A Systematic Review of Longitudinal Studies Which Measure Alzheimer's Disease Biomarkers

Abstract

Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease, with no effective treatment or cure. A gold standard therapy would be treatment to slow or halt disease progression; however, knowledge of causation in the early stages of AD is very limited. In order to determine effective endpoints for possible therapies, a number of quantitative surrogate markers of disease progression have been suggested, including biochemical and imaging biomarkers. The dynamics of these various surrogate markers over time, particularly in relation to disease development, are, however, not well characterized. We reviewed the literature for studies that measured cerebrospinal fluid or plasma amyloid-β and tau, or took magnetic resonance image or fluorodeoxyglucose/Pittsburgh compound B-positron electron tomography scans, in longitudinal cohort studies. We summarized the properties of the major cohort studies in various countries, commonly used diagnosis methods and study designs. We have concluded that additional studies with repeat measures over time in a representative population cohort are needed to address the gap in knowledge of AD progression. Based on our analysis, we suggest directions in which research could move in order to advance our understanding of this complex disease, including repeat biomarker measurements, standardization and increased sample sizes.

Keywords: Alzheimer’s disease; biomarker; cross-sectional; dementia; longitudinal.

Fig.1

Study Selection.

Fig.2

Study locations. Proportion of studies in each country. Countries in multinational studies included: France, Germany, Switzerland, and the United Kingdom. One article did not specify in which countries the study took place. One article specified multinational European study sites, 2 articles specified North American, and 1 study featured USA, Australia, Europe, and Argentina.

Fig.3

Study locations. A) Global distribution of studies identified in our systematic review. B) ADNI locations within the United States of America and Canada. C) Enlarged map of European studies.

Fig.4

Sample size. The number of studies with sample size in the displayed range.

Fig.5

Biomarkers measured. Number of studies measuring each biomarker. The table presents the number of studies that measured a combination of biomarkers.

Fig.6

Length of follow-up and number of repeat measures. A) Number of studies with average follow-up in each interval. B) Number of studies with repeat measures.

Fig.7

Age of participants. Histogram outlining the dispersion of mean age of each study population identified by the systematic review. The yellow line corresponds to the overall mean age, taken as the average of each study population, and the red line to the median age of study participants across the systematic review.