Alzheimer's Disease Inheritance and Maternal Risk
The evidence suggests a maternal bias in Alzheimer's disease inheritance, with mothers of AD patients showing 2-3 times higher risk than fathers, though this does not change the fundamental autosomal inheritance pattern where each affected parent still confers a 50% risk to offspring in autosomal dominant cases. 1, 2
Evidence for Maternal Inheritance Pattern
The maternal inheritance phenomenon in AD has been documented through multiple research findings:
Mothers of AD patients demonstrate a 2.8-fold increased age-adjusted risk compared to fathers (95% CI: 1.1-7.7), based on analysis of 118 AD families in the CERAD registry 1
In families with one affected parent and multiple affected siblings, the mother-to-father ratio was 9:1, suggesting a strong maternal transmission pattern 1
Maternal family history associates with more severe AD biomarker changes, including higher CSF tau/Aβ ratios, increased global PiB uptake on PET imaging, and greater amyloid burden in parietal cortex, precuneus, and sensorimotor regions 2
Individuals with MCI and maternal family history show significantly more AD pathophysiology markers compared to those without family history, suggesting earlier disease manifestation through maternal lineage 2
Clinical Implications for Risk Assessment
Despite the maternal bias, the fundamental genetic counseling principles remain unchanged:
For autosomal dominant early-onset AD (EOAD), the risk of inheriting a mutation from either affected parent remains 50%, as mutations in PSEN1, PSEN2, and APP follow Mendelian inheritance 3
Family history assessment should include a minimum 3-generation pedigree, documenting ages of onset, types of dementia, and causes of death for both maternal and paternal lineages 3
The lifetime risk in the general population is 10-12% over a 75-80 year lifespan, but this at least doubles with any first-degree relative affected, regardless of parent gender 4
Practical Approach to Family History Evaluation
When evaluating patients with family history concerns:
Document specific details about affected relatives: age of onset (before or after 60-65 years), number of affected individuals, degree of relationship, and whether pattern suggests autosomal dominant inheritance (≥3 individuals across ≥2 generations) 3
Consider genetic counseling referral if either parent developed AD before age 65, or if multiple family members across generations are affected, particularly through maternal lineage 4, 5
Genetic testing for EOAD genes (PSEN1, PSEN2, APP) should only be pursued in families with clear autosomal dominant patterns or early-onset cases, and must be accompanied by formal genetic counseling 3, 5
APOE testing is not clinically recommended for routine risk assessment due to limited predictive value and lack of actionable interventions 3, 4
Important Caveats
The maternal inheritance pattern does not imply mitochondrial inheritance or change genetic counseling for autosomal dominant cases:
The mechanism underlying maternal bias remains unclear but may involve maternally inherited factors, epigenetic modifications, or mitochondrial contributions that modify disease risk 2
Mixed evidence exists for parent-of-origin effects, and the 2019 population study showed inconsistent findings regarding maternal versus paternal inheritance patterns 6
Small family sizes and premature deaths can mask true inheritance patterns, making apparent sporadic cases actually represent hidden familial or autosomal dominant disease 3