How Alzheimer’s is diagnosed?

Alzheimer’s disease is a chronic degenerative disease of the brain which progresses over time. Alzheimer’s disease is the most common cause of Dementia but it is rare under the age of 60 years.

Changes in the brain

The brain in the Alzheimer’s disease becomes atrophic i.e degenerates and shrivels decreasing its density. On a microscopic level, the nervous tissue shows two features; plaques and tangles. These are the prime suspects in killing the nervous tissue causing degeneration of the brain.

Plaques:

Deposits of amyloid proteins that build up in the spaces between the cells.

Tangles:

 These are the twisted fibres of tau proteins which build up inside the cells.

Causative factors

Genetic factors

Before knowing the genetic factors of Alzheimer’s disease, it is important to recognise that there are two forms of Alzheimer’s disease; early onset and late onset. Both have different genetic bases.

Early-onset Alzheimer’s disease:

Early-onset familial Alzheimer’s disease follows an autosomal dominant inheritance pattern. It occurs before the age of 65 years but constitutes only a very small minority of the patients of Alzheimer’s disease.

The early onset Alzheimer’s disease can be attributed to mutations in one of the three genes which encode amyloid precursor protein (APP) and presenilins 1 and 2.

These mutations increase the production of small proteins called Aβ42. The increased amount of Aβ42 causes the formation of plaques in the brain.

Late-onset Alzheimer’s disease:

Majority of the cases of Alzheimer’s disease belong to this category. Its pattern of inheritance is not autosomal dominant but rather it is sporadic. It means that it is not necessary that someone who has these mutations in his genes is bound to develop Alzheimer’s disease. This phenomenon is called incomplete penetrance and the chances of developing Alzheimer’s disease is a person with these mutations is affected by environmental and lifestyle modifiers.

The best known genetic risk factor is the inheritance of the ε4 allele of the apolipoprotein E (APOE). Between 40 and 80% of people with AD possess at least one APOEε4 allele. The APOEε4 allele increases the risk of the disease by three times in heterozygotes (causative allele on one chromosome) and by 15 times in homozygotes (causative allele on both chromosomes).

Another genetic risk factor identified is the mutations in the alleles in the TREM2 gene. These mutations have been associated with a 3 to 5 times higher risk of developing Alzheimer’s disease.

Health, environmental and lifestyle factors

Some other risk factors have been implicated in increasing the chance of development of Alzheimer’s disease. These include

1- Age:

Increasing age is a very important risk factor for the development of Alzheimer’s disease. The likelihood of developing Alzheimer’s disease doubles every 5 years after one reaches 65.

2- Down’s syndrome:

 People with Down’s syndrome have a higher probability of developing Alzheimer’s disease.

3- Head injury: People who sustain a serious head injury have a higher probability of developing Alzheimer’s disease.

4- Cardiovascular disease:

Several lifestyle risk factors which increase the probability of cardiovascular disease, also increase the probability of Alzheimer’s disease. Some of these risk factors are

Obesity

Diabetes

Hypertension

Dyslipidemia

Smoking

Sedentary lifestyle

You can also find more information about clinical and pathological structure of Alzheimer’s Disease in this blog post.

Signs and symptoms of Alzheimer’s Disease

Signs of Alzheimer's

1 – Memory Loss

Impairment of memory is the most important feature of Alzheimer’s disease.

In the early stages of the disease, the impairment of memory is in the form of increasing memory lapses.

For example, the patient may forget about recent conversations or events, misplace items, forget the names of places and objects, have trouble thinking of the right word, ask questions repetitively. These occurrences are not unnatural to occur normal individuals as well but in Alzheimer’s disease, they occur with increased frequency.

As the disease progresses, the impairment in memory gets worse and worse. For example, at late stages, the patient may not even remember his children.

As the disease progresses, other symptoms start developing as well. These include

2- Increasing confusion and disorientation

3- Depression

4- Delusions and hallucinations

5- Problems with speech and language (aphasia) with gradual loss of speech.

6- Urinary and fecal incontinence and problems in swallowing may also develop at very late stages in the most advanced cases.

How is Alzheimer’s diagnosed?

There are three steps in the diagnosis of Alzheimer’s disease

1- Complete and through history.

2- Mental ability tests

3- Imaging and other laboratory tests

1- Complete and thorough history:

Very important for the diagnosis of Alzheimer’s disease. Interviews with family and caretakers are very important for the diagnosis of Alzheimer’s. The doctor tries to get a sense of the memory loss and other deteriorating brain faculties (dementia) of the patient.

2- Mental ability tests:

These tests are widely used to evaluate the cognitive impairments needed for diagnosis. Eight intellectual domains are most commonly tested —memory, language, perceptual skills, attention, motor skills, orientation, problem solving and executive functional abilities. Different tests like MMSE (mini mental state examination and other pen and paper tests are most commonly employed.

Cognity mobile app lets the users test the cognitive impairment and dementia risk very accurately. Mental abilities can be tested conveniently and remotely. The link to the app is https://cognity.app

3- Imaging and other tests:

These tests are done to exclude other causes of dementia. CT scan and MRI scan of the brain is done to visualise any changes and degeneration of the nervous tissue.

Alzheimer's MRI

Electroencephalography is also performed to rule out Creutzfeldt-Jakob disease.

Some blood tests are also done. It is common to perform thyroid function tests, assess B12, autoimmune markers for vascular diseases, rule out syphilis, rule out metabolic problems (including tests for kidney function, electrolyte levels and for diabetes), assess levels of heavy metals (e.g. lead, mercury) and anaemia.

But just these tests do not answer the question ‘How is Alzheimer’s diagnosed?’. The diagnosis of Alzheimer’s disease is one of exclusion. As already mentioned Dementia ( memory loss with other deteriorating brain faculties) is the most important feature of Alzheimer’s disease. And there are many causes of dementia. The aim of these investigations is to rule out these other causes so that Alzheimer’s can be diagnosed with certainty.

Diagnostic alternatives of Alzheimer’s disease

1- Lewy Body Dementia

Characterised by Dementia and signs of Parkinson’s disease like tremors and rigidity. Visual hallucinations are commonly seen in Lewy body dementia.

2-  Fronto-temporal dementia:

Patient presents with personality changes and language disturbance. Memory is relatively preserved in the earlier stages.

3- Dementia due to vascular diseases:

Vascular diseases of the brain like vasculitis, angiopathy and emboli may also cause dementia.

4- Dementia due to tumours:

Primary cerebral tumours and metastasis from tumours elsewhere in the body may also cause dementia.

5- Dementia due to inflammatory diseases:

Inflammatory diseases of the brain like Multiple Sclerosis are also a probable cause of dementia.

6- Dementia due to Infections:

Infections like syphilis and HIV are also a cause of dementia.

7- Dementia due to toxins:

Heavy metal and carbon monoxide poisoning may also cause dementia.

8- Dementia due to nutritional deficiencies:

Thiamine and Vitamin B-12 deficiency also compromise the mental faculties causing dementia. Alcohol consumption is a common cause of these deficiencies.

9- Dementia due to traumatic causes:

Trauma is a risk factor for the development of dementia. Trauma may also lead to conditions like hydrocephalus which causes compromised blood supply to the brain causing dementia.

10- Creutzfeldt-Jakob disease:

A very rare cause of dementia which causes a rapidly progressive dementia with myoclonus. It has characteristic features on the electroencephalogram.

A diagnosis of Alzheimer’s disease can only be made with certainty once all the other causes of dementia have been ruled out by investigators such as CT scan, MRI, EEG and blood tests.

Management of Alzheimer’s disease

There is no definite cure for Alzheimer’s disease but it can be managed.

Medication:

3 groups of drugs are used for the management of Alzheimer’s disease.

1- Acetylcholinesterase inhibitors:

Due to the death of cholinergic neurons, levels of acetylcholine is decreased in the brain. This group of drugs increases the level of acetylcholine.

2- NMDA antagonist:

Increased levels of Glutamate is toxic for neurons. Glutamate levels are increased in Alzheimer’s disease. NMDA antagonist, Memantin, combat this effect.

3- Antidepressants:

Depression almost invariably occurs in Alzheimer’s disease. So antidepressants may be used.

Psychotherapy

Different techniques are used to help the patients adapt to cognitive impairment.

Caregiving

Alzheimer’s disease is a progressive disease and the patient gradually becomes unable to take care of herself / himself. Caregiving is an important part of the management of Alzheimer’s disease.

References:

1- https://www.nhs.uk/conditions/alzheimers-disease/diagnosis/

2- Davidson’s principles and practice of medicine (22nd edition)

3- https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/in-depth/alzheimers/art-20048075

4- https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet

5- https://www.alz.org/alzheimers-dementia/what-is-alzheimers

6- https://en.m.wikipedia.org/wiki/Alzheimer%27s_disease

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