life which might explain the decreased general risk of AD amongst men if androgens play a similar neuroprotective role in men as estradiol does in women.

        Overall, it is clear that genetic sex interacts with age and general genetics to create extreme variability in risk for AD. Sub-group analyses based on gender, and preclinical and clinical trials focusing on the particular risks associated with each group, may prove to be more effective than a generalized treatment for AD.

Barnes, L. L., Wilson, R. S., & Bienias, J. L. Sex Differences in the Clinical Manifestations of Alzheimer Disease Pathology [Internet]. Archives of General Psychiatry. 2005. Available from:
Qiu, C., Kivipelto, M., Aguero-Torres, H., Winblad, B., & Fratiglioni, L. Risk and protective effects of the APOE gene towards Alzheimer’s disease in the Kungsholmen project: variation by age and sex [Internet]. Journal of Neurology, Neurosurgery, and Psychiatry. 2003. Available from:
Podcasy, J. L., & Epperson, C. N. Considering sex and gender in Alzheimer disease and other dementias [Internet]. Dialogues in Clinical Neurosciene. 2016. Available from:
Todd, S., Barr, S., Roberts, M., & Passmore, A. P. Survival in dementia and predictors of mortality: a review [Internet]. International Journal of Geriatric Psychiatry. 2013. Available from:
Bailey, M., Wang, A. C.J., & Morrison, J. H. Interactive Effects of Age and Estrogen on Cortical Neurons: Implications for Cognitive Aging [Internet]. Neuroscience. 2011. Available from:
Kim, N., Gross, C., & Krumholz, H. M. The Impact of Clinical Trials on the Use of Hormone Replacement Therapy [Internet]. Journal of General Internal Medicine. 2005. Available from:

The Protective Effects of Sleep for Neurodegeneration

        As we all know, sleep plays a critical role in brain functioning. One such function is memory, with sleep enhancing memory encoding and consolidation. Unsurprisingly, study participants deprived of sleep for 36 hours had significantly worse memory retention and poorer insight into their performance than participants who slept regularly, and administration of caffeine to overcome the decreased alertness was incapable of improving memory function in a sleep deprived sub-group. Another study, utilizing fMRI imaging, showed that sleep deprived participants had decreased activation of the medial temporal lobe in a verbal learning task, but increased prefrontal and parietal lobe activity (presumably to compensate for decreased temporal function) and a corresponding 40% decrease in memory formation of the target words. These results showcase the important role that sleep plays in memory formation, but studies within the last decade have suggested there may be an even more powerful impact on cognition.

        Insomnia is a common complaint amongst patients with neurodegenerative diseases, and was long thought to be a symptom of these disorders. More recently, however, there has been interest in how insomnia might actually be a risk factor for neurodegeneration in a bidirectional relationship. In a study following participants with and without insomnia for 6 years, those in the 90th percentile of sleep fragmentation were 1.5 times more likely to develop Alzheimer’s disease (AD) compared to those in the 10th percentile of sleep fragmentation (representing longer and deeper sleep). Another study, performed over 40 years, showed that patients with complaints of insomnia had a 33% increase in risk for dementia and a 51% increase in risk for AD. Furthermore, a PET imaging study showed that a single night of sleep deprivation significantly increased amyloid-beta deposition (Aβ), even in healthy controls. Results like these promoted further research into the link between insomnia and neurodegeneration providing insight into the neurophysiological effects of sleep.

        This raises the question; How exactly does sleep prevent Aβ buildup and reduce risk for AD and dementia? 

        As you may already know, the brain is contained within a closed cavity, and because of this, any change in volume (such as an influx of blood) will create either a change in pressure or a change in volume of something else (such as cerebrospinal fluid or CSF). Recent studies have been testing these fluid dynamics and how they might play a role in the clearance of toxic by-products such as Aβ. One such study, utilizing blood oxygen level-dependent (BOLD) fMRI imaging and EEG measurement of neural activity found a distinct pattern of fluid flow during slow-wave sleep (SWS) also known as non-rapid eye movement (NREM) sleep. Specifically, it seems that during SWS, a decrease in neural activity also creates a decrease in cranial blood flow. Slow pulses of blood during this phase of sleep are inversely correlated to CSF flow, meaning that as blood flows into the cranial cavity, CSF flows out, and vice versa, in a pulsatile fashion. Because of these pulses of blood flow, waves of CSF are first moved around the brain, mixing with interstitial fluid and taking up toxic by-products, and are then pushed out, effectively clearing toxins from the cranial cavity. In this way, SWS is crucial for neuronal health as this is the only time that hemodynamic flow is coupled with the “bathing” action of CSF. Another related function is proteostasis, the maintenance of healthy proteins and clearance of misfolded proteins. In mice, sleep deprivation impairs proteostasis and causes brain cell death.

        These studies show that lack of sleep contributes to neurodegeneration, but neurodegenerative disorders also contribute to impaired sleep. This bidirectional pathway of toxic protein accumulation causes neurodegeneration that in turn furthers sleep impairment in a repetitive cycle. Thus treatment of sleep disorders is just as important as treatment of cognitive decline in AD patients; sweet dreams!

Harrison, Y., & Horne, J. A. Sleep loss and temporal memory [Internet]. The Quarterly Journal of Experimental Psychology. 2000. Available from:
Drummond, S. P., Brown, G. G., Gillin, J. C., Stricker, J. L., & Wong, E. C. Altered brain response to verbal learning following sleep deprivation [Internet]. Nature. 2000. Available from:
Fultz, N. E., Bonmassar, G., Setsompop, K., Stickgold, R. A., Rosen, R. R., Polimeni, J. R., & Lewis, D. L. Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep [Internet]. Science. 2019. Available from:
Grubb, S., & Lauritzen, M. Deep sleep drives brain fluid oscillations [Internet]. Science. 2019. Available from:
Minakawa, E. N., Wada, K., & Nagai, Y. Sleep Disturbance as a Potential Modifiable Risk Factor for Alzheimer’s Disease [Internet]. International Journal of Molecular Sciences. 2019. Available from:
Shokri-Kojori, E., Wang, G., Wiers, C. E., Demiral, S. B., Guo, M., Won Kim, S., Lindgren, E., et. al. β-Amyloid accumulation in the human brain after one night of sleep deprivation [Internet]. Proceedings of the National Academy of Sciences of the United States of America. 2018. Available from:
Shamim, S. A., Warriachm, Z. I., Tariq, M. A., Rana, K. F., & Malik, B. H. Insomnia: Risk Factor for Neurodegenerative Diseases [Internet]. Cureus. 2019. Available from:

Memory Disorders: A Review

        As we look back upon the events of the last decade, it seems fitting to also review the
various types of memory, disorders that affect them, and what we have learned about them over
the years. We will address the neuroanatomy, symptomatology, and treatments of disorders
affecting episodic, working, procedural, and semantic memory functions. Before we do that,
however, let’s outline the basic process of “making” a memory and how this ties into these
individual memory types. In general, a memory undergoes three distinct phases of formation,
known as encoding, consolidation, and retrieval. Dysfunction at any of these stages will result in
memory impairment, manifesting differently depending on the stage affected.

        Episodic memory, refers to encoding and recalling personal experiences as though they
were an “episode” of your life. Neuroanatomically, the Papez circuit subserves encoding of
episodic memory, while the frontal lobes are crucial for its retrieval. This is evidenced by the
famous case of H.M., who underwent bilateral medial temporal lobe removal to treat severe
epilepsy, and wound up with severe anterograde amnesia (the inability to form new memories).
Damage to the hippocampal formation or other structures in the Papez circuit impairs episodic
memory encoding. Episodic memory is also lateralized with visual memory being stored
primarily in the right and verbal memory in the left hippocampus/medial temporal lobe.
Psychometric tests that measure memory dysfunction utilize figure and word-list free recall and
recognition cues. When a patient’s recall errors are improved with recognition cues we then
know that the brain dysfunction is not in Papez circuit (responsible for encoding) but in the
frontal lobes (responsible for retrieval). Normal age-related memory decline is the leading cause
of a retrieval deficit; that is why we keep lists as we get older, to serve as cues for our senior
moments. When that list no longer jogs your memory that is always the sign of a disease and
that is when it’s time to see us.

        Possible causes of damage to Papez circuit include traumatic brain injury (TBI), localized
strokes, Wernicke-Korsakoff syndrome, or transient global amnesia induced by seizure. More
commonly occurring episodic memory disorders include Alzheimer’s disease (AD) and
hippocampal sclerosis (HS). Other neurodegenerative disorders like Lewy body dementia,
Parkinson’s dementia, and frontotemporal lobar degeneration (FTLD) also tend to cause deficits
in episodic memory but present much later in their progression.

        Working memory, often referred to as short-term memory, is the ability to maintain
information in one’s mind in a malleable state so that it might be manipulated in order to
complete goal-oriented behaviors. This type of “memory” is actually more of an executive
function, with the frontal lobes playing the primary role in its maintenance. Because of this,
disorders which impact working memory tend to impact executive functioning. For example,
working memory deficits are well-established in Autism Spectrum Disorder, Attention Deficit
Hyperactivity Disorder, Schizophrenia, and Fetal Alcohol Syndrome. Working memory
dysfunction is also possible in the later phases of neurodegenerative disorders such as AD,
Frontotemporal dementia, Parkinsons, and Lewy body dementia, or after a TBI. Treatment for
executive functioning depends upon the cause of the dysfunction.

        For instance, AD working memory deficits sometimes respond to cholinesterase inhibitors, while Parkinson’s dementia responds better to dopamine replacement therapy. Even normal age-related working memory deficits can be alleviated somewhat by “training” oneself to multitask. In one study, a basic video game called NeuroRacer that involved responding to signs and keeping a car centered on a winding road, was used and after training, participants between 60-85 years old were able to enhance their working memory and multitasking abilities. The most common test of working memory involves retention/recitation of a digit span, either as it was originally given or in reverse. Interestingly, the average digit span that can be retained in working memory is 7
numbers, plus or minus 2, which is why phone numbers consist of 7 digits!

        Procedural memory is nondeclarative, meaning that they can be accessed and operated
automatically. These types of memories, like the name suggests, involve acquisition and
retention of a procedure for cognitive or behavioral skills. An example of a procedural memory
would be how to play a musical instrument or driving a manual car. The anatomical structures
involved in formation and execution of procedural memories include the basal ganglia, the
cerebellum, and the supplementary motor cortex. Impairment of procedural memory is most
common with Parkinson’s disease, but is also found in cases of Huntington’s disease or
cerebellar degeneration syndromes. Treatment and clinical testing of procedural memory deficits
are uncommon, however, treating the motor symptoms of these disorders, such as through
dopamine replacement, has been shown to allow for relearning of previously acquired skills.

        Semantic memory refers to knowledge about words and their meaning, and knowledge
about things in the environment, their relationships, and their uses. Because of the broad amount
semantically cetegorized information, their storage in the brain is distributed throughout.
Considering a given concept might engage structures associated with motion, taste, olfaction,
color, or emotion. For example, neuroimaging shows that comprehension of an action-related
concept triggers activation of motor cortices. Furthermore, diseases that affect the motor system,
like Parkinson’s disease, tend to be accompanied by deficits in action verb comprehension. In
cases with widespread semantic knowledge loss, the anterior and inferolateral temporal lobes
tend to be dysfunctional, implicating these areas as the location of amodal (not associated with
one particular sense or action) semantic knowledge. Semantic information also seems to be
lateralized, with verbal semantic knowledge being stored in the left temporal lobe, and
structural/functional information on the right. The most common test for semantic memory is the
Boston Naming Task, involving naming basic drawings of various objects or naming objects
within a category.

        The most notable cause of severe semantic memory dysfunction is the semantic variant of
primary progressive aphasia (svPPA), a subtype of FTLD, with atrophy centralized in the
anterior left temporal pole. Neuropathology of svPPA frequently includes accumulation of TAR
DNA-binding protein 43, although further research has revealed numerous genetic risk factors
and associated protein biomarkers. AD is another common cause of semantic memory deficits
but symptoms tend to be less distinct than the episodic memory deficits. Treatment of AD-
induced semantic symptoms is the same as treatment of episodic memory symptoms for AD
patients. In the case of svPPA, however, there is interest in using transcranial direct current
stimulation (tDCS) to temporarily boost semantic processing. Post-stroke aphasia, another
potential cause of semantic memory loss, also responds to tDCS. Unfortunately, the results are
inconsistent and require further study.

        Before we conclude, it is worth mentioning that there is still much to learn about these
complex memory systems. These discrete systems are more interconnected than we may think.
Neuroimaging has shown that participants learning to predict the weather with undivided
attention engaged the medial temporal lobe and had a more flexible knowledge of the task.
Participants learning with divided attention engaged the basal ganglia, and had less flexible
knowledge of the task. The basal ganglia might “pick up the slack” when the preferred medial
temporal memory system is otherwise engaged. This same effect has also been observed in
lesion studies, drawing attention to the synergy and competition that might play a role in normal
memory function. Understanding these systems in a less rigid and more holistic way may be the
next frontier of memory research using stimulation of healthy networks to subserve the lost
function of damaged networks. Watch for an upcoming blog on how pulsed light waves
(photobiomodulation) might activate networks in neurodegenerative diseases.

Matthews, B. R. Memory Dysfunction [Internet]. Behavioral Neurology and Neuropsychiatry.
2015. Available from:
Brenowitz, W. D., Monsell, S. E., & Nelson, P. T. Hippocampal sclerosis of aging is a key
Alzheimer’s disease mimic: clinical-pathologic correlations and comparisons with both
Alzheimer’s disease and non-taupathic frontotemporal lobar degeneration. Journal of
Alzheimer’s Disease. 2014. Available from:
Tsapkini, K., Webster, K. T., Ficek, B. N., Desmond, J. E., Onyike, C. U., Rapp, B., Frangakis,
C. E., et al. Electrical brain stimulation in different variants of primary progressive aphasia: A
randomized clinical trial [Internet]. Alzheimer’s & Dementia: Translational Research & Clinical Interventions. 2018. Available from:
Kandel, E. R., Dudai, Y., & Mayford, M. R. The Molecular and Systems Biology of Memory
[Internet]. Cell. 2014. Available from:
Rabinovici, G. D., Stephens, M. L., & Possin, K. L. Executive Dysfunction [Internet].
Behavioral Neurology and Neuropsychiatry. 2015. Available from:
Anquera, J. A., Boccanfuso, J., Rintoul, J. L., Al-Hashimi, O., Faraji, F., Janowich, J., Kong, E.,
et al. Video game training enhances cognitive control in older adults [Internet]. Nature. 2013.
Available from:
Foerde, K. & Shohamy, D. The role of the basal ganglia in learning and memory: Insight from
Parkinson’s disease [Internet]. Neurobiology of learning and memory. 2011. Available from:

The French Paradox: Red Wine for a Healthy Mind?

Known since 1992, the French diet is high in saturated fats, a risk for coronary heart disease (CHD), yet they have less than half the CHD-related deaths compared to the US, Sweden, and the UK. High intake of wine, thought to be 57% of alcohol consumption in France, may contribute to this disproportionately low frequency of CHD representing the French paradox. However, heavy alcohol consumption is associated with increased risk of heart attack, arrhythmia, hypertension, and sudden death. This raises the question; How does wine consumption improve cardiovascular health?

Wine, particularly red wine, contains high levels of phenols. One phenol, resveratrol, may contain cardiovascular protectant properties. It inhibits oxidative stress caused by free radicals, preventing cell damage or death. Resveratrol appears to increase lifespan and promote healthy aging. Fruit flies, fish, and nematodes given resveratrol increase their lifespan significantly! In humans low to moderate amounts of wine consumption are associated with decreased cardiovascular- and cerebrovascular disease-related deaths.

Moderate consumption of wine is also associated with lower instances of Alzheimer’s disease (AD). Normally, proteasomes are responsible for degradation of damaged and aggregated proteins such as Aβ, but their activity is impaired in AD. Oxidative stress inactivates proteasomes, which can be prevented with resveratrol administration in disease-model cell cultures. Administration of resveratrol in vitro correlates to increased intracellular degradation of Aβ by proteasomes, suggesting that moderate wine consumption may decrease one’s likelihood of developing AD. Synthetic resveratrol supplements are new to the field and require further research.

One year of resveratrol supplementation (500-2000 mg per day) slowed decline in cognition and function compared to placebo. Yet other studies found no difference with supplementation over 52 weeks. Larger studies over a longer duration are needed. Pterostilbene, a synthetic resveratrol analog, has much higher oral bioavailability and blood-brain barrier permeability warranting further research. Resveratrol administration correlates with decreased central nervous system (CNS) deposition of Aβ, and increased brain shrinkage in AD patients as a product of reduced neuroinflammation.

Resveratrol benefits a variety of other physiological functions, too. It delays or prevents cell death in a variety of cell types, decreases atherosclerotic lesion formation, reduces risk for hypercholesterolemia, maintains glucose homeostasis in diabetes, and promotes tumor suppressor gene expression. In rat models of Lewis lung carcinoma, resveratrol decreases tumor size, weight, and metastasis, indicating a diverse range of effects on chemoprevention. It has powerful effects on energy metabolism. In mice, administration increased aerobic capacity as evidenced by increased running time and oxygen consumption in muscle fibers. Its effects on energy metabolism might also minimize damage from secondary spinal cord injuries. Further research in human models is needed to validate it as a therapeutic.

While resveratrol’s impacts on cognition and AD are inconclusive, it has potential to benefit health in a variety of other ways, which may justify a glass of red wine every so often. If you can’t drink wine, resveratrol is also present in a number of foods, including grapes, peanuts, soybeans, apples, and pomegranates. Red wines contain concentrations between 0.361-1.972 mg/L, meaning that one would have to drink many bottles of wine to achieve the hypothesized therapeutic dose (TD) of 1 gram per day. Even including resveratrol containing foods such as peanuts (0.03-0.14 μg/g) and apples (400 μg/kg) does not reach the TD.  However, these measurements only account for unbound resveratrol. Food and drinks containing pure resveratrol also contain molecular constituents and resveratrol glucosides which occur in higher concentrations and, in some cell culture and animal studies, show higher potency than resveratrol itself. These molecules may actually be the driving force behind the French Paradox, but focused research and clinical trials will be required to confirm this hypothesis.

There are also supplemental tablets derived from Japanese knotweed containing a therapeutic dose of concentrated resveratrol. Unfortunately, research has shown that these supplements are a less effective source of resveratrol as it’s bioavailability and absorption is enhanced by the food matrix present in its naturally occurring forms. Regardless, with so many beneficial impacts in the body and no serious adverse effects we could all stand to increase our resveratrol intake – whether it comes from a glass of red wine, a handful of peanuts, or a supplement. This week, go out and live like the French!

Renaud, S., & de Lorgeril, M. Wine, alcohol, platelets, and the French paradox for coronary heart disease [Internet]. Epidemiology. 1992. Available from:
Catalgol, B., Batirel, S., Taga, Y., & Kartal Ozer, N. Resveratrol: French paradox revisited [Internet]. Frontiers in Pharmacology. 2012. Available from: 
Marambaud, P., Zhao, H., & Davies, P. Resveratrol Promotes Clearance of Alzheimer’s Disease Amyloid-β Peptides [Internet]. Journal of Biological Chemistry. 2005. Available from:
Keller, J. N., Hanni, K. B., & Markesbery, W. R. Impaired Proteasome Function in Alzheimer’s Disease [Internet]. Journal of Neurochemistry. 2000. Available from:
Moussa, C., Hebron, M., Huang, X., Ahn, J., Rissman, R. A., Aisen, P. S., & Turner, R. S. Resveratrol regulates neuroinflammation and induces adaptive immunity in Alzheimer’s disease [Internet]. Journal of Neuroinflammation. 2017. Available from:
Meng, J., Chen, Y., Bi, F., Li, H., Chang, C., & Liu, W. Pterostilbene attenuates amyloid-β induced neurotoxicity with regulating PDE4A-CREB-BDNF pathway [Internet]. 2019. Available from:
Ungvari, Z., Orosz, Z., Rivera, A., Labinskyy, N., Xiangmin, Z., Olson, S., Podlutsky, A., & Csiszar. Resveratrol increases vascular oxidative stress resistance [Internet]. 2007. Available from:
Weiskirchen, S., & Weiskirchen, R. Resveratrol: How Much Wine Do You Have to Drink to Stay Healthy? [Internet]. 2016. Available from:

The Gut-Brain Axis: Part 3 of 3

       We recently introduced the gut-brain axis as a bidirectional communication loop. Our bodies control, yet are in part controlled, by the living microorganisms within our gut. An irregularity at either end of the gut-brain axis often leads to poorer health, so are there ways to ensure a healthy microbiome? Welcome to part 3!—The final chapter of our series where we discuss what we can do to ensure gut health!

       Diet is a key mediator of your microbiome. Foods high in fiber, changes in fat intake, and timing of meals all effect the microbiome components and its function. Humans consuming a Mediterranean diet (MD) boosted their microbiome diversity compared to their western diet (WD) counterparts. The MD consists of large amounts of plant-based foods and a higher proportion of monosaturated fats, rather than the WD which contains high amounts of saturated fats, animal proteins, and sugars. Diets high in grains, vegetables, beans, nuts, and the like appear to be healthiest for our gut microbiome.

       Fecal samples were analyzed from individuals with (Alzheimer’s disease) AD and those without to categorize metabolites associated with AD. Metabolites, or postbiotics, are byproducts given off by our gut microbes as they digest our food. A ranking of grouped foods was created based on their strength of association to AD. Interestingly, the healthiest food rankings not associated with AD approximately mirror the MD food pyramid, emphasizing the importance of a proper diet for microbiome and overall host health.

       The internal process regulating our sleep-awake cycle is called the circadian rhythm, making it natural for us to experience half of our 24-hour day active and feeding versus the other half resting and fasting. With the development of artificial lights, humans are no longer bound to feeding only during the light phase of the day. Emerging preclinical research suggests that our gut microbiome maintains a similar circadian rhythm to us, evoking the importance of eating patterns like frequency and timing of food intake. Night shift workers that consume their meals at night are at a 40%-60% increased risk of developing obesity and metabolic syndrome, indicating how important it is for our health to adhere to our circadian rhythm, which is largely dictated by the sun. Furthermore, adding light to the night cycle of mice results in metabolism disruption, with an increased body mass index (BMI) and insulin resistance compared to mice with a proper dark/light cycle, suggesting the importance of a consistent night of sleep with minimal disruption.

       Probiotics are living microorganisms that provide health benefits when consumed in adequate quantity. Although found naturally, like in yogurts and sauerkraut, they’re most often consumed as an over the counter (OTC) supplement not requiring FDA regulation. Prebiotics are additional OTC supplements taken with probiotics and contain plants and grains to support the probiotic strains growth and establishment in the gut. These supplements are filled with a variety of bacterial strains thought to be beneficial, like Lactobacillus, and Bifidobacterium. In humans, broad-spectrum probiotics attenuated stress-induced reductions in cognition, but had no effects in the absence of stress. Probiotics were also shown to reduce depressive symptoms in individuals with irritable bowel syndrome (IBS). Diabetic individuals taking probiotics improve their brain functioning and synaptic activity compared to diabetics not taking probiotics.

       Chronic ingestion of fermented milk with probiotics was associated with reduced task responsiveness in humans compared to those on control treatment. Other studies show no difference in microbiome compilation or cognition in individuals using pre- and probiotics compared to those not. Unfortunately, our current understanding of pre-and probiotics ranges is scarce indicating the need for further research identifying harmful and beneficial strains in
those that are healthy and diseased.

       Fermented foods and drinks like kimchi and kombucha are rich in probiotics. Kombucha, made by fermenting tea and sugar with live bacteria and yeast, originated in China around 220 B.C.. It’s worldwide popularity has recently increased with the understanding of how integral our microbiomes are for our health. Since 2017, kombucha and other probiotic drink sales increased by almost 40% and is currently considered the fastest growing product in the functional beverage market.

So does it work? 

      In animal studies the probiotic drink shows evidence of anti-tumor and anti-cancer properties, and can help to inhibit neurodegenerative diseases. Unfortunately, no controlled studies with human subjects have shown any evidence of these benefits indicating the need for regulated clinical trials. Yet, the consumer market would have you believe otherwise. Luckily, it’s not considered harmful if consumed by a healthy individual at 4oz. or less per day. However, it does contain small amounts of alcohol and is therefore not recommended for pregnant women.

       Smoking and drinking have historically been known to harm the lungs and heart, but it turns out the damage is more systemic than that. Smoking induced alterations of the microbiome resemble those of obesity and inflammatory bowel disease (IBD). The cessation of smoking reversed the microbiome changes indicating that kicking the habit could return your gut to better health. Alcohol reduces bacteria with anti inflammatory activity within the gut. Alcohol and smoking both negatively affect the microbiome.

       AD drugs that inhibit the acetylcholinesterase enzyme have negative effects on rat microbiomes demonstrating that some AD drug treatments may lead to a worsening of AD pathology long-term. Although current AD drugs temporarily relieve the symptoms associated with the disease they tend to lose efficacy rather quickly, generally in a span of a couple years. The use of pre- and probiotics in conjunction with AD treatments may prevent or correct this gut dysbiosis allowing the therapeutic effects to be exploited more completely. Drugs like antibiotics decrease microbial diversity and can allow for the overpopulation of bad microbes within the gut which may also be prevented by pre- and probiotics.

       Our lifestyle has great capacity in determining our gut microbial health, which in turn affects our comprehensive health. We have the ability to maintain or modify our regiments, staying or becoming healthier by choosing good habits, like eating a proper diet. Considering the gut microbiome has vast local and systemic effects, it’s possible the future will be filled with a large variety of probiotics used to treat most any ailment, but for now more research is needed. Identifying what the good and bad microbes are still needs clarification, in addition to what makes them such. Clinical trials with the determined good microbes as treatment may then be better established. Until then, keep your diet lean and regular, don’t smoke or drink, and get good sleep routinely! Until next time!

Angelucci, Francesco, et al. “Administration of Pre/Probiotics with Conventional Drug Treatment in Alzheimer’s Disease.” Neural Regeneration Research, vol. 15, no. 3, 2020, p. 448., doi:10.4103/1673-5374.266057.
Biedermann, Luc, et al. “Smoking Cessation Induces Profound Changes in the Composition of the Intestinal Microbiota in Humans.” PLoS ONE, vol. 8, no. 3, 2013, doi:10.1371/journal.pone.0059260.
Capurso, Gabriele, and Edith Lahner. “The Interaction between Smoking, Alcohol and the Gut Microbiome.” Best Practice & Research Clinical Gastroenterology, vol. 31, no. 5, 2017, pp. 579–588., doi:10.1016/j.bpg.2017.10.006.
Chen, Yang, and Rong Xu. “Context-Sensitive Network Analysis Identifies Food Metabolites Associated with Alzheimer’s Disease: an Exploratory Study.” BMC Medical Genomics, vol. 12, no. S1, 2019, doi:10.1186/s12920-018-0459-2.
Garcia-Mantrana, Izaskun, et al. “Shifts on Gut Microbiota Associated to Mediterranean Diet Adherence and Specific Dietary Intakes on General Adult Population.” Frontiers in Microbiology, vol. 9, 2018, doi:10.3389/fmicb.2018.00890.
Kaczmarek, Jennifer L, et al. “Complex Interactions of Circadian Rhythms, Eating Behaviors, and the Gastrointestinal Microbiota and Their Potential Impact on Health.” Nutrition Reviews, vol. 75, no. 9, 2017, pp. 673–682., doi:10.1093/nutrit/nux036.
Kapp, Julie M., and Walton Sumner. “Kombucha: a Systematic Review of the Empirical Evidence of Human Health Benefit.” Annals of Epidemiology, vol. 30, 2019, pp. 66–70., doi:10.1016/j.annepidem.2018.11.001.
Nagpal, Ravinder, et al. “Gut Microbiome-Mediterranean Diet Interactions in Improving Host Health.” F1000Research, vol. 8, 2019, p. 699., doi:10.12688/f1000research.18992.1.
Papalini, et al. “Stress Matters: a Double-Blind, Randomized Controlled Trial on the Effects of a Multispecies Probiotic on Neurocognition.” 2018, doi:10.1101/263673.
Tillisch, Kirsten, et al. “Consumption of Fermented Milk Product With Probiotic Modulates Brain Activity.” Gastroenterology, vol. 144, no. 7, 2013, doi:10.1053/j.gastro.2013.02.043

The Gut-Brain Axis: Part 2 of 3

       As we discussed last week, our microbiome has profound impacts outside of the digestive system including the central nervous system (CNS). The interaction within the Gut-Brain Axis is reciprocal; our brain communicates with our gut microbes via the enteric nervous system (ENS) consisting of over 100 million neurons responsible for modulation of intestinal contraction patterns, secretion of enzymes, and regulation of blood flow necessary for digestion. Through regulation (or dysregulation) of these functions the brain has a direct impact on the microbiome. Mice exposed to 1 hour of psychological stress for a week have irregular concentrations of microbes associated with intestinal disease. 

       When compared to mice not exposed to stress, the greatest change in microbial concentration was the loss of the bacteria Akkermansia muciniphila (roughly 1-4% of total microbiota) this loss was associated with increased insulin resistance, inflammatory responses, and metabolic endotoxemia.  Brain insulin receptors are concentrated in the hippocampus, a key structure for memory function.

       Insulin resistance is associated with an increased risk for Alzheimer’s disease (AD). Healthy insulin signaling aids in the reduction of neuroinflammatory responses in the ENS and brain. Thus, stress induces an unhealthy feed-back loop in the microbiome that acts back on the brain to cause insulin resistance, increased neuroinflammation and cognitive worsening.

     This feedback loop between the brain and microbiome highlights the importance of maintaining a balance of both mental health and gut health. Communication between the brain and gut biome occurs through three pathways in the nervous, endocrine, and immune systems. These pathways regulate gut motility, gut permeability, and intestinal hormone secretions that effect microbial gene expression.

        The first of these mechanisms – gut motility, is regulated, but not initiated, by innervation from the cranial vagus nerve to the ENS in the form of the migrating motor complex (MMC). The MMC is a distinct electromechanical pattern in intestinal smooth muscles present during fasting. Impaired MMC regularity, caused by disrupted sleep and mood, decreases intestinal movement allowing overgrowth of small bowel bacteria and lowering diversity in the distal gut.

     Second, the permeability of the intestinal barrier can be changed by stress causing a dysfunctional state known as “leaky gut” via changing epithelial cell permeability and the mucosal layer. In rats both acute and chronic stress increased leakiness of gut epithelial cells allowing microbes and their by-products into surrounding cells and the bloodstream where they caused inflammation all over the body. A “leaky gut” with an inflammatory immune response was also observed in mice after premature maternal separation and was reversed with antidepressant treatment. This result highlights the powerful role that the brain can have on the microbiome, and vice versa.

      Third, stress decreases secretion of mucus by goblet cells in the gut resulting in a less protective mucus layer increasing ulcer risk and impacting the microbiome, particularly A. muciniphila that lives in and feeds upon intestinal mucus metabolizing it into short chain fatty acids (SCFAs). These fatty acids aid glucose homeostasis, lipid metabolism, appetite regulation, serotonin synthesis, and even immune function. In a healthy gut A. muciniphila stimulates mucus production leading to a healthy gut, brain, and body.

      The microbes in our gut have binding sites for many of the molecules that our nervous, endocrine, and immune systems use to communicate. One example of this is serotonin, which can be released by enterochromaffin cells (ECCs) into the intestinal lumen where it acts upon Clostridiales, another gut microbe. In response to serotonin release, Clostridiales produce secondary bile acids and SCFAs that signal back to the ECC to upregulate serotonin signaling to the CNS through vagal/spinal circuits effecting mood regulation. Release of the “fight-or-flight” transmitter norepinephrine, increases virulent traits in microbes, as well as stimulating the growth of other strains of enteric pathogens. This may explain why strenuous life events that increase norepinephrine are associated with gastroenteritis and irritable bowel syndrome.

       It is clear that there are numerous interactions occurring bidirectionally within the gut- brain axis that impact the brain and the microbiome. Unfortunately, the interactions from the brain to the gut are not nearly as well studied as those in the other direction requiring further research to parse the specific ways that psychological distress might translate to intestinal dysfunction. Furthermore, there are several disorders, including AD, anxiety, depression, Parkinson’s, and even Autism Spectrum Disorder,  that may effect interactions in the gut-brain axis but very few studies are able to confirm the direction of causality, and even fewer studies do so in humans.  There is research on ways in which we can nurture a healthy gut microbiome for both gut and brain health
that we will address in the next blog. Join us next time for the final piece of the puzzle in part three of The Gut-Brain Axis!

The Brain-Gut Connection [Internet]. Johns Hopkins Medicine. 2019. Available from:
Martin, C. R., Osadchiy, V., Kalani, A., & Mayer, E. A. The Brain-Gut-Microbiome Axis
[Internet]. Cellular and Molecular Gastroenterology and Hepatology. 2018. Available from:
Aguilera, M., Vergara, P., & Martinez, V. Stress and antibiotics alter luminal and wall-adhered microbiota and enhance the local expression of visceral sensory-related systems in mice [Internet]. Neurogastroenterology & Motility. 2013. Available at:
Mayer, E. A., Tillisch, K., & Gupta, A. Gut/brain axis and the microbiota [Internet]. The Journal of Clinical Investigation. 2015. Available at:
Noble, E. E., Hsu, T. M., & Kanoski, S. E. Gut to Brain Dysbiosis: Mechanisms Linking
Western Diet Consumption, the Microbiome, and Cognitive Impairment [Internet]. Frontiers in
Behavioral Neuroscience. 2017. Available at:
Fujio-Vejar, S., Vasquez, Y., Morales, P., Magne, F., Vera-Wolf, P., Ugalde, J. A., Navarrete, P.,
& Gotteland, M. The Gut Microbiota of Healthy Chilean Subjects Reveals a High Abundance of the Phylum Verrucomicrobia [Internet]. Frontiers in Microbiology. 2017. Available at:
Tanaka, T., Kendrick, M. L., Zyromski, N. J., Meile, T., & Sarr, M. G. Vagal innervation
modulates motor pattern but not initiation of canine gastric migrating motor complex [Internet].
Neuroregulation and Motility. 2001. Available at:
Morrison, D. J., & Preston, T. Formation of short chain fatty acids by the gut microbiota and
their impact on human metabolism [Internet]. Gut Microbes. 2016. Available at:
Rhee, S. H., Pothoulakis, C., Mayer, E. A. Principles and clinical implications of the brain-gut-
enteric microbiota axis [Internet]. Nature Reviews Gastroenterology & Hepatology. 2009.
Available at:

The Gut-Brain Axis: Part 1 of 3

         We each have a unique and complex network of microbes living within our guts known as a microbiome. It is comprised of a dynamic ecosystem of viruses, fungi, and predominately bacteria. As humans, we have been evolving and diversifying in concert with our microbiomes for at least 15 million years, indicating a close bacteria-host mutualism. Colonization of your gut microbiome occurs during birth, is highly dynamic throughout infancy, and resembles adult microbiomes in approximately three years remaining stable thereafter. Several factors influence the microbiome, such as genetics, diet, metabolism, age, geography, stress, antibiotic treatment, probiotics, disease, and more. Microbes within the microbiome are responsible for extracting energy from the food we eat, vitamin biosynthesis, pathogen overgrowth protection, educating our immune system, and more.

     Alterations in the gut microbiome are associated with an array of metabolic and gastrointestinal diseases like irritable bowel syndrome (IBS) and insulin resistance, but recent research has found that other body regions are also affected. Your gut microbiome is important and key in regulating digestion, hormones, immunity, the brain and cognition. Due to this newly established relationship between the central nervous system (CNS) and our gut microbiomes a circular communication loop, often referred to as the gut-brain axis, has been established. The loop is bidirectional with disruption at one end of the axis often instigating a dysregulation in the other. Changes to the gut microbiome have recently been associated with neurodegenerative diseases like Parkinson’s disease, multiple sclerosis, and Alzheimer’s disease (AD).

       Recent studies performed in mice suggest that alterations in the gut microbiome contribute to amyloid plaque deposition in AD. AD mice treated with long-term broad-spectrum antibiotics (to significantly alter their microbiome population) result in less amyloid plaque deposition with higher circulating soluble amyloid levels compared to untreated AD mice. Analyses of the AD mouse microbiome revealed decreased microbial diversity in treated mice with reduced Firmicutes and Bifidobacterium bacteria, but increased Bacteroidetes bacteria compared to untreated mice. Additionally, although the balance of microbiome components changed, the total abundance of the population remained similar to pre-antibiotic treatment. These findings suggest that the gut microbiome diversity plays a role in regulating individual amyloid plaque development, or amyloidosis.

       Based on animal studies, diet and physical exercise also effect the gut microbiome resulting in further downstream effects on cognition. Mice consuming a high fat diet (HFD) compared to a normal diet (ND) restructure their gut microbiomes resulting in increased anxiety. Exercise was shown to alter the microbiomes of both groups to similar magnitudes regardless of diet. Although exercise slightly improved memory in HFD mice, it could not quell their increased anxiety, indicating that exercise cannot counteract all effects of a poor diet. Exercised ND mice show increased memory and learning and result in increased Firmicutes bacterial strains when compared to ND mice without exercise. Diets high in fat and exercise both have the ability to alter the gut microbiome and behavior, but independently.

       Mice with reduced microbiomes from birth result in modified development of two particular brain regions, the amygdala and hippocampus. Signaling between the amygdala and hippocampus modulates social behaviors and anxiety, and alterations in their development may lead to disrupted behaviors. Both regions enlarged in germ free (GF) mice, but total brain volume remained similar to normal germ (NG) mice. The amygdala appeared to be hyperactive in GF mice with an underactive hippocampus compared to NG mice. GF mice have an increased stress response compared to NG mice. This research indicates that an appropriately populated microbiome is necessary for normal brain development and neural communication and might prevent the development of mental illness like depression and anxiety.

      The brains of animals with modified or absent microbiomes display a variety of molecular differences, like varied expressions of neurotransmitters and their receptors when compared to
animals with unaltered microbiomes. Reductions in brain-derived neurotrophic factor (BDNF) gene expression occurs in GF mice compared to NG mice, primarily in the hippocampus. BDNF is important for neuronal survival and growth, and learning and memory. Inhibitory neurotransmitter effects were lower in the hippocampus and amygdala of mice that ingested L. rhamnosus bacteria as a probiotic compared to those untreated. These same mice display reduced anxiety- and depression-related behavior. This not only emphasizes that our microbiome effectsour cognition, but that we can purposefully manipulate it. If we can learn more about the gut-brain axis and determine which microbes are beneficial we could use them as viable treatments.

     It’s becoming more and more clear that our microbiomes greatly influence our bodies, including the brain, but what about the effects our brains may have on our microbiomes? Do we possess the ability to modify our microbiomes to serve our bodies better? Tune in next week for part two in the three part series that is: “The Gut-Brain Axis”!!

Bray, Natasha. “The Microbiota–Gut–Brain Axis.” Nature News, Nature Publishing Group, 17 June 2019,
Kang1, Silvia S, et al. “Diet and Exercise Orthogonally Alter the Gut Microbiome and Reveal Independent Associations with Anxiety and Cognition.” Molecular Neurodegeneration, BioMed Central, 13 Sept. 2014,
Luczynski, Pauline, et al. “Adult Microbiota‐Deficient Mice Have Distinct Dendritic Morphological Changes: Differential Effects in the Amygdala and Hippocampus.” Wiley Online Library, John Wiley & Sons, Ltd (10.1111), 8 July 2016,
Mayer, Emeran A., et al. “Gut/Brain Axis and the Microbiota.” The Journal of Clinical Investigation, American Society for Clinical Investigation, 2 Mar. 2015,
Sarkar, Amar, et al. “The Microbiome in Psychology and Cognitive Neuroscience.” Trends in Cognitive Sciences, U.S. National Library of Medicine, July 2018,
Vogt, Nicholas M., et al. “Gut Microbiome Alterations in Alzheimer's Disease.” Nature News, Nature Publishing Group, 19 Oct. 2017,