In Nature Aging, researchers have published a method of predicting dementia over a decade before it actually occurs.
Early detection was known to be possible
It has been known that it is possible to observe early signs of brain deterioration years before dementia occurs [1]. However, actually performing accurate tests in a clinical setting has not been done, and figuring out ways of doing so has been identified as a research priority since 2016 [2]. Previous work has pushed towards this, discovering proteins associated with dementia, and one previous study had attempted to predict dementia using proteomics [3].
This study’s authors, however, believe that previous study to be underpowered. It had a relatively small sample size and did not categorize results into time groups, meaning that it could not estimate how long it would take for any particular individual to begin exhibiting the symptoms of dementia. Furthermore, it did not differentiate between types of dementia.
Therefore, these researchers sought to create a better study using the UK Biobank, one of the most exhaustive and well-used sources of biometric and population data in the world.
A robust cohort
Data from more than fifty thousand people, including levels of 1,463 plasma proteins, was used in this study. The participants did not have dementia at baseline and were, on average, 58 years old. 219 members of this group developed at least one form of dementia within five years, another 833 developed it within ten years, and a further 584 developed it after that.
The researchers were looking for three forms of dementia: all-cause, Alzheimer’s, and vascular. After adjusting for confounders, including sex, age, educational attainment, and the well-known Alzheimer’s-promoting allele APOE4, the researchers found hundreds of proteins associated with all-cause or vascular dementia and 16 proteins associated with Alzheimer’s.
In particular, the proteins NEFL, GFAP, and growth-differentiation factor 15 (GDF15) had among the strongest associations in predicting dementia of all three types. People with high levels of GFAP were nearly three times as likely to develop Alzheimer’s as people with low levels. Interestingly, GFAP was associated only with dementias and not with other neurological diseases, as was the protein LTBP2. Baseline elevated levels of NEFL and GDF15, on the other hand, were associated with a wide variety of neurological problems.
Combining those three biomarkers with demographic characteristics, the researchers found that they could predict future dementia with very high accuracy and few false positives in all three time period categories. Eight other additional proteins provided slightly more accuracy, but including many of the other proteins did not have any additional predictive value.
Cause or effect?
The researchers spend time discussing the roles of these proteins and review previous literature about their sources and effects. GDF15 has been previously identified as being produced in response to brain damage [4], and damage to axons has been found to cause the release of NEFL [5]. GFAP was singled out by the researchers for its accuracy and specificity to future dementia.
However, it is still unproven whether any of these proteins are potential sources of dementia or mere byproducts of brain damage. Therefore, this study offers a new method for clinicians to potentially diagnose and begin early mitigation strategies of Alzheimer’s or other dementias, but it does not directly offer any methods of treatment. Future research will have to be conducted to determine if these proteins are valid targets for potential therapies.
Literature
[1] Swaddiwudhipong, N., Whiteside, D. J., Hezemans, F. H., Street, D., Rowe, J. B., & Rittman, T. (2023). Pre‐diagnostic cognitive and functional impairment in multiple sporadic neurodegenerative diseases. Alzheimer’s & Dementia, 19(5), 1752-1763.
[2] Shah, H., Albanese, E., Duggan, C., Rudan, I., Langa, K. M., Carrillo, M. C., … & Dua, T. (2016). Research priorities to reduce the global burden of dementia by 2025. The Lancet Neurology, 15(12), 1285-1294.
[3] Walker, K. A., Chen, J., Zhang, J., Fornage, M., Yang, Y., Zhou, L., … & Coresh, J. (2021). Large-scale plasma proteomic analysis identifies proteins and pathways associated with dementia risk. Nature Aging, 1(5), 473-489.
[4] Schindowski, K., von Bohlen und Halbach, O., Strelau, J., Ridder, D. A., Herrmann, O., Schober, A., … & Unsicker, K. (2011). Regulation of GDF-15, a distant TGF-β superfamily member, in a mouse model of cerebral ischemia. Cell and tissue research, 343, 399-409.
[5] Gisslén, M., Price, R. W., Andreasson, U., Norgren, N., Nilsson, S., Hagberg, L., … & Zetterberg, H. (2016). Plasma concentration of the neurofilament light protein (NFL) is a biomarker of CNS injury in HIV infection: a cross-sectional study. EBioMedicine, 3, 135-140.
