Alzheimer’s

Overview

Alzheimer’s disease (AD) is an aging-related neurodegenerative disorder and is one of the most common causes of dementia in older age group people. Dementia is a clinical condition characterized by a steady loss of mental function. The number of people suffering from AD has been rising exponentially in recent years. This poses a potential burden on quality of life and finance. Most of the people who have Alzheimer’s are around 70-80 years old. There is no specific gender predilection noted. In the U.S., 1 out of every 9 individuals above the age of 65 years has Alzheimer’s disease. Globally, around 35 million people are living with dementia. Dr. Alois Alzheimer first described Alzheimer’s disease (AD).

From mild symptoms, AD progress to memory loss and severe dementia. Patients with Alzheimer’s may show loss of intellectual coordination skills, language difficulties, behavioral disturbances like hallucinations, depression, agitation, etc. In severe cases, patients may find difficulty in performing daily activities like dressing, eating, driving, shopping, etc. In Alzheimer’s disease, brain cells undergo degeneration and die, leading to a gradual loss of memory.

There are multiple risk factors and causes for Alzheimer’s, with age as the most significant risk factor. Genetics and familial tendency play a substantial role in developing AD. With increasing age, the risk of developing Alzheimer’s disease also increases exponentially.

Alzheimer’s disease can be categorized into early onset (<60-65 years old) and late onset (>60-65 years) forms. A late-onset Alzheimer’s disease has a more genetic influence, and about two-thirds of the cases have a familial tendency (heritable). Most of the early onset cases usually do not have a positive family history. Lifestyle and environmental factors also play a considerable role in developing AD.

There are many management options to influence patients with AD positively. However, there is no complete cure yet. Therapies targeting lifestyle and general brain health can help in leading a decently good life. However, it is important to identify changes associated with AD at an early stage and seek proper medical advice and care.

Causes

Alzheimer’s is a multi-factorial disease affecting the function of the brain. AD results due to abnormal deposition of amyloid material (protein) in the brain cells leading to their degeneration and death. Genetics and familial tendency also play an important role.

Though the exact etiology is unknown, Alzheimer’s is known to be caused by both genetic and non-genetic factors.

Genetic Factors

  • Mutations in genes like PSEN1 (Presenilin 1), PSEN2 (Presenilin 2) and APP (Amyloid Precursor Protein) can lead to Alzheimer’s diseases
  • A microtubule-associated protein, tau, helps in neuronal microtubules stabilization. Mutations in tau gene are also responsible for AD
  • Various genes are associated with late-onset Alzheimer’s disease and they include COL25A1, CLSTN1, APOE, APBB1, LRP1, etc.
  • There is an increased relative lifetime risk in people who have first degree relatives with Alzheimer’s. Genetic counseling in such patients can be of help.
  • Early-onset Alzheimer’s is usually inherited as an autosomal dominant disorder.
  • In Down’s syndrome cases who live beyond 30 years, there is an increased risk of developing AD

Non-genetic / Environmental factors

  • Other causative factors include age, middle-age uncontrollable hypertension, hyperlipidemia, uncontrolled diabetes mellitus, improper dietary habits etc., can lead to the development of AD.

Symptoms

Symptoms of AD are usually progressive and worsen as the disease progresses. The symptoms are usually related to cognitive abilities, however, non-cognitive symptoms such as motor and behavioral abnormalities are also noted. It usually starts with a mild decline in the memory, ability to do daily activities, and forgetfulness in executive function. The symptoms and the rate of progression may vary from person to person.

Based on clinical symptoms and chronicity, AD is categorized into three phases. They are ‘forgetfulness phase,’ ‘confusional phase,’ and ‘dementia phase.’

1) Initial Stages

Most of the AD cases present with a pre-clinical phase where the pathological changes start, but the patients would not manifest any symptoms. After an extended pre-clinical period, cognitive symptoms begin to show. Initially, the short-term memory will be affected. Later visuoconstructional changes might be observed. To a lesser degree, implicit memory, headache, working memory, and long-term declarative memory are affected. At early stages, patients with AD may find it difficult in handling complicated tasks, planning, and organizational skills, problem-solving capacities, judgment, etc. They may need assistance in performing financial transaction and house chores.

The initial stage of AD is ‘forgetfulness phase’. Short-term memory loss in AD patients can be identified by things like frequently misplacing things, repetition of statements or questions, forgetting names of familiar persons. They may find difficulty in orienting to time and reaching destinations. They may lose the capability of estimating speed and time, making driving a difficulty for them. In an early AD, language impairment symptoms include decreased verbal fluency, difficulty in finding words, hesitant to speak, etc. Slight behavioral changes like depression are seen in some cases.

2) Moderate and advanced stages

Patients in these stages show severe functional impairment and diminished cognitive abilities. This stage is also referred to ‘confusional phase.’ As stage progresses, they show increased dependence on others to perform daily activities. Except for few cases with moderate AD, patients at these stages find it challenging to engage themselves in community affairs. They tend to forget newly learned things, very fast. However, old memories remain largely unaffected. Patients exhibit disorientation. Moderate AD patients can still perform simple household tasks, but they require assistance while performing complicated tasks. Patients also show the behavior of denial. They also show loss of interest in surroundings and news.

In advanced stages, or ‘phase of dementia,’  individuals may find it difficult in identifying their own family members. Logical reasoning deteriorates significantly in this stage. Advanced cases may show behavioral symptoms like hallucinations, delusions, misidentifications, etc. Irritability, agitations, anxiety, psychosis, disrupted sleep cycle, physical or verbal aggression, temper tantrums, can be seen in severe AD cases. Poor concentration and minimal dysphasia are usually noted.

In advanced cases, patients become entirely dependent on nursing care. Even simple motor skills like chewing and swallowing may be impaired. Speech is reduced to simple words and phrases. Paranoia, delusion, and insomnia are also seen in severe cases. Emotional changes are seen commonly. Motor rigidity can be seen in the final stages.  Patients with end-stage AD are usually bedridden and die of complications like infection, aspiration, etc.

Risk Factors

Apart from familial or heritable factors, specific environmental factors also pose a risk of Alzheimer’s. They include:

  • Age: This is one of the most significant risk factors for developing AD. AD is usually seen in patients who are above 65-70 years. The risk of AD is increased by 2 folds in patients above 80 years of age. Early-onset AD, which usually occurs in patients of <60 years age is rare and accounts for only 1-2%. In such early-onset cases, environmental factors play a vital role rather than the genetic influence.
  • Head Injury: Traumatic head injuries may pose an increased risk of developing AD. Head injuries sometimes stimulate overexpression of amyloid proteins. Head injuries may initially cause mild dementia. However, the symptoms may worsen as days pass on, similar to Alzheimer’s.
  • Hyperlipidemia: High cholesterol levels, especially in middle age, have known to cause the risk of developing AD. Cholesterol-lowering drugs such as statins are known to minimize the risk of AD.
  • Hypertension: Increased blood pressure is one of the high-risk factors in developing AD. It is known to be associated with conditions like senile plaque, entanglement of neurofibers, atrophy of the brain, etc. which are the common causes for AD.
  • Diabetes Mellitus: People with type 2 diabetes are known to have an increased incidence of dementia and decreased mental activity. AD was also hypothesized to be ‘type-3 diabetes’. Type 2 diabetes mellitus decreases insulin transport to brain and insulin uptake, resulting in the development of AD.
  • Obesity: Recent evidence has shown a relationship between obesity and risk of AD development. Obesity prevention and treatment have shown a positive influence in preventing AD.
  • Homocysteinemia: Literature has emphasized a positive relationship between increased homocysteine levels and development of Alzheimer’s disease. It is considered a marker for the disease.
  • Dietary Factors: Certain nutritional deficiencies are known to be risk factors for AD development. Deficiency of Vitamin B12, folate and antioxidants like vitamins A, C, E are related to the development of the disease. Omega 3 fatty acids, fish, and adequate consumption of vegetables are considered to be protective.
  • Lifestyle: Low educational attainment, social inactivity, no physical and mentally stimulating activities are also risk factors for AD. Increased alcohol consumption and smoking are also related to the development of AD.
  • Psychological: Patients with depression are more prone to develop AD.
  • Others: People who are constantly exposed to electromagnetic fields, toxins and who are on hormone replacement therapy are also at high risk of developing AD.

Identifying the risk factors and modifying them promptly can help in preventing the development of AD.

Diagnosis

The diagnosis of AD in clinical settings is usually based on

  • Medical History
  • Physical examination
  • Neurological testing
  • Neuropsychological evaluation
  • Selective ancillary testing to exclude other causes
  • Biomarkers
  • Imaging modalities
  • Histopathology

A thorough history including family history has to be taken. Clinical evaluation related to symptoms and signs has to be performed. Clinical diagnosis of AD uses specific criteria and logical sequence.

International Work Group has given certain criteria for the diagnosis of AD. These criteria include:

  • Autopsy confirmation is not required to diagnose AD. It can be made on living individual based on clinical findings.
  • AD diagnosis can be made with utmost certainty. Terms like ‘probable AD’ need not be used.
  • Biomarkers can be used to exclude other diseases.
  • Clinician need not wait until the onset of dementia to make the diagnosis of AD.
  • Whether dementia is present or not, same criteria and clinico-biological approach can be used for diagnosing all stages of AD.
  • Hippocampal type of memory aberration is the most common presentation of AD
  • Several biomarkers can be used to support the diagnosis of AD
  • Topographic biomarkers like MRI, PET, and SPECT and pathophysiological markers like CSF tau measures and amyloid imaging can be used.
  • Blood investigations are used to exclude any co-morbidities. Routine blood tests include vitamin B12, thyroid-stimulating hormone, folate, blood glucose, calcium, complete blood count with differential cell count, liver function and renal function tests. In high-risk cases, serological tests like HIV, syphilis, and Borrelia have to be carried on.
  • Brain imaging is another procedure to exclude other similar conditions and detect specific findings associated with AD. CT and MRI can be used for exclusion while MRI is used to detect minute vascular changes, especially with the fluid-attenuated inversion recovery sequences. Medial temporal lobe atrophy is a diagnostic feature of AD, and it can be well documented using MRI. Functional MRI, diffusion-weighted imaging, diffusion tensor imaging, proton magnetic resonance spectroscopy, diffusion tensor imaging and MR volumetry methods, etc., are the new MRI quantitative methods for enhanced diagnosis of AD.
  • SPECT (Single Photon Emission Tomography) is gaining confidence in the recent era in the diagnosis of AD. Dopaminergic SPECT is useful in differentiating AD from other similar dementia conditions.
  • Positron Emission Tomography (PET) is another minimally invasive imaging technique to check for brain glucose metabolism. As we know in AD, the glucose metabolism in the brain is impaired.
  • Electroencephalography (EEG) is useful in differentiating psychiatric complaints and AD. Though EEG can give a characteristic diagnosis for AD, it might be normal in the early stages of the disease.
  • Neuropsychological investigations usually test for episodic memory, as it is one of the commonly impaired functions in AD. Various neuropsychological tools like Grober-Buschke (GB) paradigm are used to identify memory impairment. Prodromal AD can be detected using Free and Cued Selective Recall Reminding Test.
  • CSF analysis shows increased t-tau values and decreased Aβ42 levels. Clusterin, Complement factor H, and alpha-2-macroglobulin are considered to be consistently associated with Alzheimer’s.
  • Neuropathological diagnosis or post-mortem brain biopsy is considered to be ‘gold standard’ in the diagnosis of AD.

Treatment

The treatments available currently for Alzheimer’s disease are symptomatic. Remember that till date, there is no known cure for Alzheimer’s. The medication available is usually helpful in reducing certain neuropsychiatric symptoms and enhance or preserve cognitive abilities and help patients suffer less. Management of AD includes both pharmacological and non-pharmacological methods. Behavioral management is an important aspect in the treatment of AD.

1) Drugs commonly used

Cholinesterase inhibitors are commonly used as AD exhibits significant cholinergic deficits in imaging as well as neuropathological studies. In mild to moderate cases of AD, cholinesterase inhibitors like Donepezil, Rivastigmine, Galantamine, etc., are used and are proven to be effective in cognitive functioning improvement. These medications are well-tolerated and considered safe, though they have certain side effects like nausea, vomiting, and diarrhea. Rivastigmine is an approved drug of choice for symptomatic treatment in mild to moderate AD. Rivastigmine transdermal patch is also proven to be efficacious in AD patients. Remember, cholinesterase inhibitors can only slow the progression but cannot stop or reverse AD.

Donepezil is another effective treatment option in managing cognitive impairment in patients with mild to moderate AD.  However, higher doses showed certain adverse effects like diarrhea, muscle cramps, nausea, and vomiting. Lower doses (5mg/day) were proven to be well-tolerated than higher doses (10mg/day).

Galantamine is one of the commonly used drugs in AD patients. It has shown a significant effect on cognitive functioning in patients with AD. Also, the side effects were minimal and mild, which included gastrointestinal symptoms.

Anti-inflammatory agents (NSAIDs and corticosteroids) are also studied but didn’t show any improvement in the condition. Hence they are rarely used nowadays.

Antioxidants are also used in the treatment of AD, as it is suggested that certain free radicals that are neurotoxic are generated during oxidative metabolism and result in neurodegeneration. Vitamin E and selegiline were shown to be effective in delaying disease progression.

Postmenopausal estrogen replacement therapy was also found to be effective in minimizing the risk of AD development in women. However, further research in the same is advocated.

Alternative medicines like leaf extract of Ginkgo biloba was also tried for their anti-inflammatory and anti-oxidant properties.

To combat depression symptoms, newer serotonin reuptake inhibitors can be used. Second gen anti-psychotic drugs can be helpful in managing psychosis.

New ‘disease-modifying’ treatment options were introduced, like tramiprosate, clioquinol, clostridium, etc., which are known to block Aβ42 aggregation. Other management strategies include etanercept, nerve growth factor, phosphodiesterase-5, etc.

Intravenous immunoglobulins (IVIg) use is under research, and these immunotherapeutic approaches are currently used in various immune-mediated neurodegenerative disorders. Anti-amyloid immunotherapy is another option. Anti-tau immunotherapy is still under study.

2) Non-pharmacological management

Apart from drugs, behavioral management also plays a vital role in the management of AD. These methods may not be effective in managing memory loss but can support mild dementia. Memory retraining techniques can be aimed at mild dementia. Approaches like aromatherapy, music/dance, bright light therapy, multisensory stimulation, and pet therapy can help in managing neuropsychiatric symptoms like agitation. Deep brain stimulation can be used to support brain activity.

Prevention

As discussed, there is no proper cure yet for AD. Hence it is essential to take all possible measures to prevent the development of AD. Prevention can be defined in three levels, primary, secondary and tertiary prevention.

Primary prevention strategies focus on minimizing the incidence of AD by encouraging the maintenance of good health and lifestyle habits thus excluding potential risk factors for the disease. Secondary Prevention adopts methods to prevent the progression of AD right at the preclinical or very early stage to more aggressive phases. Tertiary prevention focuses on enhancing the quality of life after the patient manifests the disease.

Modifiable risk factors such as smoking, alcohol consumption have to be controlled to prevent the development of AD. Well-controlled type 2 diabetes mellitus, hypertension, and hyperlipidemia can help in preventing the occurrence and progression of the disease.

Certain factors that help in preventing AD include omega-3 fatty acids, antioxidants, cognitive training, anti-diabetic drugs (well-controlled diabetes), exercise, well-controlled cardiovascular conditions, etc. Maintaining a healthy diet can help in minimizing the risk of AD development. Foods that help in prevention include fish, nuts, shellfish, olive oil, fruits, fresh vegetables, whole grains, and healthy fats. Food rich in antioxidants like berries (strawberries, blueberries, cranberries), carrots, beetroot, etc., can be consumed.

FAQs

What is Alzheimer’s disease?

Alzheimer’s is a progressive, age-linked, neuro-degenerative condition, affecting mental functioning and brain activity (cognitive function).

How to identify Alzheimer’s disease at an early stage?

Patients with AD, at an early stage, show memory problems. Difficulty in finding words, the decline in logical reasoning, certain vision and spatial issues and problems with a sense of smell can be noted at an early stage.

Do Alzheimer’s effect only older people?

Alzheimer’s usually affects older people. However, early-onset dementia can be seen in people who are <65 years age and even younger.

How to minimize the risk of developing Alzheimer’s?

Most of the times, Alzheimer’s is familial or genetic. However certain sporadic cases can be minimized by altering certain risk factors. Avoiding smoking and alcohol consumption, maintaining a healthy lifestyle with regular exercise, keeping blood pressure in control, maintaining healthy cholesterol levels, etc., can help in minimizing the risk.

What diet helps in lowering the risk of AD?

A balanced diet constituting fresh fruits and vegetables, milk and milk products, starchy foods like rice, pasta, potato, rich sources of protein like egg, fish, beans, food rich in omega-3 fatty acids, turmeric and ‘super foods’ like berries and red wine can help in minimizing the risk of developing Alzheimer’s disease.

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