A new study published by the Dementia Research Centre at University College London’s Institute of Neurology has concluded that the age of onset and clinical features of autosomal dominant familial Alzheimer’s disease (ADAD) may be influenced by position of the mutation that causes the disorder and the specific causative gene responsible. This conclusion reinforces the importance of considering genetic testing in younger patients who present with dementia and additional neurological features to ensure proper diagnosis and treatment.

Familial Alzheimer’s disease is clinically similar to the sporadic form of the disease in that both are associated with progressive impairment of episodic memory, though the heritable form of the disease typically presents with a younger age of onset. Despite ADAD affecting less than 1% of all Alzheimer’s patients, the disease has long been considered a useful model to study to shed light on the disorder in general.

To further explore the relationship between the genotype and phenotype of ADAD patients, the Dementia Research Centre reviewed medical histories of approximately 213 patients in the UK and Ireland who were shown to be carriers of two mutations that led to the disease over a 28-year period. The two specific genetic mutations examined were mutations in the gene presenilin 1 (PSEN1) and mutations in a gene responsible for producing amyloid precursor protein (APP).

The results indicate that age of onset is significantly later for individuals who are carriers of APP mutations (50.4 years) than for those with PSEN1 mutations (43.6 years). Moreover, researchers learned that the age of onset in patients with PSEN1 mutations was influenced by the position of the mutation in the gene. The study also shows that the type of symptoms that presented were different between the two mutation carriers. Carriers of mutations in PSEN1 tend to present with atypical cognitive symptoms and other neurological features such as spastic paraparesis, rigidity, and ataxia in addition to the typical Alzheimer symptoms.

The study’s findings suggest that it is important to consider ADAD as an option in differential diagnoses of patients with early onset dementia and other neurological features. Moreover, the authors suggest that these findings serve to highlight the importance of investigating atypical genotypes of non-familial Alzheimer’s to better understand the complex mechanisms that lead to the disease.

Reference: Ryan NS, et al. (2016) Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: a case series. The Lancet Neurology 15(13): 1326 – 1335.