Elsevier

The Lancet Neurology

Volume 15, Issue 13, December 2016, Pages 1317-1325
The Lancet Neurology

Articles
Neurological manifestations of autosomal dominant familial Alzheimer’s disease: a comparison of the published literature with the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS)

https://doi.org/10.1016/S1474-4422(16)30229-0Get rights and content

Summary

Background

Autosomal dominant familial Alzheimer’s disease (ADAD) is a rare disorder with non-amnestic neurological symptoms in some clinical presentations. We aimed to compile and compare data from symptomatic participants in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) with those reported in the literature to estimate the prevalences of non-amnestic neurological symptoms in participants with ADAD.

Methods

We prospectively collected data from the DIAN-OBS database, which recruited participants from study centres in the USA, Europe, and Australia, between Feb 29, 2008, and July 1, 2014. We also did a systematic review of publications to extract individual-level clinical data for symptomatic participants with ADAD. We used data for age of onset (from first report of cognitive decline), disease course from onset to death, and the presence of 13 neurological findings that have been reported in association with ADAD. Using multivariable linear regression, we investigated the prevalences of various non-amnestic neurological symptoms and the contributions of age of onset and specific mutation type on symptoms.

Findings

The DIAN-OBS dataset included 107 individuals with detailed clinical data (forming the DIAN-OBS cohort). Our systematic review yielded 188 publications reporting on 1228 symptomatic individuals, with detailed neurological examination descriptions available for 753 individuals (forming the published data cohort). The most prevalent non-amnestic cognitive manifestations in participants in the DIAN-OBS cohort were those typical of mild to moderate Alzheimer’s disease, including visual agnosia (55·1%, 95% CI 45·7–64·6), aphasia (57·9%, 48·6–67·3), and behavioural changes (61·7%, 51·5–70·0). Non-amnestic cognitive manifestations were less prevalent in the published data cohort (eg, visual agnosia [5·6%, 3·9–7·2], aphasia [23·0%, 20·0–26·0], and behavioural changes [31·7%, 28·4–35·1]). Prevalence of non-cognitive neurological manifestations in the DIAN-OBS cohort was low, including myoclonus and spasticity (9·3%, 95% CI 3·8–15·0), and seizures (2·8%, 0·5–5·9) and moderate for parkinsonism (11·2%, 5·3–17·1). By constrast, prevalence was higher in the published data cohort for myoclonus and spasticity (19·4%, 16·6–22·2 and 15·0%, 12·5–17·6, respectively), parkinsonism (12·5%, 10·1–15·0), and seizures (20·3%, 17·4–23·2). In an analysis of the published data cohort, ischaemic stroke was more prevalent at older ages of onset of symptoms of ADAD (odds ratio 1·09 per 1 year increase in age of onset, 95% CI 1·04–1·14, p=0·0003); and motor symptoms were more common at younger age of onset (myoclonus 0·93, 0·90–0·97, p=0·0007; seizures 0·95, 0·92–0·98, p=0·0018; corticobulbar deficits 0·91, 0·86–0·96, p=0·0012; and cerebellar ataxia 0·82, 0·74–0·91, p=0·0002). In the DIAN-OBS cohort, non-cognitive symptoms were more common at more severe stages of disease.

Interpretation

The non-cognitive clinical manifestations of Alzheimer’s disease seem to affect a small proportion of participants with mild to moderate ADAD, and are probably influenced by disease severity, environmental, and genetic factors. When evaluating patients with potential ADAD, clinicians should note that cognitive symptoms typical of sporadic Alzheimer’s disease are the most consistent finding, with some patients manifesting non-cognitive neurological symptoms. Future work is needed to determine the environmental and genetic factors that cause these neurological symptoms.

Funding

National Institutes of Health and German Center for Neurodegenerative Diseases.

Introduction

Autosomal dominant familial Alzheimer’s disease (ADAD) is a rare, completely penetrant form of Alzheimer’s disease that typically presents at a much earlier age than do sporadic forms of Alzheimer’s disease. Despite its rarity, ADAD has been used as a model to understand pathological processes and develop potential therapies for sporadic Alzheimer’s disease because of similarities in clinical course and pathophysiology.1 Although most carriers of symptomatic mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2) genes present with early amnestic symptoms2 similar to individuals with sporadic Alzheimer’s disease, some have additional behavioural and neurological deficits, such as seizures, myoclonus, spastic paraparesis, or visual disturbances, with substantial diversity in age of onset, clinical presentation, and rate of progression.1, 3, 4, 5 The location of mutations within genes can also affect pathophysiology and age of onset, as is the case for PSEN1 mutations before and after codon 200.6

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.

As a consequence of the rarity of ADAD and the reported variability in presentation, it has been difficult to estimate the prevalence of neurological manifestations of ADAD mutation carriers as a group. We aimed to better clarify the prevalence of non-amnestic manifestations of ADAD from a prospective, global, observational ADAD study—the Dominantly Inherited Alzheimer’s Network observational study (DIAN-OBS)—and individual-level data for symptomatic participants extracted from published reports. Additionally, we aimed to assess relationships of these clinical manifestations with the age of onset and the location of ADAD mutations within affected genes.

Section snippets

Participants and systematic review

Between Feb 29, 2008, and July 1, 2014, participants in the DIAN observational study (DIAN-OBS) were recruited to study centres in the USA, Europe, and Australia. Participants were members of families of mutation carriers (APP, PSEN1, or PSEN2) known to cause ADAD.7 Each study participant and someone who knew the participant well underwent semi-structured interviews by qualified study raters to collect detailed demographic information, medical history, and family history. All study staff

Results

We included 107 participants with detailed data from the DIAN-OBS database (forming the DIAN-OBS cohort). Our systematic review yielded individual-level data for 1228 individuals; 753 individuals had a detailed description of disease course (forming the published data cohort). Compared with the published data cohort, the DIAN-OBS cohort had a significantly earlier average age of onset (p=0·0004) and shorter average follow up time (p<0·0001; table 1).

34 (32%) participants in the DIAN-OBS cohort

Discussion

In the DIAN-OBS cohort, the most frequently reported non-amnestic manifestations were cognitive, including visual agnosia, aphasia, and behavioural changes. However, in published data of individuals with ADAD, we found a lower prevalence of non-amnestic cognitive symptoms and a moderate prevalence of motor symptoms and seizures. Younger age of onset and more advanced stages of disease were related to a higher frequency of non-cognitive clinical features. Adding to potential disparity, in The

References (31)

  • NS Ryan et al.

    Correlating familial Alzheimer’s disease gene mutations with clinical phenotype

    Biomark Med

    (2010)
  • JC Morris et al.

    Developing an international network for Alzheimer research: The Dominantly Inherited Alzheimer Network

    Clin Investig

    (2012)
  • JC Morris

    The Clinical Dementia Rating (CDR): current version and scoring rules

    Neurology

    (1993)
  • C Cruchaga et al.

    Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer’s disease families

    PLoS One

    (2012)
  • DC Ryman et al.

    Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis

    Neurology

    (2014)
  • Cited by (0)

    View full text