Alzheimer’s Disease (AD) is a chronic progressive neuro-degenerative disorder affecting cognitive functioning and reducing life expectancy.

AD is one of the most common cause of dementia. It accounts almost 60-70% of all dementia cases. In most cases it co-exists with other conditions as a cause for dementia.

Its estimated that there are more than 40million cases of AD world wide. It is assumed to be one of the top 3 leading causes of death in developed countries, to take its place just after heart disease and cancer.

CLASSIFICATION ALZHEIMER’S DISEASE

• BASED ON AGE OF APPEARANCE – EARLY ONSET(before age of 65yrs, most of the cases are of FAD or Familial Alzheimer’s disease) or LATE ONSET(after 65yrs of age, most of them are sporadic cases)
• BASED ON INHERITANCE – FAMILIAL(Familial Alzheimer’s Disease also called FAD is Autosomal-Dominant Inherent condition which in almost all cases is early onset type)or SPORADIC(not of autosomal dominant inherant type and is usually late onset type)
• BASED ON INFLAMATION – INFLAMATORY or NON-INFLAMATORY
• BASED ON STAGES OF DISEASE PROGRESSION– PRODROMAL, EARLY/MILD, MODERATE and SEVERE

SIGNS AND SYMPTOMS OF ALZHEIMER’s DISEASE

Alzhermer’s Disease is characterised by gradually progressing loss of cognitive functions, especially memory and other related cognitive skills like thinking and reasoning, leading to difficulty in day to day activity – like language deterioration, forgetting and misplacing thing making it difficult to independently manage house and finances, forgeting recent events, repeatedly asking same question even after getting answer, difficulty in learning and recollecting recently learnt thing, difficulty in articulating image, recognisation of objects things and beings (non-occular visuo-spatial) all this deteriorating patients skill of reasoning and executing judgement and take initiatives resulting in dependence, further triggering mood and personality disorders.

All these basic symptoms are present in general in patient which are slowly progressing and increasing in severity throughout the continuum of the disease advancement so based on symptoms and its severity AD can be divided into four stages.

STAGES OF ALZHEIMER’s DISEASE

Based on disease progression, symptoms and its severity Alzheimer’s Disease can be divided into 4 stages which are progressive worsening of symptoms in same continuum.

• Pro-dromal phase
• Early/Mild
• Moderate
• Severe

Pro-dromal Phase

Its the phase of Mild Cognitive Impairment (MCI) or pre-dementia, not all cases of MCI are of AD as it can be seen in ageing and other conditions as well, so at this stage one cannot confirm AD untill patient shows other definitive signs and symptoms of AD which may take upto 8yrs to develop.

This stage shows following symptoms, which are of very mild degree and needs through neurophysiological evaluation to get detected.

• Occasional problems in recollecting recent events
• Occasional difficulty in exactly recollecting recently lernt facts and information
• Reduced Empathy noticed on some instances
• Mild changes is sense of humour

Early/Mild

As disease progresses further the severity of symptoms of cognitive disorders of memory, thinking, reasoning increases so as to easily becoming evident and establish diagnosis of AD and excluding other condition based on slow and gradually and progressively deteriorating cognition especially in front of memory.

• Cannot recollect event of forgetfulness, names of family and friends.
• Reduced fluency in speaking due to difficulty in recollecting words
• Difficulty grasping, learning and recollecting new facts and information. Causing minor confusions in unfamiliar simple tasks or situations.
• Unnoticeable problems in execution of complex activities of daily life, like orientation and organisation of cloths on self, and fine motor activity like drawing writting etc.
• Irrational, inability in making decisions.
• Melancholy and despondency

Moderate

Disease progressess to an extent that it starts affecting bodily functioning and day to day life to an extent that patient starts losing self confidence and starts becoming dependent on others and is now evident not only to family and his physician but also to others.

• Sometimes cannot even recollect name of close family members.
• Loss of vocabulary resulting in Language deterioration
• Reduced coordination in complex motor sequence, needs assistance in many cases in certain complex routine tasks like wearing dress. This may even cause frequent injuries and falls.
• Visuo-spatial disturbances causing difficulty in articulating image, recognisation of objects things and being causing illusionary misidentification and also delusions is seen.
• Irritability, resistance to caregivers, wandering, insecurity,frequent or constant crying.
• Difficulty determining their location.
• Difficulty differentiating relations and designations
• Lack of ability of reasoning judging and concluding.
• Sleep disorders

Severe

• General apathy
• Abusive, Cursing, paranoid, anxious
• Repeats same conversation again and again.
• Difficulty in speaking as can find word nor can frame sentence, speaks in few words or phrases
• General exhaustion and debility with muscular atrophy making person immobile giving rise to other complications like bedsores and secondary infection.
• Patients usually dies of secondary complications rather than disease itself

CAUSES OF ALZHEIMER’s DISEASE

Causes of Alzheimer’s Disease are not exactly known. It is believed to have one or more major fundamental reasons behind its pathology and pathogenesis along with multiple other factors contributing to it, in is development. With each case varing and may have the other factor more dominant than that found in the other case. Most of the hypothesis revolve around production of beta amyloid and tau protien as fundamental cause of AD.

Smoking, stress, depression, head injuries, certain CNS infections and high blood pressure are believed to increase risk in susceptible persons. Susceptibility much depends on genetics.

There are certain genes that are found to be associated but only in 5% of all the cases, head injury, depression, hypertension, smoking are also believed to be causative or contributory factors for AD.

GENETICS

Type, mode of onset, symptoms, its severity and specificity is determined by which and how many genes are involved and at which point there is SNP or mutations. More than 30 genes are found with more than 60 locus of SNP which are associated with Alzheimer’s Disease few of them are listed below.

Familial (Autosomal-Inheritant Dominant) – Familial Alzheimer’s Disease.

• Amyloid Precursor Protein
• Presenilin 1 & 2
• ABCA7
• SORL1

Mutations in above mentioned genes causes increase in a protein called Aβ42, which forms major component of Senile Plaques in Alzheimer’s Disease.

Sporadic (Not of Autosomal-Inherant Dominant type)

• APOEε4 allele – increases risk by 3 times in heterozygous and by 15 times in homozygous.
• TREM2 allele have been found to increase risk of Alzheimer’s Disease by upto 3-5times as it reduces or ceases ability of leucocytes to control the amount of βAmyloid.
• There are 19 Other genes found to be involved in Late Onset Alzheimer’s Disease (LOAD).

PATHOGENESIS

Alzheimer’s Disease is considered to be disease of Proteopathy where there is plaque deposits due ti misfolded Beta Amyloid proteins and Tau proteins in Central Nervous System which plays central role in disease pathology resulting in neurodegeneration.

There are many hypothesis trying to explain the cause and pathogenesis of Alzheimer’s Disease.

CHOLINERGIC HYPOTHESIS

Oldest hypothesis which believes that reduced acetyle choline synthesis is the fundamental cause for Alzheimer’s Disease, based on which many drugs for AD are prepared and marketed without any significant results so its not been widely accepted.

AMYLOID HYPOTHESIS

Hypothesis states that extracellular deposits of β-amyloid is the fundamental cause behind pathogenesis of Alzheimer’s Disease.

There are many evidence to suggest that there is fundamental role of beta amyloid in development of AD.

As many genetic study shows association of amyloid related genes allele and isoforms to be major risk factors in development of AD.

Examples of allele and isoforms of genes that are associated with amyloid and are present in many patients of Alzheimer’s Disease.

• Presence of Amyloid Precursor Protein gene that’s present on chromosome 21 has extra copy in people with trisomy making its expression pronounced and these people develop some features of Alzheimer’s Disease as early as 40yrs of age.
• Apolipoprotein APOEε4 breaks down Amyloid but its isoforms are not that potent in breaking down of amyloid.
• Allele of TREM2 reduces the activity of WBCof controling the amount of amyloid.

Also certain other factors that are related or associated to Beta Amyloid are found to be associated in development of Alzheimer’s Disease.

• Beta Amyloid oligomers called Amyloid Derived Diffused Ligands (ADDL) attach to neuron surface and disrupt synaptic signals.
• Presence of receptor of Amyloid oligomer, which is believed to be a misfolded three dimensional proteineceous infectious particle (prion protein).
• N-AAP is fragment of AAP adjecent to its another fragment beta-amyloid. This N-AAP undergoes self destruction by binding to TNFRSF21 also called Death Receptor6 (DR6), due to ageing genome and brain the N-AAP and TNFRSF21 pathway gets disrupted and βamyliod plays complimentary role in it.

But to contradict above findings there is also the fact that the drugs that help reduce production of beta amyloid or reduce concerntration of beta amyloid have no significant impact on disease so again amyloid hypothesis is not completely accepted.

TAU HYPOTHESIS

Tau proteins stabilises microtubules and are present in neurons of central nervous system and non-neuronal cells like astrocytes and oligodendrocytes.

As per tau hypothesis of pathogenesis of Alzheimer’s Disease, series of consequential pathological changes takes place post abnormalities in tau protein which starts with hyperphosphorilation of tau protein causes pairing with other threads giving rise to neurofibrillary tangles within the cell bodies evetually destroying microtubules resulting into destruction of cytoskeletal structure, causing disruption of neuronal transortation of biochemical mechanism and finally cell death.

OTHER HYPOTHESIS

Most of the other hypothesis revolve around production of beta amyloid and tau protien as fundamental cause of AD and are more of supportive or initiating or maintaining or risk factors that trigger fundamental pathological factor that is amyloid or tau related anomalies.

Blood Brain Barrier Hypothesis – Disturbance in integrity of blood brain barrier .

Spirochete Infection Hypothesis – Spirochete infection induced damages may further progress into AD especially by disrupting blood brain barrier

Disrupted Cellular Homeostasis of Biometals Hypothesis – It is doubted that certain ionic biometals in cells like ionic iron, copper and zinc either affect or are being affected or both by tau protein, Amyloid Precursor Protein, APOE.

Oligodendrocye Dysfunction Hypothesis – Ageing and other factors causes dysfunction of oligodendrocyes and their associated myelin, contributing to axon damage and resultant production of amyloid.

Retrogenesis Hypothesis of Barry Reisberg – This hypothesis states that certain errors in sequence of neucleotides in genome causes initiation of the reverse process of stages of neurogenesis. That is during embryogenesis the process begins with neurulation ending with myelination as final stage, just opposite to that in AD due to disturbed genetic code the reverse process is initiated that is – first demyelination, then axon death that is white matter and finally grey matter death.

Celiac Disease Association Hypothesis – Though earlier study failed to prove any relation of celiac disease with AD but more recent studies have found some link between AD and celiac disease which is under further investigation for any confirmations regarding any role.

Autoimmune Hypothesis – Autoimmune Conditions directly or indirectly affecting oligodendrocytes and myelin sheath and causing inflamatory process may trigger excessive production of amyloid production.

HOMEOPATHIC MEDICINES FOR ALZHEIMER’s DISEASE

• ANACARDIUM ORIENTALE
• HYOCYAMUS NIGER
• BACOPA MONNIERI
• LYCOPODIUM CLAVATUM
• BARYTA CARBONICA
• CONIUM MACULATUM