by Rosabel R. Young, M.D., M.S. Pharm, F.A.A.N., Q.M.E.
What is memory?
Memory in general terms is the function through which our brain stores and keeps track of our sensory experiences. Considering humans, these sensory modalities are vision, hearing, taste, smell, tactile sensation (the common five senses), as well as emotional and social experiences. We know that experiences involving multiple sensory modalities and higher emotional content (happiness, fear, depression, anxiety) are more likely to be remembered, while boring experiences and tasks are easily forgotten.
The hippocampus – a hidden area within the temporal lobes on both sides of the brain, is the memory encoding center of the brain. It performs the initial process of converting sensory input into immediate memories. We know that events associated with strong emotional content are more easily remembered. This is because the hippocampus works with the amygdala, the brain’s emotional center, to decide whether a memory will be stored or ignored. Emotional content is communicated from the amygdala as electrical signals called “sharp wave-ripples” to the hippocampus, modulated by Oxytocin. The hippocampus then consolidates different aspects of a selected experience (sights, sounds, emotions) into a (short-term) memory. It then transfers to many regions of the cerebral cortex converting it to long term memory, a process called “Synaptic Consolidation.” These hippocampal connections are enhanced when several sensory modalities are involved in a new experience to produce a memory. If you hear the word “rose” and also see a picture of a rose, you will remember it better. If you can also smell the rose, have it in your hand, feel its petals, leaves, and stem, you will remember it even better. If you received the rose from a handsome gentleman who proposed marriage, that will certainly add an emotional modality and will link thememory to the temporal, occipital, parietal, and frontal lobes of the brain. The more connections, the better.
In the diagram below, the hippocampus (green) and amygdala (red) are actually deep inside the brain, in the middle, but are shown below as if the (pink) surface of the brain were transparent:
The science of memory
Santiago Ramon y Cajal, a 19th century neurologist from Zaragoza, Spain, received the Nobel Prize in Physiology in 1906 for his landmark discoveries about brain anatomy and function. He studied brain slides and identified dendritic spines, axonal growth cones, and was the first to propose that nerve cells in the brain communicate with each other from axons to dendrites across synapses. Dendritic spines are responsible for the brain’s plasticity, which refers to the process of pruning and rebuilding connections between neurons throughout a person’s lifetime. Over the next several decades, further research showed that this process is fundamental to memory and other brain functions.
Ramon y Cajal’s drawings of dendritic spines and axons: (images from Museo Ramon y Cajal in Madrid, Spain)
We also learned that the mechanism of neuronal communication from axons to dendrites occurs in the form of electrical impulses that are produced by chemicals we call neurotransmitters. We hear a lot about dopamine, epinephrine, and acetylcholine, and most doctors are aware that medications for mood and memory can alter these chemicals in the brain. But neurochemicals that are not neurotransmitters are also critical for stabilizing the connections required for long term memory. Proteins such as KIBRA, protein kinase M-zeta, and other proteins perform supportive roles, as scaffolding support, transport mechanisms, and receptor regulation.
The most important of these is Apolipoprotein E (APoE). This protein is responsible for packaging and carrying cholesterol and other fats (lipids) through the bloodstream. In the brain, it facilitates cholesterol transport necessary to repair damaged neuron membranes and helps clear toxic debris, such as amyloid-beta plaques. It is highly concentrated in the hippocampus where it helps form new dendritic spines and plays a key role in repair of the synaptic connections that are so important in memory. The APoE protein is made from a gene on Chromosome 19 and has three variants, APoE2, APoE3, and APoE4. The APoE3 variant is the most common and carries an “average” Alzheimer’s risk. By comparison, APoE2 reduces the likelihood that you will get Alzheimer’s, and APoE4 increases that risk. Having two copies of APoE4 carries a 60% to 95% probability for the development of Alzheimer’s pathology; however, some individuals with even two copies of APoE4 will not develop clinically diagnosable dementia.
How do we identify these lucky people? Can we impart that protection on other types of dementia? In Alzheimer’s disease, the key issue is a person’s inability to rebuild neurons and support structures that are undergoing plasticity. The treatment approach has so far been to improve those repair mechanisms, because damage itself is part of necessary “dendritic synaptic pruning” that occurs as part of the normal aging process since birth and serves an important role in normal individuals. Research shows that persons with ADHD have inefficient synaptic pruning. As a result, their brains retain a higher number of synaptic connections into adulthood, and this may result in higher cognitive reserve in later age. Thus, having ADHD may be protective against dementia regardless of the cause.
There are other causes of dementia, including stroke, vascular disease, hypertension, diabetes, autoimmune diseases, Parkinson’s disease, certain viruses, etc. In these conditions, the disease process is causing more than the average rate of brain cell damage, but some of this can be prevented or controlled by targeting the primary damaging process (control of hypertension, diabetes, infection, inflammation, etc).
Treatment for Dementia:
Symptomatic Medications – improve memory temporarily but do not slow or reverse the pathology of dementia. Cholinesterase inhibitors increase acetylcholine by interfering with the enzyme that breaks down Acetylcholine, the brain chemical most directly involved in day to day memory. These agents do not help the brain repair itself, do not increase regeneration of dendritic spines, or reduce further damage. Drugs in this category include Donepezil (Aricept), Rivastigmine (Exelon), Galantamine (Razadyne, Zunveyl). In Alzheimer’s disease and vascular dementia, the accumulation of toxic proteins like amyloid-beta leads to excessive glutamate, a toxic substance that accelerates neuronal death in moderate to advanced dementia. this is why Memantine (Namenda), an NMDA receptor antagonist that reduces the toxic glutamate, is sometimes prescribed along with the Cholinesterase inhibitors. Glutamate is a stimulatory neurotransmitter that is normally present throughout the brain, but too much glutamate can overstimulate and kill brain cells. Glutamate also happens to be the common artificial salt in snacks and many packaged foods, often labeled “MSG” on the label.
Enhancing neuroplasticity – the brain’s ability to adapt, grow, and strengthen neural connections occurs are the individual brain cell body in its dendritic spines is called neuroplasticity. Drugs that may enhance neuroplasticity include psilocybin, a mushroom-derived psychedelic stimulant that has many side effects. Psilocybin itself cannot enter the brain, but is converted to the active agent, psilocin, which increases the rate of dendritic spine formation in the brain through activation of Serotonin 5-HT2A receptors. This process occurs primarily in regions where long term memory is consolidated, like the prefrontal cortex. However, like other psychedelics (LSD), it can cause transient confusion, hallucinations, and even psychosis.
BDNF (Brain-Derived Neurotrophic Factor) behaves like a neurotransmitter with axonal release to dendritic receptors across synapses. It is currently held as the key protein responsible for memory, learning, and neuroplasticity. It supports the survival of existing neurons and encourages growth of new synapses. Research shows a high-fat, low-carbohydrate (ketogenic) diet boosts production of ketones, increases cerebral blood flow, and raises BDNF levels. Vitamin D, a cholesterol-based vitamin, is directly tied to increased BDNF. A daily supplement of 2000 IU has been shown in studies to boost BDNF.
Omega-3 fatty acids found in fatty fish (like salmon and mackerel), walnuts, and chia seeds, are also believed enhance BDNF production. Oral supplementation with Docosahexaenoic Acid (DHA) has been shown to increase synaptic membrane BDNF synthesis and dendritic spines in the hippocampus. DHA is often prescribed with uridine; however, possible adverse effects include hyperglycemia, hypotension (low blood pressure), and insomnia.
Flavonoid-containing foods, including kale, spinach, red cabbage, and dark berries are also correlated with increased BDNF, and some studies suggest that persons on high flavonoid diets tend to have better cognitive performance into late adulthood.
Oxidative stress reduces BDNF, and thus Antioxidant foods, such as wild blueberries, dark grapes, and plums, which contain anthocyanins, help reduce oxidative stress and increase BDNF. Curcumin (the active compound in turmeric) increases BDNF primarily by acting as a potent antioxidant and anti-inflammatory agent. Green tea (especially Matcha) may have similar effects.
Hormones – The brain’s natural estrogen, specifically estradiol, has been shown to increase dendritic spine density in the hippocampus and supports memory consolidation. This is why dementia is more prevalent and more severe in men than in women of similar age. However, the relationship between estradiol and dementia depends on the timing of hormone therapy. Starting estradiol around the onset of menopause provides neuroprotective effects, while starting it at age 65 or older is associated with an increased risk of cognitive decline.
Reducing further brain damage
Inflammation is a step in the process of destruction in most types of dementia, including Alzheimer’s and vascular dementia. Observational studies indicate that certain anti-inflammatory drugs, such as naproxen, sulindac, and indomethacin, decrease autoimmune damage in the brain and can lower the risk of dementia in later life. Diets that reduce inflammatory stress can also be helpful, including pescatarian, vegetarian or vegan diets, and low-carbohydrate diets, including the ketogenic diet. The goal is to reduce pro-inflammatory foods, including refined carbohydrates (sugar), trans fats, and processed meats.
Depression and anxiety are known to accelerate cognitive decline in patients with mild cognitive impairment (MCI) or early-stage Alzheimer’s. Thus, it is important to treat these psychological symptoms right away, with psychotherapy and/ or medications.
In addition, certain antidepressants have specific effects on brain chemistry:
- Selective Serotonin Reuptake Inhibitors (fluoxetine, sertraline, paroxetine) increase BDNF brain levels in experimental animals.
- Bupropion (Wellbutrin), considered an atypical antidepressant, increases BDNF levels and also reduces inflammation in patients with depression.
- Serotonin-Norepinephrine Reuptake Inhibitors (venlafaxine, duloxetine) appear to stimulate BDNF expression but not actual brain BDNF levels.
- Tricyclic antidepressants (imipramine, amitriptyline) are older medications with well-documented chemical effects, including enhancing BDNF expression at BDNF receptors.
While these drugs primarily target neurochemical transport proteins in the brain, other drugs used in conjunction with antidepressants, such as aripiprazole (Abilify), act as direct 5-HT2A receptor antagonists and can impair memory. Blocking activity at 5-HT2A receptors in the cortex and hippocampus disrupts memory consolidation from sensory inputs. Patients may experience confusion, memory loss, and persistent cognitive slowing – symptoms that may be misdiagnosed as worsening depresion, misleading the doctor into raising the dose of the offending drug.
Sleep And Behavioral Modifications
Brain health and synaptic plasticity are also influenced by sleep and behavioral modifications. Restorative sleep is strongly linked to a reduced risk of dementia, specifically slow-wave sleep (Stages N3-N4) and REM sleep. These sleep stages play a vital role in clearing out toxic proteins, supporting regeneration of dendritic spines, and thus helping the brain repair itself. It is important to get sufficient restorative sleep, especially after a head injury.
Oxygen and Aerobic Exercise – Regular physical activity increases cerebral blood flow because it stimulates heart rate and breathing. Exercise also stimulates the release of growth factors that support neuroplasticity, and studies show increased brain levels of BDNF after aerobic exercise. Exercising in a high-oxygen area with lots of trees is more conducive to brain health than exercising in a stuffy, crowded gym. So put away that checkbook and head outdoors!
Conversely, smoking significantly increases the risk of developing dementia and Alzheimer’s disease. Current smokers are 30% to 50% more likely to develop cognitive decline compared to non-smokers.
Neuroplasticity is also enhanced by learning new skills that provide mental stimulation. This includes new motor skills, as well as new sensory, auditory and visual experiences. Taking up a new musical instrument, painting, drawing, pottery, and other artwork, can stimulate several senses and also engages physical dexterity. Reading and writing to recoup and analyze new experiences helps consolidate the new memories.
Consider learning to play a musical instrument – even without lessons – because teaching yourself will call up old memories that help build associated brain connections better than any teacher could! Think of a popular song you liked when you were in high school, or the song you heard when you met your wife (or first girlfriend).
Think of something new and different to do every single day. It can be as silly as writing or drawing with your left hand if you’ve always been right handed. If it feels difficult, it’s making your brain work. But don’t try anything dangerous, like driving blindfolded!
Experience Reinforcement
If you just read a book or an article, find pictures on the subject, or better yet, draw pictures yourself of the images you created in your mind as you are reading, look up more information about the topic, and keep the memory growing. Subsequent experiences like studying a textbook chapter again or going back to the place where an experience occurred, improve those long term memories because “experience reinforcement” builds new connections between axons and dendrites and makes that memory more permanent. Connecting new memories with old memories is critical if you are a caregiver of someone who has been diagnosed with dementia regardless of the cause. Persons with dementia begin to ‘reminisce’ and seem to have preserved memories for old events in their lives, but cannot remember recent events. Imagine the brain like an onion, whose outer layers easily dry up and fall away, while the deep layers are still juicy, alive and thriving. As dementia progresses, the regression is apparent, with only the earliest of a person’s memories being remembered in the terminal stages.
Activities that link new memories with old memories may help delay this progression. When looking at an old photograph album, for example, review that topic longitudinally through time as they experienced it, not just “then and now” but through the lifetime of the person with as many pictures, movies, audio recordings, and in person visits as possible.
Extensive research shows that reconnecting with old friends and family is a highly effective way to protect brain health. Positive social interactions and support networks can build cognitive reserve, prevent cognitive decline, and delay the onset of dementia by as much as five years.
Reduce stress
Have you ever thought or been told, “It’s just stress” ? Well, it’s not “just stress” – Stress is an important contributor to cognitive decline. Studies show that persons with a history of PTSD, depression, anxiety, or “life stress” have almost twice the risk of dementia. This is related to higher steroid levels in the brain, and steroids damage the hippocampus and other structures involved in memory function.
It’s impossible to avoid stress totally, but make it a habit to review and discuss both positive and negative aspects of each day with someone close to you, or at least write them down. When you come home from work, tell a family member, friend or neighbor about your day, including your positive and negative experiences. If you have children – encourage them to do the same, even if they are now adults. It’s never too late. The good news is that memory storage is not a fixed recording, but a flexible process that can be updated during retrieval via the same neuroanatomical pathways involved in the initial phase of synaptic memory encoding.
Associating a negative experience with something positive, such as a supportive family member or neighbor, or a helpful video, book or magazine article, reduces the stress of that memory, and also enhances learning by introducing a new perspective from others. Memories created and recalled in social settings, where interactions, conversations, and shared experiences influence your individual recollections, add a higher level of memory encoding and consolidation called semantic memory – memories about the meaning of the facts that you recall. This is one of the higher functions lost in Alzheimer’s disease, where it is most important to continue to engage in intellectually challenging conversations and activities with other people.
CONCLUSIONS:
Here we are, 120 years after Santiago Ramon y Cajal identified dendritic spines, axonal growth cones, and proposed that nerve cells in the brain communicate with each other from axons to dendrites across synapses. In those 120 years, our knowledge of these key components of memory and cognition has exploded with advances in neurochemistry, brain mapping, and genetics. But we still don’t have a cure for Alzheimer’s disease, and even the known treatable and preventable dementias are beyond our reach once symptoms have already developed.
If you or a family member or friend is having early signs of dementia or “mild cognitive impairment,” encourage them to have testing by a neurologist and consider trying the dietary changes and activities that I have discussed in this summary.