Plasma biomarkers and genetics in the diagnosis and prediction of Alzheimer’s disease

Abstract

Plasma biomarkers for Alzheimer’s disease-related pathologies have undergone rapid developments during the past few years, and there are now well-validated blood tests for amyloid and tau pathology, as well as neurodegeneration and astrocytic activation. To define Alzheimer’s disease with biomarkers rather than clinical assessment, we assessed prediction of research-diagnosed disease status using these biomarkers and tested genetic variants associated with the biomarkers that may reflect more accurately the risk of biochemically defined Alzheimer’s disease instead of the risk of dementia. In a cohort of Alzheimer’s disease cases (N=1439, mean age 68 years [SD=8.2]) and screened controls (N=508, mean age 82 years [SD=6.8]), we measured plasma concentrations of the 40 and 42 amino acid-long amyloid β fragments (Aβ40 and Aβ42, respectively), tau phosphorylated at amino acid 181 (P-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) using state-of-the-art Single molecule array (Simoa) technology. We tested the relationships between the biomarkers and Alzheimer’s disease genetic risk, age at onset, and disease duration. We also conducted a genome-wide association study for association of disease risk genes with these biomarkers. The prediction accuracy of Alzheimer’s disease clinical diagnosis by the combination of all biomarkers, APOE and polygenic risk score reached AUC=0.81, with the most significant contributors being ε4, Aβ40 or Aβ42, GFAP and NfL. All biomarkers were significantly associated with age in cases and controls (p<4.3x10-5). Concentrations of the Aβ-related biomarkers in plasma were significantly lower in cases compared with controls, whereas other biomarker levels were significantly higher in cases. In the case-control genome-wide analyses, APOE-ε4 was associated with all biomarkers (p=0.011- 4.78x10-8), except NfL. No novel genome-wide significant SNPs were found in the case-control design; however, in a case-only analysis, we found two independent genome-wide significant associations between the Aβ42/Aβ40 ratio and WWOX and COPG2 genes. Disease prediction modelling by the combination of all biomarkers indicates that the variance attributed to P-tau181 is mostly captured by APOE-ε4, whereas Aβ40, Aβ42, GFAP and NfL biomarkers explain additional variation over and above APOE. We identified novel plausible genome wide-significant genes associated with Aβ42/Aβ40 ratio in a sample which is fifty times smaller than current genome-wide association studies in Alzheimer’s disease.

WWOX P47T loss-of-function mutation induces epilepsy, progressive neuroinflammation, and cerebellar degeneration in mice phenocopying human SCAR12

“…We detected very frequent interictal cortical spike discharges (0-3098/hour) (Fig. 1cii) and repeated spontaneous generalized convulsive activity (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) seizures during 43-53 hour monitoring periods) in both male and female homozygous mutant mice. All three Wwox P47T/P47T mutant mice had multiple (>4) seizures during a 24 hour recording period (Supplementary Figs.…”

“…In addition, the introduction of the P47T mutation had no detrimental effect on normal mouse growth or reproduction in Wwox P47T/WT mice. Thus, the mouse model here described will not only be useful for the study of the rare ARCA such as SCAR12, but is likely more generalizable to understand the role of WWOX in the pathogenesis of a variety of far more common neurodegenerative conditions where this gene has been identified as a risk factor (e.g., Alzheimer's disease, Parkinson's disease) [11,[13][14][15][16][17][18]. Finally, this novel mouse model of neurodegeneration can provide a useful in vivo tool for testing promising therapeutic strategies for neurodevelopmental and neurodegenerative conditions in which WWOX loss of function plays a pathogenic role.…”

“…Importantly, recent large-scale genome-wide association meta-analyses and biomarker studies have also identified WWOX as a risk gene for common neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis [10][11][12][13][14][15][16][17][18]. The latter two pathologies include ataxia and impaired motor coordination, among significant clinical manifestations.…”

Advanced brain imaging for the diagnosis of Alzheimer disease

“…Additionally, fluid biomarkers may provide a window for detection of novel biomarkers that cannot be identified via brain imaging techniques. Currently, five fluid-based biomarkers have been developed into diagnostic tests for these essential brain changes in the AD process: the ratio of 42 to 40 amino acid-long Aβ peptides (Aβ42/Aβ40), a marker of Aβ plaque pathology; total-tau and phosphorylated tau (t-tau and p-tau, respectively), markers of AD-related changes in tau metabolism, phosphorylation and secretion; neurofilament light (NfL), a marker of neurodegeneration; and glial fibrillary acidic protein (GFAP), a marker neuroinflammation [123]. Originally, these biomarkers could only be measured in the CSF, but technological progress resulting in improved analytical sensitivity has now made it possible to measure them in standard blood samples as well [124].…”

Bibliometric review on biomarkers for Alzheimer’s disease between 2000 and 2023

“…With the prospect of disease improvement, the use of biomarkers to diagnose specific forms of dementia earlier. [4][5][6] Therefore, it is important to develop biomarkers that can diagnose these changes in order to improve the likelihood of monitoring and treating potential causes. Cerebrospinal fluid (CSF), plasma biomarkers, and amyloid imaging biomarkers can provide information on the neuropathological symptoms of AD.…”