Hereditary cognitive / dementia genetics splits into autosomal dominant early-onset Alzheimer disease (rare but high penetrance — APP, PSEN1, PSEN2), APOE as a risk-stratifying allele, frontotemporal dementia genetics (MAPT, GRN, C9orf72, others), familial prion disease (PRNP), and a small but important set of adult-onset leukoencephalopathies that mimic dementia (notably CSF1R-related ALSP). This page covers the highest-yield first-line test for each.

Familial Alzheimer Disease (Autosomal Dominant, Early-Onset)

• First-line test: AD NGS panel — APP, PSEN1, PSEN2 sequencing + del/dup.
• When to test:
  • Onset <65 years (especially <60).
  • Autosomal dominant family history of AD.
  • Multiple affected family members in successive generations.
• Yield: ~5–10% in early-onset familial AD; higher with strict autosomal dominant criteria.
• If panel negative: consider FTD overlap (some patients with PSEN1 variants present with FTD-like features); trio WES.
• Cascade testing: predictive testing for first-degree relatives is appropriate with formal counseling.

APOE Genotyping

• Test: APOE ε2 / ε3 / ε4 typing.
• NOT diagnostic: risk modifier for late-onset AD. ε4/ε4 increases AD risk ~12-fold; ε4/ε3 ~3-fold; ε2 mildly protective.
• When to order:
  • Before starting lecanemab or donanemab: ε4 homozygotes have higher ARIA (amyloid-related imaging abnormality) risk — informs treatment decision and MRI surveillance frequency.
  • For risk-stratified counseling in mid-life with strong AD family history.
• Do NOT: use APOE as a diagnostic test for AD or as the basis for treatment decisions in symptomatic patients without imaging biomarker support.
• GINA does not cover life / disability / long-term care insurance — counsel before testing.

Frontotemporal Dementia (Familial)

• First-line test: FTD NGS panel — C9orf72 hexanucleotide expansion + sequencing of MAPT, GRN, TBK1, VCP, CHMP2B, FUS, TARDBP, SQSTM1, others.
• Yield: ~10–20% in clinically suspected familial FTD; higher in autosomal dominant pedigrees.
• C9orf72 expansion: most common genetic cause of FTD AND ALS in many populations; standard NGS misses it — verify panel includes specialized expansion testing (RP-PCR or Southern blot).
• MAPT: progressive supranuclear palsy / corticobasal syndrome / FTD spectrum; consider especially with parkinsonian features.
• GRN: hallmark is family history of TDP-43-positive FTLD; serum progranulin levels (low) supportive before genetic test.
• If panel negative + atypical features: trio WES.

C9orf72 Hexanucleotide Repeat Expansion

• Test: C9orf72 GGGGCC hexanucleotide expansion sizing.
• Methodology: specialized repeat-primed PCR (RP-PCR) or Southern blot — standard NGS does NOT detect this. Long-read sequencing increasingly used.
• Repeat size interpretation: ~2–25 normal; ~25–60 “intermediate” (uncertain pathogenicity); ≥30–60+ disease range (often hundreds to thousands of repeats).
• Clinical relevance:
  • Most common genetic cause of both FTD AND ALS in many populations.
  • Order in: any ALS patient (regardless of family history); any FTD patient; ALS-FTD overlap; familial parkinsonism with cognitive change.

Familial / Inherited Prion Disease

• First-line test: PRNP sequencing — particularly codons 102 (GSS), 117 (GSS), 129 (codon polymorphism — risk modifier), 178 (FFI), 200 (familial CJD), and others.
• Inherited prion disease syndromes:
  • Familial CJD (codon 200 E200K most common).
  • Gerstmann-Sträussler-Scheinker (codon 102 P102L).
  • Fatal familial insomnia (codon 178 D178N with codon 129 M).
• Codon 129 polymorphism (methionine/valine): modifies phenotype and risk; included in standard testing.
• Predictive testing: same protocol as HD — formal multi-session counseling.

Adult-Onset Leukoencephalopathy with Axonal Spheroids (ALSP / HDLS)

• First-line test: CSF1R sequencing.
• Phenotype: adult-onset (30s–50s) frontal lobe syndrome + motor symptoms + leukoencephalopathy on MRI (bilateral, often with calcifications on CT).
• Imaging clue: callosal involvement + frontal predominance + restricted diffusion in white matter.
• Often misdiagnosed as FTD or MS — consider CSF1R in any adult-onset leukoencephalopathy + cognitive decline.
• Treatment: emerging — allogeneic hematopoietic stem cell transplant may slow progression in selected cases.

Other Adult-Onset Cognitive Genetic Syndromes

• Familial CJD with rapidly progressive dementia → PRNP.
• Familial British / Danish dementia (rare hereditary CAA forms with dementia) → ITM2B.
• Adult-onset leukodystrophies with cognitive features → see Leukodystrophies page.
• CADASIL with prominent dementia phenotype → NOTCH3 (overlap with stroke chapter).
• Dementia in Wilson disease → ATP7B (overlap with movement disorders chapter; clinical/biochemical drives workup).

Disease → Test Quick Reference Table

Pitfalls and Pearls

• Familial AD genes (APP, PSEN1, PSEN2) cause autosomal dominant early-onset AD — rare but high-penetrance.
• APOE: risk modifier, NOT diagnostic. ε4/ε4 increases lecanemab / donanemab ARIA risk.
• C9orf72 expansion is the commonest genetic cause of both FTD and ALS in many populations — order in any ALS or FTD patient.
• Standard NGS misses C9orf72 — verify panel includes specialized expansion testing.
• GRN-FTD: serum progranulin (low) supportive before genetic testing.
• MAPT: think with parkinsonian features (PSP / CBS overlap).
• Familial prion disease: PRNP codons 102 (GSS), 178 (FFI), 200 (familial CJD); codon 129 modifies phenotype.
• ALSP / HDLS: often misdiagnosed as FTD or MS — consider CSF1R in adult-onset leukoencephalopathy + cognitive change.
• Predictive testing protocol: formal counseling × 2 sessions, mental health screening, cooling-off period.
• GINA does not protect life / disability / long-term care insurance — counsel before predictive testing.

References

1. Bateman RJ, Xiong C, Benzinger TL, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012;367(9):795-804.
2. Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011;72(2):257-268.
3. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72(2):245-256.
4. Mead S. Prion disease genetics. Eur J Hum Genet. 2006;14(3):273-281.
5. Konno T, Tada M, Tada M, et al. CSF1R-related leukoencephalopathy: a major player in primary microgliopathies. Neurology. 2018;91(24):1092-1104.
6. Sims R, Hill M, Williams J. The multiplex model of the genetics of Alzheimer’s disease. Nat Neurosci. 2020;23(3):311-322.
7. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9-21.
8. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease. JAMA. 2023;330(6):512-527.