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Brain. 2015 Apr;138(Pt 4):1036-45. doi: 10.1093/brain/awv004. Epub 2015 Feb 15.

Early behavioural changes in familial Alzheimer's disease in the Dominantly Inherited Alzheimer Network.

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1 Mary S. Easton Centre for Alzheimer's Disease Research at UCLA, 10911 Weyburn Ave., #200, Los Angeles, CA, 90095, USA
2 David Geffen School of Medicine at UCLA, Dept. of Medicine, 911 Broxton, Los Angeles, CA, 90024, USA.
1 Mary S. Easton Centre for Alzheimer's Disease Research at UCLA, 10911 Weyburn Ave., #200, Los Angeles, CA, 90095, USA.
1 Mary S. Easton Centre for Alzheimer's Disease Research at UCLA, 10911 Weyburn Ave., #200, Los Angeles, CA, 90095, USA 3 GRECC/Neurobehaviour Service, VA Greater Los Angeles Healthcare System, Bldg. 500-3257, #127, Los Angeles, CA, 90095, USA.
4 Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
5 Department of Neurology, Knight Alzheimer's Disease Research Centre at Washington University School of Medicine, 4488 Forest Park Ave., St. Louis, MO, 63108, USA.
6 Department of Neurology, Indiana University, 355 W. 16th Street, Suite 4700, Indianapolis, IN 46202, USA.
7 Department of Pathology and Laboratory Medicine, Indiana University, 635 Barnhill Drive, MS A 142, Indianapolis, IN, 46202, USA.
8 Alzheimer Disease Research Centre, University of Pittsburgh School of Medicine, 4-West Montefiore University Hospital, 200 Lothrop Street Pittsburgh, PA 15213, USA.
9 The Florey Institute, The University of Melbourne, Parkville, Victoria, Australia 3010.
10 Columbia University, College of Physicians and Surgeons 630 West 168th Street New York, New York, 10032, USA.
11 Dementia Research Centre, Department of Neurodegeneration, Institute of Neurology, University College London, Queen Square, London WC1 3BG, UK.
12 Brown University, Butler Hospital, 345 Blackstone Blvd. Providence, RI, 02906, USA.
13 Neuroscience Research Australia, Barker St., Randwick, Sydney 2031, Australia and School of Medical Sciences, University of New South Wales, Sydney 2052, Australia.
14 Cleveland Clinic Lou Ruvo Centre for Brain Health, 888 W. Bonneville, Las Vegas, NV, 89106, USA.

Erratum in


Prior studies indicate psychiatric symptoms such as depression, apathy and anxiety are risk factors for or prodromal symptoms of incipient Alzheimer's disease. The study of persons at 50% risk for inheriting autosomal dominant Alzheimer's disease mutations allows characterization of these symptoms before progressive decline in a population destined to develop illness. We sought to characterize early behavioural features in carriers of autosomal dominant Alzheimer's disease mutations. Two hundred and sixty-one persons unaware of their mutation status enrolled in the Dominantly Inherited Alzheimer Network, a study of persons with or at-risk for autosomal dominant Alzheimer's disease, were evaluated with the Neuropsychiatric Inventory-Questionnaire, the 15-item Geriatric Depression Scale and the Clinical Dementia Rating Scale (CDR). Ninety-seven asymptomatic (CDR = 0), 25 mildly symptomatic (CDR = 0.5), and 33 overtly affected (CDR > 0.5) autosomal dominant Alzheimer's disease mutation carriers were compared to 106 non-carriers with regard to frequency of behavioural symptoms on the Neuropsychiatric Inventory-Questionnaire and severity of depressive symptoms on the Geriatric Depression Scale using generalized linear regression models with appropriate distributions and link functions. Results from the adjusted analyses indicated that depressive symptoms on the Neuropsychiatric Inventory-Questionnaire were less common in cognitively asymptomatic mutation carriers than in non-carriers (5% versus 17%, P = 0.014) and the odds of experiencing at least one behavioural sign in cognitively asymptomatic mutation carriers was lower than in non-carriers (odds ratio = 0.50, 95% confidence interval: 0.26-0.98, P = 0.042). Depression (56% versus 17%, P = 0.0003), apathy (40% versus 4%, P < 0.0001), disinhibition (16% versus 2%, P = 0.009), irritability (48% versus 9%, P = 0.0001), sleep changes (28% versus 7%, P = 0.003), and agitation (24% versus 6%, P = 0.008) were more common and the degree of self-rated depression more severe (mean Geriatric Depression Scale score of 2.8 versus 1.4, P = 0.006) in mildly symptomatic mutation carriers relative to non-carriers. Anxiety, appetite changes, delusions, and repetitive motor activity were additionally more common in overtly impaired mutation carriers. Similar to studies of late-onset Alzheimer's disease, we demonstrated increased rates of depression, apathy, and other behavioural symptoms in the mildly symptomatic, prodromal phase of autosomal dominant Alzheimer's disease that increased with disease severity. We did not identify any increased psychopathology in mutation carriers over non-carriers during the presymptomatic stage, suggesting these symptoms result when a threshold of neurodegeneration is reached rather than as life-long qualities. Unexpectedly, we found lower rates of depressive symptoms in cognitively asymptomatic mutation carriers.


Alzheimer; behaviour; depression; familial; prodromal

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