Introduced in 2014, primary age-related tauopathy, or PART, is a newer pathological designation that describes a pathology that is often observed in the brains of aged individuals. Numerous autopsy studies have demonstrated neurofibrillary tangles in the brains of aged individuals indistinguishable from tangles present in Alzheimer’s disease, in the absence of (or with minimal deposition of) beta-amyloid plaques.

Tauopathic changes in the brain are not unique to Alzheimer’s disease or primary age-related tauopathy. Consequently, relying on pathology may not be sufficient in reliably providing accurate diagnoses or providing accurate insight into the progression of neurological diseases, like Alzheimer’s disease.

Let’s take a closer look into primary age-related tauopathy, Alzheimer’s disease pathology, tau pathology in other neurological diseases, and how to place neurological disease patients precisely on a disease continuum.

Primary Age-Related Tauopathy

Most adult human brains have at least focal neuropathic changes. Neurofibrillary tangles in the brains of aged individuals are, for the most part, restricted to structures in the medial temporal lobe, basal forebrain, brain stem, and olfactory regions of the brain, meaning it does not typically progress extensively to neocortical regions.

Because of this restricted pathoanatomical pattern, the majority of individuals with primary age-related tauopathy do not progress to dementia. However, mild cognitive impairment is possible. Symptoms of primary age-related tauopathy typically range from normal to amnestic cognitive changes. A very small percentage of individuals with primary age-related tauopathy exhibit profound cognitive impairment. 

This variation in degrees of cognitive changes is hypothesized to be related to comorbid pathologies—research suggests that comorbid pathologies may contribute to cognitive impairment in patients with primary age-related tauopathy.

Alzheimer’s Disease Pathology

Neuropathology plays a crucial role in characterizing the pathogenesis of neurological diseases, such as Alzheimer’s disease. Neuropathological hallmarks of Alzheimer’s disease consist of positive and negative lesions. Positive lesions include tau hyperphosphorylation, neurofibrillary tangles, beta-amyloid plaques, cerebral amyloid angiopathy, and glial responses, while negative lesions include neuronal and synaptic loss. However, Alzheimer’s disease is most commonly characterized by beta-amyloid plaques and neurofibrillary tangles resulting from abnormal tau hyperphosphorylation.

Tau Pathology in Other Neurological Disorders

The presence of tau pathology is not unique to aged individuals nor is it unique to Alzheimer’s disease. Tau pathology is present across a breadth of neurological diseases and disorders, including Parkinson’s disease, frontotemporal dementia, Huntington’s disease, progressive supranuclear palsy, and chronic traumatic encephalopathy, among others.

Challenges with Current Alzheimer’s Diagnostic Tools

Because of the overlapping pathologies between primary age-related tauopathy, Alzheimer’s disease, and other neurological disorders, relying on pathology-based diagnostic tools, such as positron emission scans and cerebrospinal fluid analysis, may not be sufficient to distinguish between diseases and conditions with common pathologies and accurately diagnose specific neurological diseases. 

Moreover, protein levels and other neuropathological characteristics are not necessarily indicative of where a patient lies precisely on a disease continuum, particularly as pathologies can affect each patient uniquely. In other words, protein levels do not necessarily correlate to how the patient is doing or how the patient is functioning. While protein levels and degrees of atrophy may correlate with neurocognitive decline to some degree, it is not a 1:1 relationship.

A More Reliable Measure of Neurological Disease States

Understanding at a highly granular level how an individual’s Activities of Daily Living (ADLs) are changing is arguably the most compelling method for identifying, measuring, and monitoring neurocognitive changes in patients, and, consequently, diagnosing neurological diseases early and accurately. Quantitative, robust measurement of patients’ abilities to complete complex ADLs more accurately correlates with their neurocognitive function, allowing providers to know with higher certainty what phase of a neurological disease a patient is in.

The ability to place patients precisely on a disease continuum not only enables improved diagnostic accuracy but also can help providers identify proper therapeutic windows, analyze how disease pathology may be affecting patients uniquely, and provide insight into how patients may progress.

Alzheimer’s disease clinical research is rapidly shifting towards decentralized clinical trials, particularly as pharmaceutical companies and researchers continue to navigate new challenges stemming from the COVID-19 pandemic. As this shift progresses, the method for data collection, subject screening, and subject monitoring must align with the needs of this digital transformation.

The future of Alzheimer’s disease clinical research will likely rely heavily on digital adoptions—namely, digital biomarkers—to not only meet the need for decentralized and/or digitized clinical trials but also to provide new, more powerful insights via high-density data from sensors, wearables, and app-based technologies.

Below, we take a closer look at the utilization of digital biomarkers in clinical trials for Alzheimer’s disease.

Digital Biomarkers in Clinical Trials for Alzheimer’s Disease

Pharmaceutical companies face many challenges and barriers that contribute to expensive, prolonged, or failed Alzheimer’s disease clinical trials. Alzheimer’s disease drug trials have had a 99% failure rate—but this doesn’t necessarily mean all of the failed drugs were ineffective. Many experts believe that these failures stem largely from narrow-natured, unreliable data originating from non-ecologically valid assessment methods.

While an incredibly promising Alzheimer’s drug development pipeline is emerging, methods for subject screening (diagnostic tools) and subject monitoring (cognitive assessment tools) for clinical trials remain outdated and insufficient. The use of such tools can skyrocket subject recruitment costs, significantly prolong trial timelines, and contribute to clinical trial failures. 

Digital biomarkers have the power to transform the face of Alzheimer’s disease clinical trials, improving cost efficiency, speed, and success. Currently, there are two primary use cases for digital biomarkers in clinical trials for Alzheimer’s disease: 

1. Improving subject screening and selection 
2. Improving longitudinal monitoring of subjects 

Subject Screening and Selection

Screening and selecting the “right” patients for Alzheimer’s clinical trials is currently extremely cost-inefficient due to a lack of precision diagnosis. To determine subject eligibility, many Alzheimer’s drug clinical trials require expensive positron emission (PET) scans or invasive cerebrospinal fluid analyses as a part of the key inclusion criteria to establish protein levels, such as beta-amyloid and tau. With thousands of potential subjects, the screening and selection process can drive clinical trial expenses through the roof. 

Furthermore, with many Alzheimer’s trials, pharmaceutical companies need to understand where in the disease course each potential subject is, as their drug may only be effective at a specific phase or severity of the disease. Digital biomarkers, along with strong analytical tools, have the potential to be utilized to determine precisely where on the Alzheimer’s disease continuum a given patient lies. This method can serve as an initial tool to narrow down the subject pool, filtering out ineligible subjects before completing costly imaging or diagnostic procedures needed for key inclusion criteria. This will ensure pharmaceutical companies are selecting the right patients for their trials while greatly reducing costs associated with subject selection.

Longitudinal Monitoring of Trial Subjects

Promptly reaching the all-important go/no-go decision, particularly in early phase Alzheimer’s clinical trials, is an ongoing challenge for pharmaceutical companies. At the end of the day, the longer a trial runs, the more money spent. 

Understanding at a highly granular level how an individual’s Activities of Daily Living (ADLs) are changing is arguably the most compelling method for monitoring brain function in Alzheimer’s disease patients. However, longitudinally assessing the effect of Alzheimer’s disease-modifying drugs on trial subjects is currently largely dependent on costly and time-consuming imaging and outdated, unreliable cognitive assessment tools.

Confidently reaching a go/no-go decision as early as possible can help achieve proof of concept more rapidly and at lower costs—and digital biomarkers may very well be the means to achieve this. 

While traditional endpoints and traditional biomarkers are still fundamental and necessary for trials, digital endpoints and digital biomarkers in clinical trials provide pharmaceutical companies with the granular, supplemental, and contextual information needed to arrive at a go/no-go decision more confidently and efficiently.

Altoida: Improving and Accelerating Neurological Disease Drug Development

At Altoida, we are dedicated to providing a reliable, accessible, and affordable solution for Alzheimer’s disease clinical trials. Here is what sets us apart from traditional and digitized cognitive assessment tools:

Out of all of your organs, your brain requires the most energy. Because the brain is so rich in nerve cells and is responsible for just about every aspect of your daily functioning, it is the most energy-demanding organ in the entire body.

All 11 organ systems, including your central nervous system, need energy to function properly. This energy is provided by the food you eat. While most foods you eat will provide you with calories, or the basic building blocks of energy, not all calories are created equal. 

Over the years, researchers have established a strong understanding of the role of diet and nutrition in brain function and overall brain health. Diets high in saturated and trans fats have been linked to increased cognitive decline and an increased risk of dementia development. However, some specific foods and diets are associated with healthy cognitive aging and reduced dementia risk.

Let’s take a closer look at diets and foods that benefit the brain and how to monitor brain health when modifying your diet.

Foods That Benefit the Brain

While there are currently no proven strategies to prevent dementia, strong evidence from increasing amounts of research suggests that several aspects of healthy living, including eating a heart-healthy, anti-inflammatory diet, may significantly reduce the risk of developing dementia.

When it comes to diet and nutrition, what is good for your heart is good for your brain; research has revealed that foods that benefit the brain also promote heart health.

Here are some of the top foods that benefit the brain:

• Berries: Many berries contain compounds with anti-inflammatory and antioxidant properties that can prevent damage to the brain and mitigate or reduce inflammation. Additionally, berries are packed with various phytochemicals, including a class of polyphenols called flavonoids, the compounds that give berries their vibrant hues, that may improve memory. 
• Leafy greens: Leafy greens, like spinach, kale, lettuce, and collards, are abundant with brain-healthy nutrients such as folate, nitrate, phylloquinone, kaempferol, and lutein. Each of these nutrients has been positively and significantly associated with lower rates of cognitive decline. 
• Fatty fish: Fatty fish, like salmon, cod, tuna, and pollack, are fantastic sources of omega-3 fatty acids, a healthy unsaturated fat. Omega-3 fatty acids have been linked to lower levels of beta-amyloid, the protein responsible for forming damaging clumps in the brains of those with Alzheimer’s disease.
• Nuts: Nuts are a great source of protein, healthy fats, antioxidants, and vitamin E, which are beneficial for heart and brain health. Recently, walnuts have received special attention after a 2015 study linked walnut consumption to improved cognitive function.

Diets That Benefit the Brain

Three of the most studied and well-established diets for brain health and dementia prevention are the Mediterranean diet, Dietary Approaches to Stop Hypertension (DASH) diet, and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND).

These diets are relatively similar and typically are very low in sugar, processed carbohydrates, and saturated fats. They often include foods like leafy green vegetables, fatty fish, whole grains, poultry, legumes, nuts and seeds, berries, and healthy fats like olive oil. 

A 2019 systematic review of available literature surrounding these three diets found that:

• Higher adherence to the Mediterranean diet was associated with better cognitive scores in nine of 12 cross-sectional studies and 17 of 25 longitudinal studies.
• Higher adherence to the DASH diet was associated with better cognitive performance in one cross-sectional study and two of five longitudinal studies.
• Higher adherence to the MIND diet was associated with better cognitive performance in one cross-sectional study and two of three longitudinal studies.
• Higher adherence to the Mediterranean diet was associated with lower Alzheimer’s risk in one case-control study and six of eight longitudinal studies.
• Higher adherence to the DASH and MIND diets was associated with a lower Alzheimer’s risk in one longitudinal study.

Monitoring Brain Health While Modifying Diet

When modifying your diet and incorporating foods that benefit the brain to improve brain function, you or your provider will likely want to measure and quantify brain health over time to understand how dietary changes may be affecting it.

As Alzheimer’s disease progresses, patients are likely to have increased problems with speech and understanding language, which can make communication challenging for all parties involved. However, it’s very possible to continue to communicate with late-stage Alzheimer’s patients as the disease progresses—it simply requires patience, a new mindset, good listening skills, and different listening and speaking techniques. 

Continuing to listen, communicate, and connect is not only important for maintaining relationships with late-stage Alzheimer’s patients but also for understanding how their function is changing with time to effectively adjust treatment and care plans to meet their changing needs.

Below, we provide basic information on communicating with late-stage Alzheimer’s patients, including what sorts of changes in communication to expect, helpful tips, and how to monitor changes in function to enable the best care and quality of life possible for patients.

Understanding Changes in Communication Skills

First and foremost, it is important to understand that Alzheimer’s is a complex disease that affects each individual uniquely. It is essential to not make any assumptions regarding an Alzheimer’s patient’s ability to communicate. Communication with two patients in the late stages of Alzheimer’s disease may look completely different. Typically, in the late stages of Alzheimer’s disease, you may expect changes in communication abilities such as those detailed below:

• Difficulty finding the right word
• Substituting words or repeatedly using familiar words
• Repeating words, phrases, stories, or questions
• Speaking less often than before
• Describing familiar objects or gesturing towards them instead of referring to them by name
• Relying more on gestures than on speaking
• Difficulty organizing words, ideas, or phrases logically
• Reverting to speaking a native language
• More frequently losing a train of thought
• Mixing unrelated ideas or phrases

Helpful Tips for Communicating with Late-Stage Alzheimer’s Patients

To improve understanding for both the patient and yourself, there are several things you can do. Some patients may still have the ability and desire to communicate verbally, while others may not be able to communicate verbally but can show their thoughts, needs, and emotions in other ways. Keep in mind that it is okay to not know exactly what to say—what matters is your presence, comfort, and friendship. Below are some helpful tips for communicating with late-stage Alzheimer’s patients.

• Remove distractions: Prepare the room in which you will be communicating with the patient. Eliminate any background noise and visual distractions to make it easier for the patient to hear you and concentrate on the conversation.
• Identify yourself: Approach the individual from the front and identify yourself. Even if the patient’s family member, companion, caregiver, or support system is present, speak directly to the patient while maintaining eye contact. 
• Encourage non-verbal communication: Encourage and interpret non-verbal communication techniques, such as gestures, facial expressions, and body language. If it isn’t clear what they are trying to say, ask them to point or gesture. 
• Bring a comforting and respectful presence: Treat the patient with dignity and respect. Show a loving, warm, and matter-of-fact manner and be open to their concerns. Use appropriate physical contact, such as hand-holding, to offer reassurance and comfort. Speak calmly and slowly while making sure not to talk down to the patient. Be aware of the volume and tone of your voice and your body language, as the patient may rely heavily on non-verbal cues.
• Stay connected: Make eye contact and use appropriate physical contact, such as hand-holding, to offer reassurance and comfort. 
• Keep it simple: Try using simple, step-by-step instructions. Allow plenty of time for the patient to interpret and respond in their own way. If needed, repeat instructions and allow more time for a response. If this level of communication is not possible, try asking short and simple yes or no questions.
• Be creative: Try using senses of touch, sight, sound, smell, and taste as a way to communicate.
• Check for understanding: Be aware of how the patient is reacting verbally and non-verbally to what you are saying.

Monitoring Changes to Inform Proper Care Adjustments

Regularly interacting and communicating with late-stage Alzheimer’s patients can certainly give you a general understanding of how their brain function is changing over time to help inform proper adjustments to care and treatment. However, the ability to effectively update care plans in the most personalized manner possible requires routine testing of brain function to assess patients’ ability to complete Activities of Daily Living.

Epileptic seizures occur in patients with Alzheimer’s disease and Parkinson’s disease at a higher prevalence compared to healthy elderly individuals. An estimated 10% to 22% of individuals with Alzheimer’s disease will have at least one unprovoked seizure throughout the course of the disease. Additionally, the five-year epilepsy incidence rates among Medicare beneficiaries with Alzheimer’s and Parkinson’s disease are almost double the rate in those without a neurodegenerative diagnosis, with 4.5%, 4.5%, and 2.5% incidence rates in Alzheimer’s, Parkinson’s, and controls, respectively.

The prevalence of seizures and epilepsy in Alzheimer’s and Parkinson’s has resulted in research investigating the relationship between neurological diseases and seizures.

Let’s take a closer look into the connection between neurological diseases and seizures and the impact of seizures on Alzheimer’s and Parkinson’s disease patient care.

Relationship Between Neurological Diseases and Seizures

Because epileptic seizures can often be subtle, particularly with focal onset seizures, it is unclear precisely how common they are in neurological disease patients. However, the statistics, along with supporting research, suggest that both Alzheimer’s disease and Parkinson’s disease may be risk factors for seizures. 

Parkinson’s Disease as Risk Factors for Seizures and Epilepsy

A 2018 cohort study with a nested case-control analysis found that among 23,086 individuals with incident Parkinson’s disease and 92,343 individuals without Parkinson’s disease, 898 patients with incident epileptic seizures were identified. This suggests that incident Parkinson’s disease is associated with an increased risk of incident epileptic seizures.

The mechanism that triggers seizures in Parkinson’s disease is not yet clear. However, decreased cortical inhibition and increased cortical excitability have been reported in both Parkinson’s and epilepsy patients, meaning this hyperexcitable state may contribute to the onset of epileptiform activity in Parkinson’s disease patients.

Alzheimer’s Disease as Risk Factors for Seizures and Epilepsy

Typically, Alzheimer’s-related seizures occur in the later stages of Alzheimer's disease (≥6 years into the duration of the disease). Additionally, seizures are more likely to occur in those with early-onset Alzheimer’s, particularly when a familial presenilin I mutation is present. 

The precise mechanism that triggers seizures in Alzheimer’s disease patients is not yet clear. However, damage and structural changes in the brains of those with Alzheimer’s disease are likely to play a role in the increased seizure risk. Additionally, researchers have hypothesized that the buildup of amyloid and tau proteins in the brain may make neurons more excitable, as they are known to interfere with neuron-to-neuron communication. When nerve cells become hyper-excitable, they can behave uncontrollably, causing epileptic seizures.

Seizures and Alzheimer’s Disease Progression

When seizures occur in Alzheimer’s disease, they appear to be infrequent. However, seizures and epilepsy are known to affect cognitive function, causing cognitive impairment. This poses the question of how seizures affect the progression of Alzheimer’s disease.

In more advanced Alzheimer’s patients, the rate of seizures is known to be higher. This suggests that either:

1. Seizures may lead to increased rates of cognitive decline in Alzheimer’s patients, or
2. Seizures may be an epiphenomenon or a marker of more advanced Alzheimer’s stages.

Monitoring Changes in Neurocognitive Function to Inform Patient Care

There is a clear connection between neurological diseases and seizures, particularly between Alzheimer’s disease and seizures. While more research is needed to understand the true impact seizures may have on Alzheimer’s disease progression, it appears prolonged or recurrent seizures may lead to increased rates of cognitive decline.

Because of this, it is crucial to measure and monitor the neurocognitive function of patients who have experienced Alzheimer’s disease-related seizures, as this may impact patient treatment and care needs. Understanding at a detailed level how a patient’s function and ability to complete Activities of Daily Living are changing over time can help ensure patients’ care plans are effectively updated to provide the most effective care possible for each patient.

Brain health is an essential part of overall health and wellbeing, as it plays a vital role in our ability to live long, healthy, and full lives. Our brains are responsible for just about every aspect of our existence. They are fundamental to our ability to think, learn, communicate, problem-solve, make decisions, respond to our environments, balance, move, and so much more. Each physical and mental activity we perform is initiated and carried out by our brains.

While some changes to brain health are likely to occur as you age, it is important to understand what are considered “normal” changes to brain health and what may be signs for concern. Regularly assessing and monitoring brain health as you age is crucial to detecting cognitive impairment early before irreversible damage is done to the brain.

Below, we explain everything you need to know about brain health as you age, including what are considered normal and abnormal changes, how to keep your brain healthy, and how to monitor your brain health.

Understanding Brain Health As You Age

As you get older, changes occur in all parts of the body, including the brain. As you age, some changes to brain health are normal. Aging may cause minor changes to cognitive abilities, such as memory, planning, organizing, and decision-making. For example, as you get older, you may:

• Takes slightly longer than before to learn new things.
• Forget to pay a bill every once in a while.
• Experience minor decreases in your ability to pay attention.
• Be slower to find the right word to use.
• Have mild difficulty with multitasking.

However, changes that interfere with your ability to complete everyday activities, or Activities of Daily Living (ADLs), like finding your way home, driving, using your phone, shopping for groceries, or preparing a meal, are not normal. Cognitive impairment is not a normal part of aging and may be an early sign of Alzheimer’s disease or other causes of dementia. Examples of abnormal changes in brain health include:

• Repeatedly asking the same questions.
• Struggling to follow a list of instructions.
• Becoming lost in familiar places or areas.
• Difficulty understanding time or place.
• Misplacing or losing things often.

Seven Steps Toward Better Brain Health

Advancements in neuroscience and neurological disease research have provided us with information that may enable us to maintain or even improve brain health. In general, what is good for your heart is good for your brain, as cardiovascular conditions and risk factors are also risk factors for dementia. Here are seven steps you can take to take charge of your brain health:

1. Stop smoking: Tobacco use can cause harm to many of your organs, including your brain. Additionally, smoking increases your risk for heart disease—a well-known risk factor for dementia.
2. Control alcohol consumption: In addition to liver damage, excessive alcohol consumption can lead to several heart conditions, such as high blood pressure, while increasing the risk of stroke and heart attack, and consequently, the risk of developing dementia. Light-to-moderate alcohol consumption is no more than two drinks per day for men and no more than one drink per day for women.
3. Eat a healthy diet: Heart-healthy diets, such as Mediterranean diets, the DASH diet, and the MIND diet, can protect your heart and reduce the risk of developing dementia. These diets typically include an increased intake of fruits and vegetables, legumes, whole grains, nuts and seeds, and healthy fats such as olive oil, as well as a reduced intake of sugar, processed carbohydrates, and saturated fats.
4. Exercise daily for 30 to 60 minutes: Regular physical activity helps maintain a healthy weight and reduces the risk of cardiovascular conditions, including high blood pressure and high cholesterol.
5. Stimulate your mind: Mental and social engagement may promote and support brain health. Consider learning a new skill, doing puzzles, participating in a book club, crafting, cooking, gardening, or any other mental and social activities that stimulate your brain or keep you engaged with friends and family.
6. Get adequate sleep: Over the past several years, increasing amounts of research have indicated a strong connection between sleep and neurodegenerative diseases. For adults aged 18 to 60, the CDC recommends seven or more hours of sleep per night. For adults aged 61 to 64, seven to nine hours are recommended, and for adults aged 65 and older, seven to eight hours are recommended.
7. Minimize stress: Research suggests that chronic stress may be a risk factor for the development of Alzheimer’s disease. Find ways to manage and cope with stress, such as exercising, meditating, or reading a book.