A recent study published in JAMA evaluates the potential of plasma biomarkers for Alzheimer’s disease (AD) and cardiometabolic risk factors to predict the risk of other types of dementia.
Study: Changes in Alzheimer Disease Blood Biomarkers and Associations With Incident All-Cause Dementia. Image Credit: Aquarious Studio / Shutterstock.com
Early diagnosis of dementia
The diagnosis of AD and other forms of dementia often occurs after symptoms have emerged, at which point the accumulation of pathological brain changes limits the ability to effectively treat these diseases. Thus, there is an urgent need to identify plasma biomarkers that can screen for AD pathology and neurodegeneration, particularly among presymptomatic patients.
The presence of cardiometabolic disorders in middle-aged adults is a known risk factor for dementia. However, it remains unclear how altered levels of plasma biomarkers associated with these diseases may support the prediction of neurological conditions.
Although several studies have investigated the potential of plasma biomarkers for the early diagnosis of dementia, they have been limited due to their cross-sectional study design, homogenous study populations, and lack of analyses that consider the potential impact of attrition or selection biases.
In an effort to overcome the limitations associated with these studies, the researchers of the current study examined plasma biomarker levels, alone and in association with cardiometabolic risk factors, in a diverse population over several decades to establish the validity and utility of these biomarkers in predicting the risk of dementia.
About the study
All data were obtained from the Atherosclerosis Risk in Communities (ARIC) study, which comprised 1,525 participants. The mean age of the study participants at the first plasma sample collection was 58 years, and 76 years at the second.
The levels of AD-specific markers, including the amyloid-β 42 to amyloid-β 40 (Aβ42:Aβ40) ratio and phosphorylated tau at threonine 181 (p-tau181), as well as neurodegeneration markers neurofilament light (NfL) and glial fibrillary acidic protein (GFAP), were measured in all plasma samples.
Study participants were monitored until they reached a mean age of 81. Between January 1, 2012, and December 31, 2019, new cases of dementia from all causes were identified. Risk factors for dementia, including hypertension, diabetes, lipids, coronary heart disease, cigarette smoking, and physical activity, were also evaluated for their temporal association with plasma biomarkers.
What did the study show?
About 60% of the study participants were women, and 26% were Black. There were 252 new cases of dementia, which reflected 16.5% of the study cohort. A dementia diagnosis was more likely to occur among study participants with low plasma levels of Aβ42:Aβ40 and higher levels of p-tau181, NfL, and GFAP.
For those who carried the apolipoprotein E epsilon 4 (APOEε4) gene, the rate of change in these biomarkers was higher than for non-carriers. For NfL and GFAP, the association with new-onset dementia in late life was stronger than in midlife, independent of APOEε4 status.
Study participants with high blood pressure and diabetes exhibited higher levels of NfL and GFAP that exceeded the expected rise for each decade. As compared to individuals with hypertension, NfL levels rose slower, and GFAP levels doubled in people with diabetes.
AD biomarkers in midlife were associated with an increased risk of all-cause dementia risk in late life. An 11% increased risk in this form of dementia was observed for every one standard deviation (1-SD) reduction in Aβ42:Aβ40, whereas every 1-SD increase in p-tau181 levels increased the risk by 15%.
All AD biomarkers were associated with an increased risk of late-life dementia, with the most significant association observed with NfL.
A combination of all four markers in late life improved the ability to predict dementia as compared to the use of any biomarker alone. However, combining late-life biomarkers with demographic data achieved the highest discrimination capability, irrespective of the use of APOEε4.
Conclusions
AD-specific plasma biomarkers in midlife predict an increased risk of all-cause dementia in late life, whereas neurodegeneration markers in midlife are not associated with the same predictability. In late life, both AD-specific and neurodegenerative markers are associated with late-life dementia risk. The best performance in dementia prediction was observed when late-life biomarkers and demographic data were combined.
The study findings provide crucial insights into AD biomarker research by assessing the trajectory of four key plasma biomarkers and how changes in the levels of these proteins fluctuate when other risk factors for dementia are considered. Nevertheless, future research should is needed to confirm these findings, as neurodegeneration markers could be used to monitor the efficacy of treatments aimed at reducing the vascular risk factors associated with these conditions.
Journal reference:
- Lu, Y., Pike, J. R., Chen, J., et al. (2024). Changes in Alzheimer Disease Blood Biomarkers and Associations With Incident All-Cause Dementia. JAMA. doi:10.1001/jama.2024.6619.
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