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Signs and symptoms preceding the diagnosis of Alzheimer's disease: A systematic scoping review of literature from 1937 to 2016

Bature, Fidelia; Guinn, Barbara Ann; Pang, Dong; Pappas, Yannis


Fidelia Bature

Dong Pang

Yannis Pappas


Late diagnosis of Alzheimer's disease (AD) may be due to diagnostic uncertainties. We aimed to determine the sequence and timing of the appearance of established early signs and symptoms in people who are subsequently diagnosed with AD.
We used systematic review methodology to investigate the existing literature. Articles were reviewed in May 2016, using the following databases: MEDLINE, PsycINFO, CINAHL, British Nursing Index, PubMed central and the Cochrane library, with no language restriction. Data from the included articles were extracted independently by two authors and quality assessment was undertaken with the quality assessment and diagnostic accuracy tool-2 (QUADAS tool-2 quality assessment tool).
We found that depression and cognitive impairment were the first symptoms to appear in 98.5% and 99.1% of individuals in a study with late-onset AD (LOAD) and 9% and 80%, respectively, in early-onset AD (EOAD). Memory loss presented early and was experienced 12 years before the clinically defined AD dementia in the LOAD. However, the rapidly progressive late-onset AD presented predominantly with 35 non-established focal symptoms and signs including myoclonus (75%), disturbed gait (66%) and rigidity. These were misdiagnosed as symptoms of Creutzfeldt-Jacob disease (CJD) in all the cases. The participant with the lowest mini-mental state examination score of 25 remained stable for 2 years, which is consistent with the score of the healthy family members.
The findings of this review suggest that neurological and depressive behaviours are an early occurrence in EOAD with depressive and cognitive symptoms in the measure of semantic memory and conceptual formation in LOAD. Misdiagnosis of rapidly progressive AD as CJD and the familial memory score can be confounding factors while establishing a diagnosis. However, the study was limited by the fact that each one of the findings was based on a single study.


Bature, F., Guinn, B. A., Pang, D., & Pappas, Y. (2017). Signs and symptoms preceding the diagnosis of Alzheimer's disease: A systematic scoping review of literature from 1937 to 2016. BMJ open, 7(8), Article e015746.

Journal Article Type Review
Acceptance Date Jun 7, 2017
Online Publication Date Aug 28, 2017
Publication Date Aug 1, 2017
Deposit Date Sep 3, 2019
Publicly Available Date Sep 3, 2019
Journal BMJ Open
Print ISSN 2044-6055
Electronic ISSN 2044-6055
Publisher BMJ Publishing Group
Peer Reviewed Peer Reviewed
Volume 7
Issue 8
Article Number e015746
Public URL
Publisher URL


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This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:

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