GeneticsTier 1Medical Sciences concept

Alzheimer's disease genetics (APP, PSEN1/2, chromosome 21, Down syndrome link)

Core concept

Two genetically distinct diseases sharing a phenotype
- Autosomal dominant, early-onset (<1% of all AD) - fully penetrant, onset 30-60 y
- Sporadic, late-onset (>95%) - polygenic; APOE is a risk allele, not a causative gene
All three dominant genes converge on amyloid precursor protein processing
- APP (chromosome 21q21) - the substrate; ~10-15% of familial cases
- PSEN1 (14q24) - catalytic subunit of gamma-secretase; commonest (~50-70%) and earliest onset (often 40s)
- PSEN2 (1q42) - rarest, later and more variable onset
Mechanism: shift of APP cleavage toward the amyloidogenic pathway
- Non-amyloidogenic: alpha-secretase cleaves within the Abeta sequence -> no plaque
- Amyloidogenic: beta-secretase (BACE1) then gamma-secretase (presenilin) -> Abeta40 and Abeta42
- -> inc Abeta42 : Abeta40 ratio -> oligomerisation -> plaques -> tau hyperphosphorylation -> neurofibrillary tangles -> neuronal loss
- The dominant mutations raise the ratio, not necessarily total Abeta - the direct evidence for the amyloid hypothesis

Down syndrome - the natural experiment

APP sits on chromosome 21 -> trisomy 21 gives three copies -> lifelong Abeta overproduction
Essentially 100% have AD neuropathology by age 40; clinical dementia in ~50-70% by 60
- Median onset of dementia ~mid-50s - decades earlier than sporadic AD
Individuals with partial trisomy 21 that excludes APP do not develop early AD - the confirmatory experiment
Presentation in Down syndrome differs: behavioural/frontal change, seizures (myoclonic), and functional regression often precede memory complaint

APOE - chromosome 19q13

ApoE4 impairs Abeta clearance across the blood-brain barrier and promotes aggregation
Not diagnostic and not predictive at the individual level - many e4 carriers never develop AD, and ~40% of AD patients carry no e4
- -> routine APOE genotyping for risk prediction is not recommended; it is now done for a different reason (see below)
e2 is also the allele of type III hyperlipoproteinaemia (e2/e2 + a second hit)
>75 additional loci from GWAS - TREM2 (R47H, ~3x), SORL1, ABCA7, CLU, CR1, PICALM - clustering on microglial function, lipid handling and endocytosis, not on APP itself

Genetics of the non-AD dementias (the exam's discriminators)

FTD/ALS - C9orf72 hexanucleotide expansion (commonest), MAPT (tau), GRN (progranulin)
CADASIL - NOTCH3; migraine with aura -> subcortical stroke -> vascular dementia; anterior temporal pole and external capsule white matter change
Prion (CJD) - PRNP; codon 129 methionine homozygosity increases susceptibility
Huntington - HTT CAG
Lewy body / Parkinson dementia - GBA and SNCA (also the strongest genetic risk factors for PD)

When to consider genetic testing: onset <65 y, an autosomal dominant pedigree, or Down syndrome; late-onset sporadic AD is not an indication
- Predictive testing in an at-risk relative uses the Huntington-style counselling protocol
APOE genotyping is now performed before anti-amyloid monoclonal therapy, because it stratifies ARIA risk
- ARIA-E (oedema) and ARIA-H (haemorrhage/siderosis) - mostly asymptomatic and detected on protocol MRI, but can be fatal
- Incidence rises steeply with e4 dose; ~33% (lecanemab) and ~41% (donanemab) in e4 homozygotes
- Anticoagulation and probable cerebral amyloid angiopathy markedly increase the risk of severe ARIA
Lecanemab and donanemab (anti-Abeta protofibril/plaque IgG1) slow decline modestly in early symptomatic AD with confirmed amyloid; require MRI monitoring and an infusion service
Biomarker-first diagnosis has replaced clinical-only diagnosis: CSF Abeta42/40 with p-tau181 or p-tau217, amyloid PET, and now plasma p-tau217, which performs close to CSF
Gamma-secretase inhibitors failed - the enzyme also cleaves Notch; BACE inhibitors worsened cognition. Only the antibody route succeeded

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