Alzheimer’s disease

AD is a degenerative brain disease. Over time, the condition of the patient worsens. The changes in the brain can begin 20 or more years before the symptoms start to appear. An individual starts to experience noticeable changes with symptoms like memory loss or language problems only after years. These symptoms occur due to the damaged nerve cells responsible for different cognitive functions such as thinking, memory, and learning. Dementia due to AD is defined when a person’s ability to perform daily activities independently is affected by these symptoms.

In the end, the impairment is severe enough to prevent basic bodily functions; difficulty in speaking, swallowing and walking become prominent (Alzheimer’s association 2018).

Eventually, the patients are bed-ridden and require continuous help from caregivers.

AD is a multifactorial disorder having different risk factors intertwined with each other. These range from non-modifiable factors (age, genetics, etc.) to various modifiable factors (sedentary lifestyle, high blood cholesterol levels, etc.). Putative risk and protective factors that have been associated with the AD summarized in Table 1.

Table 1: Potential risk and protective factors associated with Alzheimer`s Disease

Risk Factors Protective Factors

Age >65 Years APOE-ε4 Hypertension Diabetes mellitus Cardiovascular disease

Smoking Depression Head injury

APOE-ε2 Cognitive activity Intellectual activity

Social activity Mediterranean diet

Changes in the brain associated with Alzheimer’s disease

Although the exact causes are still not fully clear, amyloid plaques and neurofibrillary tangles are considered the hallmarks of AD (Ballard et al. 2011). The amyloid plaques accumulate outside the neurons and tau proteins accumulate inside. While amyloid deposits may contribute to the neuronal death by blocking cell to cell signaling at synapses, tau pathology prevents the nutritional and other essential molecular transport (National Institutes of Health 2018). These two also activate microglia, immune system cells in the brain that clear the debris produced by the widespread dying cells, leading to chronic inflammation. The functional ability of the cells is compromised, and the brain loses the ability to mobilize the main source of energy, glucose.

Aβ fibrils, which represent one of the primary changes in AD, may deposit in the brain decades before the onset of dementia (Sperling et al. 2011). One recent study (Gordon et al. 2018) reported that amyloid deposition started 22 years, decreased glucose metabolism 18 years and atrophy of the brain 13 years before the anticipated start of the symptoms.

The human brain tries to compensate for the early changes made by these pathological processes. An individual usually maintains a normal or asymptomatic living during this period.

With time, the brain cannot keep up with the changes and subtle symptoms start to appear.

Furthermore, amyloid and tau pathology starts to spread to other parts of the brain (Alzheimer’s association 2019). The obvious symptoms due to cognitive decline then start to appear gradually as a result of marked neuronal damage.

Stages of Alzheimer's disease

Recent diagnostic criteria have described 3 stages of AD: preclinical AD, MCI due to AD and dementia due to AD (Albert et al. 2011, Jack Jr et al. 2011, McKhann et al. 2011, Sperling et al. 2011). While preclinical AD is asymptomatic, later stages are categorized by varying degrees of AD symptoms.

A. Preclinical Alzheimer's disease

The preclinical disease stage has become an important target for the prevention of progression to later, clinically manifest stages. Asymptomatic status, however, makes it difficult to identify individuals with preclinical AD. Researchers have been trying to use biomarkers as the earliest tools to predict AD conversion. Although few of them have been successful identifying some of the early pathological changes in the brain (Alzheimer’s association 2019), more studies are required to diagnose preclinical AD accurately before making them available for widespread use. It is important to mention that many individuals with the presence of AD biomarkers progress to MCI or dementia but not all (Bennett et al. 2006, Knopman et al. 2003).

B. MCI due to Alzheimer's disease

In MCI, individuals suffer from mild cognitive deterioration greater than anticipated for age.

The degree of impairment does not hamper daily activities but there is a noticeable change in the brain identified with AD biomarkers (Roberts & Knopman 2013). Usually, family members or friends who live in close contact with an individual with MCI also notice the decline. Around 15-20% of people aged 65 years and older suffer from MCI due to different causes (Roberts &

Knopman 2013). These MCI individuals are likely to develop AD especially if they are suffering from memory impairment compared to cognitively normal individuals (Kantarci et al.

2009, Mitchell & Shiri‐Feshki 2009). While one recent study with 2 years of follow-up found that 15% of MCI developed dementia (Petersen et al. 2018), one systemic review and meta-analysis with 5 or more years of follow-up period saw the percentage increased to 32% (Ward et al. 2013) and 38% (Mitchell & Shiri‐Feshki 2009) respectively.

C. Dementia due to Alzheimer's disease

In dementias, a patient suffers from obvious memory, thinking and behavioral abnormalities that hinder daily activities. AD patients also have similar characteristics besides evidence of AD pathology in the brain. These patients experience over the years worsening in multiple symptoms. The progression time from mild to moderate and then to severe symptoms varies from one person to another.

The mild stage does not usually fully incapacitate an individual from activities like driving, work or other regular recreational activities. Most people can function relatively independently but may need help in several activities.

Moderate stage is frequently the longest among the three dementia stages. Difficulty in communication and performing routine chores like dressing or bathing, incontinence at times, changes in personality or behavior along with agitation and suspiciousness are some of the common features during this stage.

In the severe dementia stage, an AD patient requires continuous monitoring from care providers for assistance with daily activities. The severity of AD in an individual is physically noticed during this stage. Damage in areas of the brain connected to mobility causes a patient to be bed-ridden which brings conditions such as clots, sepsis and skin infections triggering inflammatory reactions throughout the body and ultimately can trigger multi-organ failure. Drinking and eating is affected due to damaged brain areas related to swallowing, with the risk that food particles or water may enter the trachea and further to the lung. This can cause lung infection known as aspiration pneumonia which is one of the causes of death in AD patients.

Therapeutic approaches in AD A. Pharmacological approaches

There are no effective disease modifying medications available to halt or slow down the progression of AD. Galantamine, rivastigmine, memantine, donepezil are some of the common drugs approved, that are used to ease the symptoms or delay the severity of the symptoms.

Memantine is a N-Methyl-D-aspartate receptor antagonist while others are acetylcholinesterase inhibitors. The user response of these drugs is variable, and they have a restricted duration of action. Knowledge gaps about the underlying specific molecular pathology, a long trial period to observe the outcome of the drugs and issues regarding recruiting participants for clinical

trials are some of the factors that have so far made it difficult to find effective drugs (Alzheimer’s association 2019).

Due to the long duration of AD pathology development, current drug development research in AD is increasingly focused on testing treatments early in the preclinical or MCI stage, which may efficiently delay or halt AD progression and maintain cognition. For this reason, research on identifying accurate biomarkers and more accessible methods for measuring them during early disease stages has increased (Bloudek et al. 2011). These could detect the early stages as well as will be useful to measure the effectiveness of the drugs. Researchers have already started using biomarkers to assess AD brain changes after the administration of drugs in different trials (McKhann et al. 2012). Most trials are still mainly targeting amyloid pathology, although tau pathology is also targeted in several trials.

B. Non-pharmacological approaches

Lack of effective medication has emphasized the importance of non-pharmacological approaches to prevent or treat AD. Non-pharmacological trials have been conducted in both patients with AD dementia and cognitively unimpaired adults, to prevent or reduce cognitive impairment. In the case of AD dementia, the primary aim is to improve the overall quality of life. Additional aims are to decrease behavioral manifestations such as aggression, depression, sleeping disorder, agitation, apathy, etc. For instance, computerized programs are used for memory training, specialized lighting is used to prevent sleeping disorders and music is used as an instrument to stimulate recall. These methods, nevertheless, do not stop or slow down the undergoing pathological process that causes the symptoms.

One meta-analysis (Groot et al. 2016) and systematic reviews (Aguirre et al. 2013, Farina et al.

2014) of randomized controlled trials involving non-pharmacological approaches reported some beneficial effects to AD patients suffering from dementia. These randomized controlled trials were assessing different physical exercises (Farina et al. 2014, Groot et al. 2016) and cognitive stimulation (Aguirre et al. 2013). According to the meta-analysis, aerobic exercise and with a mixture of non-aerobic and aerobic exercise were beneficial for cognitive function.

A systematic review (Farina et al. 2014) reported a positive impact of exercise on cognitive function. Another systematic review (Aguirre et al. 2013) concluded that cognitive stimulation benefits cognitive function.

A systematic review (Butler et al. 2018b) of the benefit of over-the-counter supplements on cognitive function, MCI or AD found little to no effect. Another systematic review (Butler et al. 2018a) assessing cognitive training programs in cognitive impairment reported that the performance improved in individual domains such as executive function but there was a lack of evidence on the effect on preventing or delaying cognitive impairment or dementia.

Similarly, another systematic review (Brasure et al. 2018) lacked evidence while associating physical activity with the prevention of AD dementia progression or slowing down of cognitive decline.

More recent dementia prevention trials have been testing multi-domain lifestyle interventions that combine multiple non-pharmacological approaches to target several risk factors at the same time. The importance of this multi-domain approach has also been emphasized in the 2019 World Health Organization Guidelines on risk reduction of cognitive decline and dementia.

Biomarkers

Biological markers are naturally occurring molecules produced during physiological or pathological pathways indicating the risk, progression, and presence or absence of disease.

There are many biomarkers that are used for a variety of purposes. For instance, blood cholesterol level is used to determine the risk of cardiovascular diseases and C-reactive protein (CRP) is a well-known marker for inflammation. Regarding AD, abnormal tau and beta-amyloid levels (e.g. in the CSF or on PET scans) are the most investigated biomarkers, which are also used in clinical trials. Discovering an easy and inexpensive method for accurately measuring such biomarkers for example in blood could additionally help to diagnose AD or measure the disease progression.

Diagnosis criteria for Alzheimer's disease

In the clinic, AD is diagnosed based on a series of assessments including, but not limited to, family and medical history, informant interview about behavioral, cognitive changes and daily life activities, physical and cognitive tests, blood and imaging investigations. Medical professionals are usually successful in diagnosing dementia, but the cause can be difficult to detect. NIA/AA and International Working Group (IWG) have been developing a diagnostic framework to identify AD already in asymptomatic stages. Table 2 below summarizes recent updates from both these groups to compare the criteria. While it focuses on the biomarkers defining different pathological AD states of an individual, Table 3 is based on the NIA/AA 2018 criteria merging clinical features and biomarkers.

Table 2: Comparison of diagnostic criteria between research groups

Table 3: Syndromal cognitive staging combined with biomarkers, based on the most

Abbreviations: AD, Alzheimer disease; A: Aggregated Aβ or associated pathologic state (CSF Aβ42, or Aβ42/Aβ40 ratio or Amyloid PET), T: Aggregated tau (neurofibrillary tangles) or associated pathologic state (CSF phosphorylated tau or Tau PET), (N): Neurodegeneration or neuronal injury, MCI: mild cognitive impairment.