Alzheimer’s disease: Pathogenesis, Signs & Symptoms and Treatment.

Author- Dr. Md. Shamim, MD.

Introduction:

Alzheimer’s disease is a major neurological disorder characterized by chronic and progressive dementia. Other mental abnormalities such as language abnormality, difficulty in calculation, unable to take judgement etc. are also associated with Alzheimer’s disease. It is a most common cause of dementia.

Pathogenesis:

Destruction of cholinergic neurons:

• Cortex
• Limbic structures of brain particularly amygdala, basal forebrain, and Hippo campus.Courtesy; freepik.com

Risk Factors of Alzheimer’s disease:

• Old age
• Positive family history
• History of head trauma with concussion
• Genetic factors

Courtesy; freepik.com

Symptoms and Signs of Alzheimer’s disease:

• Dementia
• Disorientation
• Poor judgment
• Poor concentration
• Aphasia (Difficulty in speech)
• Apraxia (Difficulty in performing task)
• Frustrated

Courtesy: freepik.com

Therapeutic goal:

• No drugs are available to cure the disease, only relieve the symptoms.
• To increase the level of Acetylcholine in brain.
• To minimise the effect of excitatory neuron.
• To increase the energy utilisation of brain.

Treatment:

• Central Acetylcholinesterase inhibitors.
• NMDA receptor inhibitors.
• Increase energy utilisation in brain.
• secretase enzyme   inhibitors.
• Antiepileptics.
• Antidiabetic agents.

Central Acetylcholinesterase inhibitors:

• Donepezil
• Tacrine
• Rivastigmine
• Galantamine

Donepezil:

Mechanism of action (MOA):

• Reversible Cholinesterase inhibitors.
• Selectively inhibits Acetylcholine in brain   Increase Acetylcholine level in cerebral cortex.

ADME

• Well absolved orally.
• Cross BBB.
• Long t_1/2 (about 70 hr.) So, administered OD.

Adverse effects (A/E):

• GI side effects- nausea, vomiting, diarrhea.
• Not associated with hepatotoxicity.

  Tacrine:

• First Centrally acting cholinesterase inhibitor approved for the treatment of AD.

 ADME

• Lower bioavailability and shorter t_1/2 than donepezil   So administered in multiple doses.

 A/E

• Hepatotoxicity (due to acridine).
• Peripheral cholinergic side effects.
• Diarrhoea, Nausea.
• Urinary incontinence
• Because of these adverse effects.
• Few patients can tolerate higher doses.
• SO, Tacrine has been withdrawn from the market.

Rivastigmine:

• Newer centrally acting reversible cholinesterase inhibitor.
• Taken in divided doses.
• Significantly slow the progression of AD.
• Recently transdermal formulation of Rivastigmine was introduced. Applied every 24 hours.      Increase patient compliance and simplifying care giver for administration.

Galantamine:

• Newer Centrally acting reversible cholinesterase inhibitor.
• Discovered from the extracts of bulbs of the daffodil, narcissus, pseudonarcissus.
• Like Rivastigmine slow the progression of AD.

NMDA receptor inhibitors:

Memantine:

• Recently approved agent.
• New MOA for treatment of AD.
• Non-competitive antagonist at N-methyl D-Aspartate (NMDA) receptor.
• Working by attenuating the excitatory effect of Glutamate.
• Excreted largely unchanged by kidney.
• The combination of Memantine extended release with donepezil is also available. To improve the efficacy and compliance.

 Increase energy utilisation in brain:

 Caprylidene:

• Medical food metabolised to Ketone bodies.   Brain can use for energy when the processing of glucose is impaired.
• Replaces depleted Glucose levels to treat patients with age associated memory impairment and AD.

Secretase enzyme inhibitor*:

• NSAIDS such as fluriprofen may decrease the formation of aggregates by inhibiting secretase enzymes.

Antiepileptic drugs*:

• Valproic acid- it may block the dissociation of microtubules and by action on glycogen synthase kinase.

Antidiabetic agents*:

• Rosiglitazone

  Increases insulin sensitivity and glucose utilisation.       Improve cognitive function in AD.

Note: – * drugs are not approved yet for the treatment of AD, but are in clinical trials.

Precautions:

• Memory Aids- Note books, Daily reminders
• Stop driving
• Need safety precautions in bedroom, bathroom, kitchen etc.
• Moral support from family or caregivers.

Reference;

1. CMDT
2. Harrison’s Principle of Internal Medicine
3. Katzung, Basic & Clinical Pharmacology.
4. Alzheimer’s Disease
5. Overview Alzheimer’s disease