Genetic cause of Alzheimer's Disease

Describe the genetic basis of early onset alzheimer's.

- Trisomy 21 (down syndrome) predisposes to AD.

- Mutations in APP, Presenilin and Tau can cause AD.

How does trisomy 21 lead to alzehimer's disease?

- Amyloid precursor protein (APP) is on chromosome 21.

- There are 3 copies of chromosome 21 which means there is more expression of APPs which leads to more β-amyloid and therefore more β-amyloid plaques.

How do APP mutations cause AD?

Causes cleavage of APP leading Aβ42 production which is used to produce β-amyloid plaques and therefore cause neuronal cell death.

How do presinilin mutations cause AD?

- Mutations increase PSEN1 and PSEN2 expression.

- This enhances γ-secretase activity, leading to excessive Aβ42 production from APP cleavage.

- Increased β-amyloid plaques trigger neuronal cell death, driving AD progression.

How do Tau mutations cause AD?

- Mutations increase Tau phosphorylation, forming neurofibrillary tangles.

- This disrupts axonal transport, causing neuronal death and Alzheimer's progression.

What is ApoE?

- Lipid-binding lipoprotein involved in the transport and metabolism of lipids.

- The ApoE4 allele (a genetic variant) is associated with an increased risk of late-onset Alzheimer's disease.

How does ApoE lead to AD?

- Carrying 2 ApoE4 alleles increases Alzheimer's risk.

- Apolipoproteins in plaques help clear β-amyloid, but ApoE4 impairs this, causing plaque buildup.

- This leads to neuronal death and cognitive decline, driving Alzheimer's progression.