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Brain. 2019 May 1;142(5):1429-1440. doi: 10.1093/brain/awz050.

Clinical, pathophysiological and genetic features of motor symptoms in autosomal dominant Alzheimer's disease.

Author information

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany.
Washington University School of Medicine, 660 South Euclid, Saint Louis, MO, USA.
German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
Hertie Institute for Clinical Brain Research, University of Tübingen, Germany.
Department of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, and Gertrude H. Sergievsky Center, Columbia University Irving Medical Center, 710 West 168th Street Box 176, New York, NY, USA.
University of Pittsburgh, 3471 Fifth Ave #900, Pittsburgh, PA, USA.
Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
Indiana University School of Medicine, Indianapolis, IN, USA.
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Butler Hospital, 345 Blackstone Boulevard, Providence, RI, USA.
Osaka City University Medical School, Asahimachi, Abenoku, Osaka 545-8585, Japan.
Neuroscience Research Australia, Sydney, Australia.
School of Medical Sciences, University of New South Wales, Sydney, Australia.
Florey Institute, University of Melbourne, Level 5, Kenneth Myer Building, 30 Royal Parade, Parkville, Victoria, 3010, Australia.
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, B1065, New York, NY, USA.
Dementia Research Centre, Institute of Neurology, University College London, Queen Square, London, UK.
FLENI, Montañeses 2325 (C1428AQK), Bs As, Argentina.
Keck School of Medicine of University of Southern California, Center for the Health Professionals, 1540 Alcazar Street, Suite 209F, Los Angeles, CA, USA.
Department of Neurology, Technical University of Munich, Munich, Germany.
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Biomedical Center (BMC), Metabolic Biochemistry, LMU Munich, Germany.
German Center for Vertigo and Balance Disorders, Ludwig Maximilians University, Munich, Germany.
Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, 72076 Tübingen, Germany.


Owing to an early and marked deposition of amyloid-β in the basal ganglia, autosomal dominant Alzheimer's disease could distinctly involve motor symptoms. Therefore, we aimed to assess the prevalence and characteristics of motor signs in autosomal dominant Alzheimer's disease. Baseline Unified Parkinson Disease Rating Scale part three scores (UPDRS-III) from 433 participants of the Dominantly Inherited Alzheimer's Network observational study were analysed. Motor symptoms were scrutinized with respect to associations with mutation carrier status, mutation site within PSEN1, basal ganglia amyloid-β as measured by Pittsburgh compound B PET, estimated years to symptom onset and Clinical Dementia Rating Scale-Sum of Boxes. Motor findings in mutation carriers were compared to patients with sporadic Alzheimer's disease using data of the National Alzheimer's Coordination Center. Mutation carriers showed motor findings at a higher frequency (28.4% versus 12.8%; P < 0.001) and severity (mean UPDRS-III scores 2.0 versus 0.4; P < 0.001) compared to non-carriers. Eleven of the 27 UPDRS-III items were statistically more frequently affected in mutation carriers after adjustment for multiple comparisons. Ten of these 11 items were subscale components of bradykinesia. In cognitively asymptomatic mutation carriers, dysdiadochokinesia was more frequent compared to non-carriers (right hand: 3.8% versus 0%; adjusted P = 0.023; left: 4.4% versus 0.6%; adjusted P = 0.031). In this cohort, the positive predictive value for mutation carrier status in cognitively asymptomatic participants (50% a priori risk) of dysdiadochokinesia was 100% for the right and 87.5% for the left side. Mutation carriers with motor findings more frequently were basal ganglia amyloid-β positive (84% versus 63.3%; P = 0.006) and showed more basal ganglia amyloid-β deposition (Pittsburgh compound B-standardized uptake value ratio 2.472 versus 1.928; P = 0.002) than those without. Frequency and severity of motor findings were greater in post-codon 200 PSEN1 mutations (36%; mean UPDRS-III score 3.03) compared to mutations pre-codon 200 PSEN1 (19.3%, P = 0.022; 0.91, P = 0.013). In mutation carriers, motor symptom severity was significantly positively correlated with basal ganglia amyloid-β deposition, Clinical Dementia Rating scores and estimated years to symptom onset. Mutation carriers with a Clinical Dementia Rating global score of 2 exhibited more pronounced motor symptoms than sporadic Alzheimer's disease patients with the same Clinical Dementia Rating global score (mean UPDRS-III scores 20.71 versus 5.96; P < 0.001). With a prevalence of approximately 30% and increasing severity with progression of dementia, motor symptoms are proven as a clinically relevant finding in autosomal dominant Alzheimer's disease, in particular in advanced dementia stages, that correlates with deposition of amyloid-β in the basal ganglia. In a very small per cent of cognitively asymptomatic members of families with autosomal dominant Alzheimer's disease, dysdiadochokinesia may increase the chance of an individual's status as mutation carrier.


Alzheimer’s disease; Unified Parkinson Disease Rating Scale; amyloid-β; genetics; motor symptoms

[Available on 2020-05-01]

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