Atypical Symptoms in Familial Alzheimer’s Partly Determined by Mutation Type, Study Finds

The mutated gene, as well as the position of the mutation within a gene, impact the kind of symptoms patients with dominantly inherited Alzheimer’s disease develop, according to new research.

These findings also underscored the notion that familial Alzheimer’s is a highly variable condition, making genetic testing a crucial component when examining young people with dementia and other neurological symptoms.

The study, “Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: a case series,” recently appeared in the journal The Lancet Neurology.

Mutations in the genes PSEN1, PSEN2, and APP cause an inherited form of Alzheimer’s disease in a small proportion of patients. Scientists know that, much like patients with sporadic forms of the condition, dominantly inherited Alzheimer’s patients often have cognitive symptoms other than memory impairment.

Not much is known about factors that may determine if a patient is likely to develop a particular symptom, however. Researchers from University College London decided to explore such factors in patients treated at the Dementia Research Centre in London.

The research team analyzed data retrospectively, including patients with familial Alzheimer’s caused by mutations in the genes APP and PSEN1, and treated at the center between July 1, 1987, and Oct. 31, 2015.

Information about the age of symptom onset was available for 213 people, and 121 had detailed information that included medical history and results of neurological examinations.

Patients carried a total of 38 different PSEN1 mutations, four of which had not been described before, and six in APP, of which one mutation was new.

Patients with PSEN1 mutations were younger than those with APP mutations when they developed the disease: 43.6 years versus 50.4 years.

Five mutations in the PSEN1 gene were linked to a particularly early onset. All these mutations were present in the same region of the gene, indicating that this region is important for certain processes.

Only 84 percent of patients with PSEN1 mutations had memory problems, compared to 97 percent of those with APP mutations, making atypical cognitive symptoms much more common in patients with Alzheimer’s caused by PSEN1 mutations.

In addition to atypical cognitive symptoms, which included behavioral problems and difficulties in language processing, myoclonus (a type of muscle spasms) and seizures were very common. Among patients with PSEN1 mutations, 47 percent had myoclonus, and among those with APP mutations, the number was 33 percent.

This is much higher than what was found in another study, examining atypical symptoms in familial Alzheimer’s disease, published in the same issue of The Lancet Neurology.

In addition, only patients with PSEN1 mutations had other types of movement symptoms, such as parkinsonism or coordination difficulties. Certain types of movement problems could be linked to mutations in a specific area of the PSEN1 gene.

In a linked comment, published in the same journal, Wiesje M Van der Flier, with the VU University Medical Center in the Netherlands, highlighted the large differences in atypical neurological symptoms noted in the two studies of familial Alzheimer’s disease.

The differences reflect the fact that various types of research bias likely affect study results, she argued, but also highlight the notion that familial Alzheimer’s disease produces very variable symptoms.

Recognizing the less typical features of the condition is crucial for physicians examining young patients, to avoid the risk of a missed diagnosis.

Since the investigated mutation types could not explain all the variability in symptoms, Van der Flier also maintained that more research — exploring potential environmental, metabolic, or additional genetic factors — is crucial if researchers are to succeed in developing new treatments for this complex condition.