Neurodegenerative disease is an umbrella term for a range of progressive diseases and conditions that primarily affect neurons in the brain. Neurons, or nerve cells, are the fundamental units of the nervous system. Neurons do not divide, regenerate, or renew themselves, so if they are damaged or die, they are not replaced.

While some neurodegenerative diseases have genetic influences, many of the diseases are multifactorial, meaning they are not caused by a single factor but rather develop from a combination of several factors, such as genetics, environment, and lifestyle.

Research increasingly suggests that adopting a healthy lifestyle can help prevent neurodegenerative diseases. As new therapies and treatments emerge, the importance of understanding your risk and taking action is higher than ever.

Below, we discuss the top risk factors for neurodegenerative disease.

Risk Factors for Neurodegenerative Disease

While aging is the primary risk factor for most neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, other risk factors include sex, poor lifestyle habits, vascular conditions, and newly identified risk factors such as hearing loss.

1. Sex

Research suggests that there may be a physiological difference in how males and females develop neurodegenerative diseases. The pathology and mode of manifestation appear to differ between sexes. The prevalence of many neurodegenerative diseases is biased towards one sex or the other but varies between diseases.

For example, studies indicate that the female sex is highly at risk for developing Alzheimer’s disease, with approximately two-thirds of those living with Alzheimer’s being female. Females exhibit a faster rate of hippocampal atrophy and more neurofibrillary tangles as well as a higher rate of cognitive decline.

On the other hand, Parkinson’s disease is biased towards the male sex. Men are twice as likely to develop Parkinson’s disease and experience a faster rate of disease progression on average.

2. Poor Lifestyle Habits

Poor lifestyle habits, such as insufficient exercise, an unhealthy diet, and alcohol and tobacco usage, are believed to contribute to the development of neurodegenerative diseases. 

Nutrition appears to play a critical role in the pathogenesis, or the manner of disease development, and progression of neurodegenerative diseases. High-sugar, high-fat diets and high caloric intake influence the onset, severity, and duration of these diseases. In a study analyzing the impact of diet and nutrition on memory and cognitive impairment, data suggested that malnutrition and a low body mass index were associated with a higher development of dementia. Alcohol and tobacco addiction can also have an impact on neurodegenerative disease development.

Researchers are also investigating the relationship between brain function and the gut microbiome, or the community of bacteria, viruses, and other microbes in the gastrointestinal tract. Imbalances in the gut microbiome may contribute to the development of neurodegenerative diseases.

3. Vascular Conditions

The risk of developing several causes of dementia, such as vascular dementia and Alzheimer’s disease, is believed to be increased by several conditions that damage the heart and blood vessels. This concept is often referred to as the heart-brain connection and suggests that brain and heart health are closely linked. A healthy heart ensures that a sufficient amount of blood is pumped to the brain, while healthy blood vessels ensure the oxygen-rich blood reaches the brain.

Vascular conditions include stroke, heart disease, high blood pressure, diabetes, and high cholesterol.

4. Hearing Loss

Hearing loss is a rather surprising risk factor for neurodegenerative disease. In a study that tracked more than 600 adults for almost 12 years, researchers found that hearing loss correlated strongly with the development of dementia. Mild hearing loss doubled dementia risk, moderate hearing loss tripled the risk, and those with severe hearing impairment were five times more likely to develop dementia.

While the mechanism linking hearing loss to neurodegeneration is not yet clear, one contributing factor may be the social isolation that often accompanies those with hearing loss. Lack of social and mental engagement is connected with several neurobiological changes that correspond to faster cognitive decline.

Since the discovery of Alzheimer’s disease, many potential pathological mechanisms of the disease have been proposed and explored. The growing understanding of the pathogenesis of Alzheimer’s disease has given rise to many potential avenues for treating the disease. 

Neuropathological hallmarks of Alzheimer’s disease consist of positive lesions that include tau hyperphosphorylation and neurofibrillary tangles, beta-amyloid plaques, cerebral amyloid angiopathy, and glial responses, and negative lesions that include neuronal and synaptic loss. Most commonly, Alzheimer’s disease is characterized by beta-amyloid plaques and neurofibrillary tangles resulting from abnormal tau hyperphosphorylation.

Similar to how Aducanumab (Aduhelm) aims to target and reduce beta-amyloid plaques in the brain, future treatments may include tau-targeting therapies for Alzheimer’s disease.

Below, we explore tau pathology in Alzheimer’s disease, potential tau-targeting therapies, and tau’s role in the detection of Alzheimer’s disease.

Tau Pathology in Alzheimer’s Disease

Tau, a microtubule-associated protein, is normally located on the axon and plays an important role in the brain. Tau physiologically facilitates axonal transport by binding and stabilizing microtubules that help guide nutrients and molecules from the cell body to the axon and dendrites. Microtubules provide structural stability as well as a physical scaffold for transporting vesicles, mitochondria, and chemicals to the synaptic junction.

In those who develop Alzheimer’s disease, tau becomes altered and accumulates, forming neurofibrillary tangles within nerve cells up to 15 years before symptom onset. This alteration involves the translocation of tau to some somatodendritic compartments and the hyperphosphorylation, misfolding, and aggregation of tau. Neurofibrillary tangles are intraneuronal aggregates of this hyperphosphorylated, misfolded tau and block the neuron’s transport system, harming the synaptic communication between neurons.

Exploring Potential Tau-Targeting Therapies for Alzheimer’s

Tau is a newly understood component in the pathophysiological biomarker landscape, and potential concepts for tau-targeting therapies for Alzheimer’s are still being researched to inform future drug and therapy discoveries. 

It is believed that tau pathology better correlates with the decline of neurocognitive impairments that occur in Alzheimer’s disease compared to beta-amyloid lesions. The pattern of tau aggregation in the brain appears to mirror the progressive loss of function in brain regions observed in those with Alzheimer’s. This suggests that once the clinical onset of symptoms is evident, tau-targeting therapies for Alzheimer’s disease may be more effective than those that aim to clear or reduce beta-amyloid plaques.

Currently, the abnormal hyperphosphorylation of tau is the most compelling cause of the dysfunctional, toxic tau that ultimately results in progressive neurodegeneration. Potential approaches to blocking tau-mediated toxicity include the following:

• Directly inhibiting the pathological tau aggregation
• Inhibiting tau after translational modifications and before pathological tau aggregation
• Inhibiting tau propagation
• Stabilizing microtubules

The Role of Tau in the Detection of Alzheimer’s Disease

While the discovery of tau pathologies and growing understanding of their significance to the disease provides new and promising avenues for potential tau-targeting therapies for Alzheimer’s disease, they are challenging to use to detect Alzheimer’s. Similar to beta-amyloid plaques, tau can be detected with tau positron emission tomography brain imaging technology and can serve as a biomarker in cerebrospinal fluid analyses. However, they do not assess the impact of Alzheimer’s disease on an individual's ability to complete complex Activities of Daily Living (ADLs), meaning they are not ecologically valid. Furthermore, such diagnostic tools lack cost efficiency.

Regardless of the pathology present in someone with Alzheimer’s, their ability to complete ADLs will be impacted. Understanding at a highly granular level how an individual’s ADLs are changing is perhaps the most compelling method for Alzheimer’s disease diagnostics and monitoring.

Digital technology has made a mark on just about every part of our lives, and more recently, in healthcare. For years, we relied solely on arm cuffs to check blood pressure and thermometers to measure body temperature. Now, these measurements can be taken from wearable devices, such as smartwatches and smart rings. Similarly, neurologists have historically relied on invasive and expensive procedures, such as lumbar punctures and positron emission tomography scans, to indicate the presence of neurological diseases, but new digital approaches may enable a whole new paradigm for detecting, assessing, and monitoring these diseases.

The digitization of healthcare is beginning to revolutionize the way we prevent, diagnose, monitor, treat, and manage health conditions. Digital biomarkers can both enhance the health measurements we have today and pioneer new measurements tomorrow. They may enable healthcare to move from a reactive to a preventive approach.

What are digital biomarkers? Below we detail everything you need to know about digital biomarkers, from important terminology to their significance in healthcare.

Understanding What Digital Biomarkers Are

Before we jump into the significance of digital biomarkers, let’s introduce some important terminology to help you understand what digital biomarkers are.

The Significance of Digital Biomarkers

There is an ever-growing wealth of health data as more individuals embrace digital health technologies, like Fitbits, Apple Watches, and Oura rings, among many others. As healthcare continues to undergo its technological transformation, more health data from diverse populations becomes available.

Large quantities of data can be paired with strong analytical tools, such as machine learning and other forms of artificial intelligence, to track trends and patterns within individuals and across populations. Artificial intelligence can then build models that weigh large data sets of digital biomarkers to detect diseases and disorders. Similarly, tracking granular, intra-individual changes of health longitudinally can help determine an individual’s risk for developing a disease or disorder.

Premorbid functioning assessments are neuropsychological intelligence tests that aim to estimate the level of neurocognitive and memory function prior to some pathological event, such as neurological traumas like traumatic brain injury or the development of neurological diseases such as Alzheimer’s disease and Parkinson’s disease. The estimate is determined based on the assessments that are performed after the damage or pathological event has occurred. These assessments may also include demographic considerations such as education level and occupational history. 

Understanding the premorbid functioning of patients or clinical trial subjects can help determine whether or not a decline in neurocognitive performance has occurred following a pathological event as well as the degree of loss or impairment. Below we explore common premorbid functioning assessments, use cases of premorbid functioning assessments in clinical trials, and limitations of such assessments.

Common Premorbid Functioning Assessments

Three of the most common methods for estimating premorbid functioning are the Test of Premorbid Functioning (ToPF), the Wechsler Adult Intelligence Scale 4th Edition (WAIS-IV), and the National Adult Reading Test (NART). The ToPF is a 10-minute word reading test composed of a list of 70 words that have atypical grapheme-to-phoneme translations. The ToPF aims to estimate premorbid intellectual and memory abilities. Similarly, the NART consists of 50 words with atypical phenomic pronunciation which must be read aloud.

The WAIS-IV is considered to be a more advanced measure of intellectual and neurocognitive abilities. It is a 60- to 90-minute assessment composed of 10 core subtests and five supplemental subtests and can be administered via pencil and paper or on a computer. This assessment produces four index scores that represent core components of intelligence:

• Verbal Comprehension Index 
• Perceptual Reasoning Index
• Working Memory Index
• Processing Speed Index

Two overarching scores—Full Scale IQ and General Ability Index—can be derived from the assessment results.

Premorbid Functioning Assessments in Clinical Trials

Clinical trials that require clinical neuropsychological assessments often need to be able to compare obtained scores with an estimate of neurocognitive function and intelligence prior to a given pathological event. 

Premorbid functioning assessments are often used in clinical trials for analyzing neurocognitive health and/or intelligence as a dependent variable while altering independent variables, such as the use of drugs, therapies, and other medical interventions such as sleep, diet, and exercise. 

Examples of clinical trials that required premorbid functioning assessments to determine neurocognitive function and intelligence before neurological disease onset or brain damage include the following:

• Comparison of 3 Learning Methods to Improve Independent Activities of Daily Living (ADLs) in Alzheimer’s disease via the NART and Mini-Mental State Examination (MMSE)
• Exercise, Hypoxia, and Circulating Progenitor Cells In Traumatic Brain Injury Patients via WAIS-III and a battery of cognitive tests, including the Trail Making Test, Stroop Test, and verbal memory-RAVLT
• The Role of the Noradrenergic System in Nonmotor Symptoms of Parkinson’s disease via WAIS-IV and a battery of cognitive and neuropsychological assessments

Many clinical trials choose to include a large battery of many different neurocognitive and neuropsychological assessments, as they provide higher data granularity and can provide insight into a wider range of neurocognitive domains to better assess the changes or improvements in overall brain health and the impact on Activities of Daily Living (ADLs)  in a more robust manner. For these studies, the battery of tools must be sensitive to intra-individual changes in brain health, as these small changes in neurocognitive function may be indicative of the efficacy of the given independent variable.

Improving Premorbid Functioning Assessments

To fully understand premorbid functioning for highly complex neurological diseases and disorders, a full battery of neuropsychological assessments is needed. While integrating multiple assessments may be able to provide higher data granularity, it may not be feasible to do so on a large scale or in a remote setting, which is often required for clinical trials. Additionally, many premorbid functioning assessments, such as WAIS-IV, require significant time for administration, interpretation, and reporting, further limiting the feasibility of implementing multiple assessments in clinical trials.

Delivering a Full Neuropsychological Assessment Battery

Incorporating an integrated battery of neurological assessments to assess premorbid functioning can greatly improve clinical trial efficiency and provide a means to detect minute changes in neurocognitive function that may not otherwise be detected.

Establishing a benchmark for both cognitive and functional aspects of brain health has several important applications within the field of neurology, including the ability to provide earlier diagnoses for Alzheimer’s and other neurological diseases. Baseline testing also has critical applications for younger athletes. It helps establish an individual’s unique benchmark for brain function to better understand when they can return to sport, work, or school in the event of a concussion.

Below we detail the importance of baseline testing for younger patients and athletes, limitations of traditional baseline assessments and tools, and how to improve assessment of neurocognitive function.

Baseline Testing For Younger Patients and Athletes

Baseline testing for younger patients, whether it’s for neurological disease or concussions, allows doctors and their patients to make informed decisions. Baseline testing for athletes assesses brain function, such as verbal and visual memory, cognitive processing speed, and reaction time. Standard assessments used to detect signs of neurological diseases traditionally look primarily at a narrow range of neurocognitive functions, including memory, orientation, attention, visuospatial abilities, language, learning, and judgment. 

While cognitive impairments may be present after a head injury, concussion is a functional brain injury, meaning a scan or simple cognitive test is not sufficient to determine if both cognitive and functional impairments are no longer present before returning to sport. Similarly, many neurological diseases present with both cognitive and functional impairments, yet most testing methods place a narrow focus on specific, symptom-oriented cognition testing. While tools exist to assess functional impairments in neurological diseases, they lack the sensitivity and specificity required to detect small changes in functional brain health. 

Neurological Diseases

Baseline testing for younger patients, even as young as 30, is crucial for early diagnosis of a wide range of neurological diseases, such as Alzheimer’s disease, Parkinson’s disease, Lewy body dementia, and Huntington’s Disease. With the rapidly growing prevalence of Alzheimer’s and other neurological diseases, there is a clear need for earlier diagnosis to provide better patient outcomes. This is particularly important as new therapies and treatments emerge, as many neurological diseases are more treatable in the earlier, less severe stages. Early and regular testing of brain function can help detect small changes in brain function even before clinical onset, paving the way for the early detection of neurological diseases.

Traditional tools for detecting neurological disease only assess a few neurocognitive domains and thus only scratch the surface for understanding cognitive and functional brain health as it relates to a patient’s ability to complete Activities of Daily Living (ADLs). Take the Mini-Mental State Exam (MMSE) and Montreal Cognitive Assessment (MoCA), for example. Simple memory tests do not evoke a neurocognitive state representative of ADLs and thus may not be ecologically valid. The narrow nature of traditional assessments and the lack of data granularity may result in a missed opportunity for early detection. Such assessments may not have the specificity and data granularity to detect small cognitive or functional changes that could provide an early indication of the development of neurological disease.

While functional assessments, such as the Katz ADL and Lawton-Brody Instrumental ADL, can be used to assess functional impairments, they may not be sensitive to small, incremental, intra-individual changes.

Concussion and Traumatic Brain Injury 

Baseline testing for younger patients, particularly for athletes, is typically conducted by a healthcare provider to provide a pre-season assessment of an athlete’s brain function. This provides their unique baseline to support healthcare providers in interpreting scores of post-concussion tests. It can further be used to determine when an athlete has recovered from the concussion and is fit to return to sport. In other words, when an athlete’s post-concussion brain function scores align with their pre-season baseline scores, providers may clear them to return to sport with minimal risks. 

Baseline concussion tests, such as the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT), are typically computer-based assessment tools that take approximately 20 minutes to complete and must be interpreted by a healthcare professional. While such assessments may provide a good indication of overall cognitive function, they may not provide a comprehensive analysis of cognitive and functional abilities.

Providing More Comprehensive Understanding of Neurocognitive Function

To adequately understand neurocognitive function for neurological disease or post-concussion brain function, a more comprehensive approach that addresses an individual’s ability to complete complex ADLs can provide a significantly greater degree of insight into cognitive and functional aspects of brain health.

Vascular dementia is the second most common cause of dementia following Alzheimer’s disease. Although vascular dementia is recognized as common, experts believe it remains relatively underdiagnosed. In general, vascular dementia is caused by conditions that reduce blood flow to the brain, such as stroke, brain hemorrhages, or chronically damaged or narrowed blood vessels in the brain or at any location in the body. Insufficient blood flow can cause damage to brain cells, eventually killing them. 

After receiving a vascular dementia diagnosis, many individuals are told that it is similar to Alzheimer’s disease. While those diagnosed with mixed cortical or subcortical vascular dementia may experience a handful of symptoms that are comparable to those found in Alzheimer’s disease, there are both clinical and pathological differences. This confusion leads individuals to wonder, “What is mixed cortical and subcortical vascular dementia?” 

Below, we detail the key distinctions between mixed cortical and subcortical vascular dementia, other causes of vascular dementia, treatments, and how to understand cognitive and functional changes occurring in people living with vascular dementia.

Mixed Cortical and Subcortical Vascular Dementia

Mixed cortical and subcortical vascular dementia can be differentiated by the location of damage, and there are clinical and pathological differences as well. 

Mixed Cortical Vascular Dementia

Cortical dementia develops as a result of disorders that affect the cerebral cortex, the outermost layer of the brain. Cortical dementia typically yields a dementia signature consistent with symptoms of Alzheimer’s disease, meaning symptoms primarily involve a decline in cognitive abilities, such as memory. Mixed cortical vascular dementia is the combination of multiple dementias, including vascular dementia, that expresses the cortical dementia signature in addition to that of vascular dementia. 

In the most common form, the beta-amyloid plaques and neurofibrillary tangles associated with Alzheimer’s disease are present in addition to blood vessel changes associated with vascular dementia. According to the Alzheimer’s Society, mixed dementia accounts for at least 10% of dementia diagnoses. Symptoms of mixed cortical vascular dementia may include those of Alzheimer’s, those of vascular dementia, or a combination of the two.

Subcortical Vascular Dementia

Subcortical vascular dementia, also known as Binswanger’s disease, is caused by diseases of the small blood vessels that lie in the subcortex deep within the brain. The vessel walls become thick and narrow, resulting in reduced blood flow. 

Due to the location of the damage, symptoms associated with subcortical vascular dementia are predominantly functional impairments similar to those of Parkinson’s disease. While some cognitive impairments may be present, symptoms primarily involve challenges with function and movement, such as psychomotor slowness, poor balance, unsteady gait, and changes in speech, among others.

Other Causes of Vascular Dementia

There are several other causes of vascular dementia, including post-stroke dementia and single-infarct and multi-infarct dementia. The primary differentiation between vascular dementias lies in the causes of brain damage as well as the portion of the brain that is impacted.

Post-Stroke Dementia

A major stroke occurs when blood supply to a portion of the brain is suddenly and permanently cut off, providing insufficient blood flow to the brain. As a result, the brain does not receive enough oxygen, causing brain tissue to die. Depending on the severity of stroke and location of damage, the degree of vascular dementia symptoms can vary widely and may also include functional impairments in addition to cognitive impairments. Not all individuals who have had a stroke will develop vascular dementia; however, it is estimated that one-third of stroke survivors will experience a significant degree of cognitive impairment within the first months after the event.

Single-Infarct and Multi-Infarct Dementia

Single-infarct and multi-infarct dementia are caused by one or more smaller strokes, respectively. When medium or large blood vessels become blocked with a clot, blood supply may be cut off for several minutes, leading to an infarct, or small area of dead tissue, within the brain. Similar to post-stroke dementia, the range of symptoms varies depending on the location and severity of damage.

Treating Vascular Dementia

Currently, the treatment of vascular dementia relies heavily on managing health conditions and controlling risk factors that contribute to vascular dementia. Implementing lifestyle changes, such as participating in regular physical activity, eating a healthy diet, engaging in mental and social activities, and avoiding alcohol and smoking may help slow the progression of vascular dementia.

While there are currently no approved treatments for vascular dementia, emerging research investigates how molecular mechanisms, such as oxidative stress, neuroinflammation, neuronal apoptosis, and synaptic plasticity, may provide future treatment options. 

Individuals with mixed cortical vascular dementia involving beta-amyloid plaques may benefit from new Alzheimer’s drugs, such as lecanemab.

Understanding Cognitive and Functional Changes in Vascular Dementia

Regular assessments of both cognitive and functional abilities are critical for those diagnosed with vascular dementia to inform proper patient care and treatment. To do so, it is important to assess many neurocognitive domains and analyze highly granular data for the most detailed understanding of brain health.

Computerized cognitive assessment and care plan development services are critical for newly diagnosed dementia patients to receive safe and proper care for the state of their cognitive, mental, and physical health. As an initial tool, these services can develop a baseline for care and can help determine the proper living situations for dementia patients, whether that be with in-home caregivers or in assisted living facilities. The required level of caregiver involvement can also be determined through such tools.

More often than not, these services are utilized sporadically, largely due to the lack of cognitive assessment tools available for longitudinal assessment of neurocognitive health. Furthermore, most tools only assess either cognition or function, making the practicality of longitudinal assessments of neurocognitive health challenging. As the cognitive and functional abilities of diagnosed patients change over time, the ability to complete Activities of Daily Living (ADLs) will also change, potentially resulting in new care needs. To effectively update care plans with changing needs, the ability of patients to complete complex ADLs should be regularly assessed and tracked over time.

Below, we explore commonly recommended measures to be taken for assessing several domains of care planning, the benefits of computerized cognitive assessments for care plan development, and how new neurocognitive assessment tools can improve patient care.

Domains of Care Planning

According to the Alzheimer’s Association, there are nine domains of care planning that should be assessed to determine care plans for dementia patients. Two of the most influential care planning domains include cognition and function. Let’s take a look into common tools used to assess these two critical domains.

Cognition

The most common and widely recognized tools are the Mini-Mental State Exam (MMSE), the Montreal Cognitive Assessment (MoCA), the Mini-Cog, and the General Practitioner Assessment of Cognition (GPCOG). The Alzheimer’s Association recommends the use of the Mini-Cog, the GPCOG, and the short MoCA. All of the assessments aim to assess the presence of cognitive impairment and incorporate similar aspects, such as memory, visuospatial functioning (Clock Drawing Test), language, orientation, attention, and calculation.

These assessments are good indicators of overall cognitive function. However, they pose several challenges and limitations. From a feasibility perspective, these assessments require a caregiver or healthcare professional to administer, interpret, and report on the results, making regular assessments of cognitive function challenging while also introducing the risk of bias or human-to-human variability. However, this issue may be addressed with computerized cognitive assessment and care plan development. 

These surface-level assessments rely on specific, symptom-oriented testing that may not provide the level of data granularity and specificity needed to fully understand a patient’s cognitive function to provide proper personalized care.

Function

To assess a patient’s functional abilities, the Alzheimer’s Association recommends the use of the Katz ADL and Lawton-Brody Instrumental ADL (IADL). Both assessments aim to assess a patient’s ability to perform ADLs or tasks necessary to live independently in a community. The respective categories for the assessment of functional abilities are detailed below.

While both assessments may not be sensitive to small, incremental, intra-individual changes, the Lawton-Brody IADL is considered to assess ADLs of higher complexity compared to the Katz ADL. However, assessing a patient's ability to complete the eight types of activities through a demonstration of each task is very time-consuming and may lead to self-reporting or surrogate reporting methods. This can yield significant inaccuracies such as the overestimation or underestimation of functional abilities. 

Benefits of Computerized Cognitive Assessments for Care Plan Development

More recently, some caregivers and healthcare professionals have turned to computerized cognitive assessments for care plan development and, in some cases, computerized functional assessments. In general, computerized assessments have several advantages, including the following:

• Digital tools are often easier to deploy and don’t rely on caregivers to administer.
• Digital tools may provide better data quality from digital technologies.
• Digital tools can be more user-friendly.

While computerized versions of existing tools eliminate several of the challenges associated with the assessments detailed above, they still have similar limitations regarding the data granularity and specificity required to provide a comprehensive understanding of a patient’s cognitive and functional abilities to provide personalized patient care.

Is dementia hereditary? Many individuals with dementia and their family members express concern that they may pass down or inherit dementia, but the vast majority of dementias are not hereditary. In rare causes of dementia, such as familial Alzheimer’s disease, Huntington’s disease, and Familial Creutzfeldt-Jakob disease (CJD), there may be strong genetic links. However, such dementias account for a small fraction of dementia cases.

Below, we detail the hereditary nature of dementias with genetic influences and other factors for developing dementia.

When is Dementia Hereditary?

While inheriting dementia is rare, there are particular causes of dementia that have strong genetic influences. Let’s take a look into the hereditary nature of several dementias, including Alzheimer’s disease, Huntington’s disease, and Creutzfeldt-Jakob disease.

Alzheimer’s Disease

Researchers have found that there are specific genes and genetic mutations linked to each type of Alzheimer’s, though the presence of a genetic mutation does not necessarily indicate that an individual will develop Alzheimer’s disease. Alzheimer’s is typically categorized into two types:

1. Early-onset Alzheimer’s disease: Early-onset Alzheimer’s disease, or young-onset Alzheimer’s disease, is less common, accounting for less than 10% of Alzheimer’s cases, and refers to individuals under 65 who develop Alzheimer’s.
2. Late-onset Alzheimer’s disease: Late-onset Alzheimer’s disease is the most common form of Alzheimer’s and refers to individuals 65 and older who develop the disease.

Familial early-onset Alzheimer’s disease accounts for less than 1% of all cases of Alzheimer’s and is known to be linked to genetics. Research has revealed that inherited genetic mutations on three specific deterministic genes—amyloid precursor protein on chromosome 21, presenilin 1 on chromosome 14, and presenilin 2 on chromosome 1—can cause early-onset Alzheimer’s. Mutations in any of these three genes follow an autosomal dominant inheritance pattern, meaning that only a single copy of the defective gene will lead to the development of the disease. 

Risk genes for late-onset Alzheimer’s disease include genetic variants on the APOE gene on chromosome 19. The presence of one or two copies of APOE ε4 can indicate a higher risk of developing late-onset Alzheimer’s disease. However, it should be noted that genetics are not the only factor involved in the development of late-onset Alzheimer’s, meaning the presence of even two copies of APOE ε4 does not definitively indicate that an individual will develop Alzheimer’s.

Huntington’s Disease

Huntington’s disease is a rare autosomal dominant disorder that is caused by an inherited defect in a single gene. In particular, Huntington’s disease is the result of a mutation of the Huntingtin (HTT) gene on chromosome 4. The disease induces progressive degeneration of nerve cells in the brain and causes changes in the central area of the brain, resulting in a wide range of cognitive and functional impairments.

Familial Creutzfeldt-Jakob Disease

CJD is a prion disease that causes a type of dementia that progresses abnormally fast. It is generally categorized into three types:

1. Sporadic CJD accounts for approximately 85% of cases and develops spontaneously for no known reason.
2. Familial CJD accounts for roughly 15% of cases and is inherited in an autosomal dominant pattern.
3. Acquired CJR is rare, accounting for roughly 1% of all cases, and can be acquired through outside sources, such as medical procedures and meat or other cattle products infected with bovine encephalopathy.

While sporadic CJR and acquired CJR do not have any hereditary influences, familial CJR is caused by a mutation on the prion protein gene. The mutation causes the normal prion protein to change into the infectious form, which then continues to reproduce, causing severe dementia.

Other Factors Involved in Developing Dementia

Many causes of dementia are caused by environmental and lifestyle risk factors. While age is an obvious risk factor, other contributing factors include smoking, alcohol usage, insufficient physical activity, poor diet, a lack of mental and social engagement, and poor sleep. While many causes of dementia do not have direct hereditary influences, underlying risk factors that have hereditary influences may be at play. For example, a parent may pass down particular genes that increase the risk of high blood pressure, diabetes, and heart disease and may contribute to developing vascular dementia.

It is particularly important for all aging individuals, including those with risk factors, to regularly assess their neurocognitive health to understand when and if changes are occurring. Regular assessments of neurocognitive health are critical for those diagnosed with dementia to inform proper patient care and treatment.

Alzheimer’s disease and other causes of dementia impact more than 55 million people worldwide, with nearly 10 million new cases diagnosed every year. Alzheimer’s is the most common cause of dementia, a general term for memory loss and a decline in mental abilities that interfere with an individual’s ability to complete Activities of Daily Living (ADLs). Alzheimer’s disease accounts for roughly 60-80% of all dementia cases. Other causes of dementia include vascular dementia, Lewy body dementia, Parkinson’s disease dementia, and Huntington’s disease.

Alzheimer’s is characterized by a gradual decline in neurocognitive function, meaning there is a decline in both cognitive and functional aspects of brain health. Earlier stages of the disease may be more biased towards cognitive impairment with small magnitudes of functional impairment. In the later stages of the disease, both cognitive and functional impairments are typically present and can significantly impact an individual’s ability to complete ADLs. According to researchers, Alzheimer’s disease is not caused by a single factor, but rather develops from multiple factors, including genetics, lifestyle, and environment. 

Neuropathological hallmarks, or neuropathological changes that occur within the brain of an individual with Alzheimer’s disease, include beta-amyloid plaques, tau hyperphosphorylation, neurofibrillary tangles, and neuronal and synaptic loss.

Below, we detail the clinical and pathological aspects of common causes of dementia.

Common Causes of Dementia

While Alzheimer’s is the most common cause of dementia, there are other causes of dementia with varying pathologies. Let’s take a look into some of the other common causes of dementia.

Vascular Dementia

Vascular dementia is the second most common cause of dementia and is caused by conditions that reduce blood flow to the brain, such as brain hemorrhages and strokes. Insufficient blood flow can cause damage to brain cells, eventually killing them. However, brain changes linked to vascular dementia can also be caused by any condition that causes damage to blood vessels anywhere in the body. Individuals with vascular dementia experience a decline in thinking, memory, judgment, reasoning, planning, and other cognitive abilities. 

Symptoms of vascular dementia can vary significantly depending on the severity of blood vessel damage as well as the part of the brain that is impacted. Approximately 5-10% of dementia cases are attributed to vascular dementia alone. However, vascular dementia is more common as part of mixed dementia. Individuals with mixed dementia may experience changes to the brain associated with Alzheimer’s, vascular dementia, and Lewy body dementia, though the most common form of mixed dementia is Alzheimer’s and vascular dementia.

Lewy Body Dementia

Lewy body dementia, also referred to as dementia with Lewy bodies, is believed to be the third most common cause of dementia. 

Lewy body dementia is a progressive dementia and is clinically characterized by a decline in thinking, reasoning, and independent function. Individuals with Lewy body dementia may also experience visual hallucinations and changes in attention and alertness. Lewy bodies, which are protein deposits made of abnormal filaments composed of alpha-synuclein, develop in nerve cells within the regions of the brain responsible for memory, thinking, and motor control. While alpha-synuclein is found naturally in the brain, its function is not yet fully understood. An estimated 5% of individuals living with Lewy body dementia show evidence of Lewy body dementia alone; however, most people with Lewy body dementia also have Alzheimer’s disease pathology.

Many individuals with Lewy body dementia experience functional impairments, such as rigid muscles, hunched posture, tremors, and difficulty walking. 

Parkinson’s Disease Dementia

Parkinson’s disease dementia is a decline in cognitive function that develops in many individuals with Parkinson’s disease, a progressive nervous system disorder caused by genetics and environmental triggers that affects movement. Similar to how many individuals with Lewy body dementia and Alzheimer’s disease may develop functional impairments, many individuals with Parkinson’s disease develop cognitive impairments. 

According to the Alzheimer’s Association, a large study found that about three-quarters of people living with Parkinson’s for more than 10 years will develop dementia. As changes in the brain caused by Parkinson’s disease spread, cognitive abilities become impaired. The main neuropathological hallmark associated with Parkinson’s disease and Parkinson’s disease dementia is the presence of Lewy bodies. 

The overlap in symptoms between Lewy body dementia and Parkinson’s disease dementia suggests a link between the two diseases and their pathologies. The two diseases may be connected to the same underlying abnormalities in how the brain processes alpha-synuclein. 

Huntington’s Disease

Huntington’s disease is a rare hereditary disease that causes progressive degeneration of nerve cells in the brain. Huntington’s causes changes in the central area of the brain, resulting in a broad range of cognitive and functional impairments. Functional impairments may include involuntary writhing movements, slow or abnormal eye movements, impaired posture, gait, balance, and difficulty speaking, while cognitive impairments may include difficulty organizing and prioritizing tasks, lack of flexibility and impulse control, changes in mood, difficulty learning new things, and a slow processing speed.

Huntington’s disease is caused by a single defective gene of chromosome 4. As this genetic defect is dominant, only one copy of the gene will cause an individual to develop Huntington’s.

Although Alzheimer’s disease and Parkinson’s disease are both neurological disorders, a simplistic and high-level perception of the two diseases has notoriously given rise to frequent misdiagnoses.

Alzheimer’s disease is primarily perceived as causing a decline in memory, language, problem solving, and other cognitive abilities, while Parkinson’s is typically perceived as causing a decline in functional abilities, such as the presence of tremors, slowed movement, muscle stiffness, changes in speech, and loss of automatic movements.

Neuropathological hallmarks of Alzheimer’s include tau hyperphosphorylation, neurofibrillary tangles, beta-amyloid plaques, cerebral amyloid angiopathy, glial responses, and neuronal and synaptic loss. The main neuropathological changes associated with Parkinson’s include the progressive degeneration of dopaminergic neurons in the substantia nigra as well as the presence of Lewy bodies made of abnormal filaments composed of alpha-synuclein.

Alzheimer’s and Parkinson’s may present with overlapping symptoms, making clinical diagnosis challenging. The ability to quantifiably determine distinctions between the diseases is critical to diagnostic accuracy and consequently proper care and treatment of patients. 

Let’s explore the connection between Alzheimer’s and Parkinson’s disease, relevant research, and how diagnostic accuracy can be improved.

Exploring the Connection Between Alzheimer’s and Parkinson’s Disease

While the exact interplay of the clinical and pathological features between the two diseases is not fully established, there is a definite connection between Alzheimer’s and Parkinson’s disease. Similar cognitive and functional impairments are observable in both diseases. However, different proportions, varying manifestations along the disease continuums, and different rates of occurrence set the two apart.

Typically, Parkinson’s patients will show early signs of functional impairment and in later stages may experience cognitive impairment, such as memory issues, if they develop dementia. According to the National Parkinson’s Foundation, recent studies that followed Parkinson’s patients over the course of the disease estimate that 50-80% of people with the disease may eventually develop dementia. Conversely, earlier symptoms of Alzheimer’s patients may be more biased towards cognitive impairment, with functional impairments observed in later stages of the disease. 

Research Surrounding the Connection Between Alzheimer’s and Parkinson’s Disease

While the genetic connection between Alzheimer’s and Parkinson’s disease remains unclear, they share many clinical and pathological features. For example, research indicates the two diseases share similar cascades of neuronal reactions leading to progressive neurodegeneration due to the alpha-synuclein and tau toxicity in Parkinson’s and Alzheimer’s, respectively. The intersection of pathological changes that occur in both Alzheimer’s and Parkinson’s disease include the following:

• Activation of glycogen synthase kinase-3 beta
• Mitogen-activated protein kinases
• Cell cycle reentry
• Oxidative stress

Potential mechanisms linking the clinical and pathological similarities between Alzheimer’s and Parkinson’s include alpha-synuclein and Lewy pathology in Alzheimer’s. Studies revealed that up to 50% of patients with Alzheimer’s disease displayed extra aggregation of alpha-synuclein into Lewy bodies. According to statistical tests, no significant difference in levels of alpha-synuclein in cerebrospinal fluid was found between Alzheimer’s and Parkinson’s patients.

Another study analyzed an interaction network using data from genome-wide association studies. The research revealed that there may be significant interaction between Alzheimer’s and Parkinson’s susceptibility genes.

Improving Diagnostic Accuracy 

The misdiagnosis of Alzheimer’s and Parkinson’s disease is often due to the lack of data granularity and specificity present in neuropsychological tests combined with the misconception that Alzheimer’s is strictly linked to cognitive impairment and Parkinson’s is strictly linked to functional impairment.

Utilizing an assessment battery that measures both cognitive and functional aspects of brain health with highly granular, clinically significant data can not only provide a more accurate and timely diagnosis but can also help to identify patterns and traits associated with Alzheimer’s and Parkinson’s, furthering our understanding of the diseases and potentially informing future drug discoveries. 

Combined with artificial intelligence, digital biomarkers associated with cognitive and functional impairment may pave the way to identifying signatures for neurological diseases, including Alzheimer’s and Parkinson’s, while enabling earlier diagnosis and consequently, more effective treatment.

The Future of Diagnostic Devices

Altoida is radically changing the standard for measuring and monitoring brain health and neurological disease. Altoida is developing a Precision Neurology platform—built on over 20 years of cutting-edge scientific research—that will measure and analyze nearly 800 cognitive and functional digital biomarkers. Users complete a series of immersive augmented reality and digital motor activities in Altoida’s app-based device on their smartphones or tablets. The digital biomarker data from the activities provides powerful insights into brain health.