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

Abstract

Objective: 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.

Methods: 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).

Results: 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.

Conclusions: 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.

Keywords: Alzheimer's disease (AD); early signs and symptoms; early stage of AD; mild cognitive impairment (MCI); systematic scoping review.

Figure 1

Flowchart indicating the process for the selection of studies. The flowchart indicates the articles identified through the search: those reviewed as title and abstract, those reviewed fully and the ones that met the inclusion criteria.

Figure 2

Graph representing the risk of bias and applicability concerns. Each domain is represented as a percentage across included studies for the review; the red colour indicates high risk, while green indicates low risk. However, none of the studies were given an unclear risk of bias and applicability concerns (QUADAS-2 tool).

Figure 3

Summary of the risk of bias and applicability concerns. The reviewer’s judgement on each domain for the included studies is shown with a high risk of bias and applicability concerns on index test for.