ALZHIMER DISEASE
SAKSHI HINGU
NOTES
, INTRO
• Dementia is an umbrella term used to define the loss of cognitive functioning—thinking,
remembering, and reasoning—and behavioral abilities that interferes with a person’s daily
life and activities
• Alzheimer disease (AD), which is a gradually progressive dementia affecting cognition,
behavior, and functional status, being the most common.
• Alzheimer disease profoundly affects the family as well as the patient. The need for
supervision and assistance increases until the late stages of the disease, when people with
AD become totally dependent on a caregiver for all basic needs. T
Common Types of DEMENTIA
1. Alzheimer disease
2. Vascular dementia
3. Dementia with Lewy bodies
4. Mixed dementia
5. Others (eg, Parkinson disease dementia, Frontotemporal dementia, Huntington disease,
Creutzfeldt–Jakob disease)
6. Potentially reversible causes of cognitive dysfunction (eg, normal pressure hydrocephalus,
thyroid dysfunction, vitamin B12 deficiency, delirium, depression, Wernicke–Korsakoff
syndrome, infectious and autoimmune encephalitis)
, ETIOLOGY
1. Genetics of Alzheimer’s Disease
I. Early-Onset Alzheimer’s Disease (EOAD)
• Occurs before age 65 (often in 30s–50s).
• Rare (<1% of all AD cases) but strongly genetic (familial AD).
• Inheritance: Autosomal Dominant.
• Main genes:
a. Amyloid Precursor Protein (APP) gene – Chromosome 21
• APP is a large membrane protein in neurons.
• Normally, it is cut (cleaved) by secretase enzymes:
– α-secretase → safe, non-toxic fragments
– β- and γ-secretase → produces Aβ peptides (40–43 amino acids)
• Problem:
– Mutations in APP → increased production of Aβ42 (sticky and toxic).
– Aβ42 clumps → amyloid plaques → neuronal damage.
• Link to Down syndrome (trisomy 21): Extra APP gene copy → higher risk of AD.
b. Presenilin-1 (PSEN1) – Chromosome 14
• PSEN1 is part of the γ-secretase complex.
• 160 mutations identified.
• Mutations → increase production of longer Aβ42 peptides.
• Most common cause of familial EOAD.
c. Presenilin-2 (PSEN2) – Chromosome 1
• Less common than PSEN1.
• Also alters γ-secretase activity → more Aβ42.
• Seen in certain families (e.g., Volga German kindreds).
SAKSHI HINGU
NOTES
, INTRO
• Dementia is an umbrella term used to define the loss of cognitive functioning—thinking,
remembering, and reasoning—and behavioral abilities that interferes with a person’s daily
life and activities
• Alzheimer disease (AD), which is a gradually progressive dementia affecting cognition,
behavior, and functional status, being the most common.
• Alzheimer disease profoundly affects the family as well as the patient. The need for
supervision and assistance increases until the late stages of the disease, when people with
AD become totally dependent on a caregiver for all basic needs. T
Common Types of DEMENTIA
1. Alzheimer disease
2. Vascular dementia
3. Dementia with Lewy bodies
4. Mixed dementia
5. Others (eg, Parkinson disease dementia, Frontotemporal dementia, Huntington disease,
Creutzfeldt–Jakob disease)
6. Potentially reversible causes of cognitive dysfunction (eg, normal pressure hydrocephalus,
thyroid dysfunction, vitamin B12 deficiency, delirium, depression, Wernicke–Korsakoff
syndrome, infectious and autoimmune encephalitis)
, ETIOLOGY
1. Genetics of Alzheimer’s Disease
I. Early-Onset Alzheimer’s Disease (EOAD)
• Occurs before age 65 (often in 30s–50s).
• Rare (<1% of all AD cases) but strongly genetic (familial AD).
• Inheritance: Autosomal Dominant.
• Main genes:
a. Amyloid Precursor Protein (APP) gene – Chromosome 21
• APP is a large membrane protein in neurons.
• Normally, it is cut (cleaved) by secretase enzymes:
– α-secretase → safe, non-toxic fragments
– β- and γ-secretase → produces Aβ peptides (40–43 amino acids)
• Problem:
– Mutations in APP → increased production of Aβ42 (sticky and toxic).
– Aβ42 clumps → amyloid plaques → neuronal damage.
• Link to Down syndrome (trisomy 21): Extra APP gene copy → higher risk of AD.
b. Presenilin-1 (PSEN1) – Chromosome 14
• PSEN1 is part of the γ-secretase complex.
• 160 mutations identified.
• Mutations → increase production of longer Aβ42 peptides.
• Most common cause of familial EOAD.
c. Presenilin-2 (PSEN2) – Chromosome 1
• Less common than PSEN1.
• Also alters γ-secretase activity → more Aβ42.
• Seen in certain families (e.g., Volga German kindreds).
