Last updated 2mo ago
A 55-year-old presents with personality changes, disinhibition, and language difficulties. Family history reveals a parent with similar dementia and an aunt who died of ALS.
AD; multiple genes
| Gene | Protein | Key Features |
|---|---|---|
| GRN | Progranulin | Haploinsufficiency; variable onset (45-70); reduced penetrance |
| MAPT | Tau | Earlier, more predictable onset; parkinsonism common |
| C9orf72 | - | GGGGCC hexanucleotide; can cause FTD and/or ALS |
| TARDBP | TDP-43 | Can cause FTD and/or ALS; + TDP-43 inclusion bodies |
| CHMP2B | CHMP2B | Danish founder variant |
Remember: "Granny's Mind Can't Think Clearly" (each subtype has its own GeneReviews page)
Disease Progression:
-
Early (frontal/temporal lobe): Behavioral and personality changes (disinhibition, apathy, poor judgment, loss of empathy) and/or language difficulties. Unlike Alzheimer's, memory is relatively preserved early.
-
Later (motor symptoms may develop):
- Parkinsonism (especially MAPT)
- ALS-like features (especially C9orf72, TARDBP): muscle weakness/wasting, swallowing difficulty, fasciculations
- Second most common early-onset dementia (after Alzheimer's)
- Onset typically 45-65 years
- Behavioral changes come FIRST, motor symptoms come LATER (if at all)
- Clinical diagnosis using consensus criteria for behavioral-variant FTD or primary progressive aphasia, supported by neuropsychological testing
- MRI shows frontal and temporal atrophy; FDG-PET shows frontotemporal hypometabolism (helps distinguish from Alzheimer's)
- Molecular testing of GRN, MAPT, and C9orf72 in familial disease or early onset; low plasma progranulin suggests GRN haploinsufficiency
- C9orf72 repeat expansion testing where ALS/FTD features coexist; cascade testing for at-risk relatives (autosomal dominant, reduced penetrance for GRN)
- No disease-modifying therapy; care centers on behavioral and environmental strategies plus caregiver support
- SSRIs for disinhibition, compulsions, and agitation; avoid antipsychotics where possible (extrapyramidal sensitivity, especially with parkinsonism)
- Cholinesterase inhibitors are generally not helpful and may worsen behavior; speech therapy for language variants
- Screen for and manage emerging ALS features (swallowing, respiratory); advance care and safety planning
"C9orf72 links ALS and FTD": The same GGGGCC hexanucleotide repeat expansion in C9orf72 can cause ALS, FTD, or both. These are on a spectrum.
FTD vs Alzheimer's: FTD = personality/behavioral changes come FIRST, memory is relatively preserved early. AlzheiMErs = MEmory loss comes first.