Abstract
Background
Dementia is a syndrome that comprises many differing pathologies, including Alzheimer’s disease dementia (ADD), vascular dementia (VaD) and frontotemporal dementia (FTD). People may benefit from knowing the type of dementia they live with, as this could inform prognosis and may allow for tailored treatment. Beta‐amyloid (1‐42) (ABeta42) is a protein which decreases in both the plasma and cerebrospinal fluid (CSF) of people living with ADD, when compared to people with no dementia. However, it is not clear if changes in ABeta42 are specific to ADD or if they are also seen in other types of dementia. It is possible that ABeta42 could help differentiate ADD from other dementia subtypes.
Objectives
To determine the accuracy of plasma and CSF ABeta42 for distinguishing ADD from other dementia subtypes in people who meet the criteria for a dementia syndrome.
Search methods
We searched MEDLINE, and nine other databases up to 18 February 2020. We checked reference lists of any relevant systematic reviews to identify additional studies.
Selection criteria
We considered cross‐sectional studies that differentiated people with ADD from other dementia subtypes. Eligible studies required measurement of participant plasma or CSF ABeta42 levels and clinical assessment for dementia subtype.
Data collection and analysis
Seven review authors working independently screened the titles and abstracts generated by the searches. We collected data on study characteristics and test accuracy. We used the second version of the ‘Quality Assessment of Diagnostic Accuracy Studies’ (QUADAS‐2) tool to assess internal and external validity of results. We extracted data into 2 x 2 tables, cross‐tabulating index test results (ABeta42) with the reference standard (diagnostic criteria for each dementia subtype). We performed meta‐analyses using bivariate, random‐effects models. We calculated pooled estimates of sensitivity, specificity, positive predictive values, positive and negative likelihood ratios, and corresponding 95% confidence intervals (CIs).
In the primary analysis, we assessed accuracy of plasma or CSF ABeta42 for distinguishing ADD from other mixed dementia types (non‐ADD). We then assessed accuracy of ABeta42 for differentiating ADD from specific dementia types: VaD, FTD, dementia with Lewy bodies (DLB), alcohol‐related cognitive disorder (ARCD), Creutzfeldt‐Jakob disease (CJD) and normal pressure hydrocephalus (NPH). To determine test‐positive cases, we used the ABeta42 thresholds employed in the respective primary studies. We then performed sensitivity analyses restricted to those studies that used common thresholds for ABeta42.
Main results
We identified 39 studies (5000 participants) that used CSF ABeta42 levels to differentiate ADD from other subtypes of dementia. No studies of plasma ABeta42 met the inclusion criteria. No studies were rated as low risk of bias across all QUADAS‐2 domains. High risk of bias was found predominantly in the domains of patient selection (28 studies) and index test (25 studies).
The pooled estimates for differentiating ADD from other dementia subtypes were as follows: ADD from non‐ADD: sensitivity 79% (95% CI 0.73 to 0.85), specificity 60% (95% CI 0.52 to 0.67), 13 studies, 1704 participants, 880 participants with ADD; ADD from VaD: sensitivity 79% (95% CI 0.75 to 0.83), specificity 69% (95% CI 0.55 to 0.81), 11 studies, 1151 participants, 941 participants with ADD; ADD from FTD: sensitivity 85% (95% CI 0.79 to 0.89), specificity 72% (95% CI 0.55 to 0.84), 17 studies, 1948 participants, 1371 participants with ADD; ADD from DLB: sensitivity 76% (95% CI 0.69 to 0.82), specificity 67% (95% CI 0.52 to 0.79), nine studies, 1929 participants, 1521 participants with ADD. Across all dementia subtypes, sensitivity was greater than specificity, and the balance of sensitivity and specificity was dependent on the threshold used to define test positivity.
Authors’ conclusions
Our review indicates that measuring ABeta42 levels in CSF may help differentiate ADD from other dementia subtypes, but the test is imperfect and tends to misdiagnose those with non‐ADD as having ADD. We would caution against the use of CSF ABeta42 alone for dementia classification. However, ABeta42 may have value as an adjunct to a full clinical assessment, to aid dementia diagnosis.
Plain language summary
How accurate is the ABeta42 test for distinguishing Alzheimer’s disease from other types of dementia in patients seen in a specialist clinic?
Why is improving dementia diagnosis important?
Dementia is a condition characterised by progressive problems with memory and thinking. Dementia can be caused be a number of different conditions (for example, by Alzheimer’s disease), and the best treatments depend on the underlying cause. Levels of the protein ABeta42 in blood or spinal fluid may determine the underlying cause of dementia. This could help clinicians choose the best treatments.
What is the aim of this review?
The aim of this review was to find out how accurate are the levels of ABeta42 in blood or spinal fluid for determining the cause of dementia.
What was studied in the review?
We included studies that examined the levels of ABeta42 taken from samples of blood or spinal fluid. At present, this test is only used in specialist clinics. Levels of ABeta42 may be lower in persons with Alzheimer’s dementia compared to those with other types of dementia.
What are the main results of this review?
We included 39 studies with a total of 5000 participants. All studies used spinal fluid tests of ABeta42. None of the included studies used a blood test of ABeta42.
In theory, the results of these studies indicate that if ABeta42 were to be used in a specialist clinic in a group of 1000 people, where 520 (52%) have Alzheimer’s dementia, an estimated 602 would have an ABeta42 result. This would indicate that Alzheimer’s dementia is present. Of these, 192 (32%) would be incorrectly classified as having Alzheimer’s disease. Of the 398 people with a result indicating that Alzheimer’s disease is not present, 110 (28%) would be incorrectly classified as not having Alzheimer’s disease. The included studies used different levels of ABeta42 to make the diagnosis of Alzheimer’s disease, and the accuracy of the test depended on the level of ABeta42 used.
How reliable are the results of the studies in this review?
In most of the included studies, the diagnosis of Alzheimer’s dementia was made by assessing all participants with standard diagnostic criteria.This is likely to have been a reliable method for deciding whether patients really had Alzheimer’s disease. However, there were some problems with how the studies were conducted. This may result in ABeta42 appearing more accurate than it really is.
To whom do the results of this review apply?
The results apply to patients undergoing dementia assessment in a specialist setting.
What are the implications of this review?
Measuring levels of ABeta42 in spinal fluid may help distinguish Alzheimer’s disease from other types of dementia, but the test is not perfect. ABeta42 is unlikely to be used in isolation for making a diagnosis, and may have greatest value when used in addition to the other assessments and tests that are undertaken to make a diagnosis of dementia.
How up‐to‐date is the review?
The review authors searched for and included studies published up to February 2020.
