Alzheimer's disease - 

Most common Neurodegenerative disorder

Most common form of dementia (Alzheimer's disease > Vascular dementia)

Cortical Type of dementia (A symptoms)  ; Mini-Mental state examination (MMSE) < 24

"Neurodegenerative disease with insidious onset and chronic progressive impairment of behavioral and cognitive functions including memory , comprehension , language , attention , reasoning , judgement"

Risk factors - 

1. Old age (>/= 65 yrs) is strongest predisposing factor for Regular Alzheimer's disease

2. Gender - Females > Males

3. family history of dementia is strongest predisposing factor for Early onset Alzheimer's disease

4. Diabetes mellitus

5. Hypertension

6. Obesity

7. Dyslipidemia

8. Peripheral atherosclerosis

9. Cerebrovascular disease

10. Smoking

11. Sleep deprivation

12. Low socioeconomic status 

13. Low educational status

14. Head injury

15. Dysfunction in Ubiquitin proteasome system (UPS)

16. Genetic factors 

Genetic factors - 

• Presenilin 1 (chr 14)  > Presenilin 2 (chr 1) {Familial Alzheimer's disease} 

• Amyloid Precursor protein (chr 21) - Early onset Alzheimer's disease ; Early onset familial Alzheimer's disease is Autosomal dominant ; since APP gene is located on chr 21 , individuals with trisomy 21 (Down's syndrome) are at increased risk of early onset (at 50 yrs) Alzheimer's disease due to APP overexpression

• Apolipoprotein E4 (chr 19) - Late onset Alzheimer's disease ; Apolipoprotein E2 is protective i.e.., decreases risk of Alzheimer's disease

• TREM 2 ( Triggering receptor expressed on myeloid cells - 2 ) (chr 6)

• Tau (chr 17)

Protective factors - NSAIDs , Apolipoprotein E2

Pathogenesis -

 Neurotransmitters affected mainly - Acetylcholine deficiency in subcortical areas especially in Nucleus basalis of Meynert leading to decline in cognitive abilities and also Glutamate and serotonin can be involved in pathogenesis 

Clinical features -

Cortical Type of dementia (A symptoms)

• Anterograde memory loss

• Apraxia

• Anosognosia

• Acalculia

• Alexia

• Agnosia

• Apathy 

• Logopenic aphasia

• Agitation

• Aggression

• Anxiety

• Anosmia (Entorhinal complex involved)

• Delusions , Hallucinations ,Paranoia

• Visuospatial deficits

• Urinary incontinence

Histopathology findings - 

Neurofibrillary tangles (composed of Tau proteins) (Tau proteins are intracellular , Stain with Gallyas silver stain) (Braak topographical staging of neurofibrillary tangles) (INTRACELLULAR)

Senile neuritic plaques (Amyloid deposits - Amyloid beta which stains with Congo red shows apple green birefringence in polarized light) (EXTRACELLULAR)

Hirano bodies (Bright eosinophilic intracytoplasmic inclusions ,  aggregates of actin and actin associated proteins)

Neuronal loss in Nucleus basalis of Myenert

Synaptic loss

Granulovacuolar degeneration of hippocampal pyramidal cells by amyloid angiopathy

Radiological findings -

MRI brain - Cortical and Subcortical atrophy in Parietal and Temporal lobes especially hippocampus and also amygdala , parahippocampal gyrus , cingulate cortex associated with ventriculomegaly and hydrocephalus ex vacuo

DSM-5 diagnostic criteria for alzheimer's disease (2 or more areas of cognitive deficits , Progressive worsening of memory and learning)

Treatment -

Drugs -

1) Central Ach esterase inhibitors 

• Donepezil - Reversible , Mixed Competitive & Non competitive Ach esterase inhibitor (Mild to severe dementia) , only drug approved in all stages of Alzheimer's disease.

• Galantamine - Reversible , Competitive , Teritiary alkaloid (Mild to moderate Alzheimer's disease)

• Rivastigmine - Reversible , Non competitive inhibitor of both AChE and BuChE (Mild to moderate Alzheimer's disease) ; Available as Transdermal patch (Transdermal delivery reduces fluctuations of dose and prevents direct gastric irritation)

• Tacrine (not used anymore ; Hepatotoxic)

Side effects of Ach esterase inhibitors - Bradycardia , Heart block , Syncope (as they affect SA & AV node)

Note - Irreversible Ach esterase  antagonists are not indicated in Alzheimer's disease.

2) NMDA antagonist 

Memantine - Non competitive NMDA antagonist (Moderate to Severe Alzheimer's disease) ; used along with donepezil ; Reduce Glutamate induced calcium mediated Excitotoxicity

3) Aducanumab - It is monoclonal IgG1 antibody that binds to amyloid beta and reduces amyloid plaques in brain.

4) SSRI (Citalopram) / Benzodiazepines - For Rx of agitation and for sleep

5) Atypical antipsychotics - For Rx of Psychotic symptoms

#crackmbbs