Research in context
Evidence before this study
We reviewed publications in the Alzheimer Disease & Frontotemporal Dementia Mutation Database and the Alzheimer Research Forum database and searched PubMed for articles published in English before Jan 27, 2015. We identified 188 peer-reviewed journal articles that reported individual-level data for age of onset, disease course from onset to death, and the presence of 14 neurological findings previously reported to be associated with autosomal dominant familial Alzheimer’s disease (ADAD). 169 of these reports were on a small number of subjects or families and across a wide spectrum of clinical severity. These reports suggested a relatively high prevalence of non-cognitive neurological manifestations, including behavioural changes, motor symptoms, and seizures, which might be further influenced by the specific gene mutation. However, we identified only six single-centre and three multicentre studies of cohorts and no compiled individual-level data reviews.
Added value of this study
We compared the prevalences of symptoms between the Dominantly Inherited Alzheimer’s Network observational study and published data for participants with ADAD, and determined correlations between clinical features and gene mutation type and position. This study provides one of the largest and most diverse collections of data for prospectively followed, symptomatic, ADAD populations. With the large number of PSEN1 mutation carriers, we were also able to explore whether atypical clinical features were associated with specific codon position, as has been suggested previously. However, we found no clear associations of clinical features with PSEN1 codon position.
Implications of available evidence
This study indicates that the prevalence of atypical clinical features in ADAD is low and might have been overestimated. Non-cognitive neurological symptoms of Alzheimer’s disease seem to affect a minority of ADAD mutation carriers, suggesting that the mutations are not the predominant factor for non-cognitive neurological manifestations of Alzheimer’s disease. The factors that influence the presence of neurological symptoms include unidentified genetic and environmental factors, with some impact from the age of onset, stage of disease, and type of mutation. Non-amnestic cognitive impairment is common in ADAD, as in sporadic Alzheimer’s disease. As ADAD has provided a wealth of understanding of Alzheimer’s disease pathophysiology, future work comparing ADAD with sporadic Alzheimer’s disease should lead to a better understanding of both sporadic and dominantly inherited Alzheimer’s disease.