Recent advances suggest that Alzheimer’s disease (AD) has a lengthy period in which cerebral lesions gradually accumulate in the absence of clinical symptoms, eventually causing sufficient synaptic and neuronal damage that results in symptomatic AD (Price and Morris, 1999; Price et al., 2009; Jack et al., 2010). Potential disease-modifying therapies for AD may be most beneficial when initiated in the preclinical stage, before the occurrence of irreversible brain damage (Dubois et al., 2016). Therefore, it is crucial to increase the capacity to identify individuals at high risk for developing symptomatic AD not only for research purpose but in clinical practice. “Antecedent Biomarkers of AD: The Adult Children Study (ACS)” is a longitudinal study which has been conducted by Washington University since 2005; it aims to validate biological markers, imaging features, and other indicators of preclinical AD (Coats and Morris, 2005). This study revealed that family history (FH) for AD is associated with age-related changes in several cerebrospinal fluid (CSF) biomarkers in cognitively normal individuals, independent of the ε4 allele of apolipoprotein E (APOE ε4) (Xiong et al., 2011).

However, given the invasiveness of the CSF collection method, these biomarkers are not used extensively in clinical settings. Plasma is a more convenient and applicable biomarker, and increasing evidence has demonstrated the applicability of plasma biomarkers. Studies regarding the genetic risk of AD in Down syndrome showed higher concentrations of plasma amyloid beta (Aβ)_1–42 in individuals with Down syndrome compared with the controls (Mengel et al., 2020; Hendrix et al., 2021). Higher levels of Aβ_1–42 and a higher Aβ_1–42/Aβ_1–40 ratio were noted in mutation carriers in the preclinical and clinical stages of autosomal-dominant AD (Quiroz et al., 2015). Plasma measurements of Aβ and tau are increasingly showing a positive predictive value for AD-related neuropathology in patients with mild cognitive impairment and AD (Risacher et al., 2019; Li et al., 2022). Meanwhile, plasma amyloid and tau levels may predict cognitive decline and subsequent AD dementia (van Oijen et al., 2006; Graff-Radford et al., 2007; Abdullah et al., 2009; Chouraki et al., 2015; Janelidze et al., 2020; Nam et al., 2020; Cullen et al., 2021).

Family history for AD as a risk factor for developing AD and cognitive decline has been well documented (Huang et al., 2004; Jayadev et al., 2008), and changes in CSF biomarkers in the adult children (AC) of parents with AD has been previously reported (Xiong et al., 2011). However, studies regarding the potential of plasma biomarkers in these AC are limited and most of them only focus on the level of Aβ compared with normal controls (Ertekin-Taner et al., 2001, 2008). To the best of our knowledge, the plasma Aβ_1–42/Aβ_1–40 ratio, total tau (T-tau) and tau phosphorylated at threonine 181 (P-tau 181) in this population and a comparison of these potential biomarkers between AC and their AD parents has not been previously addressed.

The Aβ_1–42/Aβ_1–40 ratio is more strongly associated with tau and clinical progression than Aβ_1–42 or Aβ_1–40 alone (Risacher et al., 2019; Delaby et al., 2022). Therefore, we conducted the current study to evaluate the plasma biomarkers (Aβ_1–42, Aβ_1–40, Aβ_1–42/Aβ_1–40 ratio, T-tau and P-tau 181) and their correlations in cognitively normal individuals with AD parents and compared this data with their parents and non-demented controls (NC) (unrelated controls). The hypothesis is that the AC of AD parents who potentially have AD, will demonstrate indicators of AD at a greater frequency than the normal controls and this will demonstrate that these plasma indicators are antecedent biomarkers of AD.

We have demonstrated that compared to the NC group, there was a decreased level of Aβ_1–42 and a lower Aβ_1–42/Aβ_1–40 ratio, as well as an elevated level of Aβ_1–40, and P-tau and a higher P-tau/T-tau ratio in the AD and AC groups. There was no statistical difference in these protein levels in the AD and AC groups except for a significantly higher Aβ_1–40/T-tau ratio in the AD group compared with the AC group. The significant correlations between the levels of Aβ_1–42 and Aβ_1–40 and the levels of T-tau and P-tau were only in the AC group, not the AD group.

To the best of our knowledge, this is the first study to explore the plasma levels of Aβ and tau, and their concurrent correlations in AD, their AC and NC group, especially in individuals of Chinese ethnicity. Our study speculated that AC, in part, is potentially to develop AD in the view of our reports to these changes of plasma biomarkers. Our study also showed that a FH for AD was associated with a change in plasma biomarkers in cognitively normal AC, indicating their potential role as antecedent biomarkers of AD. The loss of a correlation between the level of Aβ_1–42 and Aβ_1–40 and the level of T-tau and P-tau could be indicative of AD clinical stage. Early diagnosis of AD even before the onset of symptoms by using these biomarkers could allow future treatments with disease-modifying effects and vigorously control modifiable cardiovascular risk factors to stop disease progression.

Unlike previous studies (Ertekin-Taner et al., 2001, 2008), a decreased plasma level of Aβ_1–42 was noted in AC with AD parents in the current study. Ertekin-Taner et al. (2008) found that plasma Aβ_1–42 was significantly elevated in late-onset AD first-degree relatives in comparison to unrelated controls. This discrepancy may not be related to the difference in the frequency of the APOE ε4 allele due to its similar frequency in both studies (40% in their study and 39.5% in our study), but it may be related to the age of the recruited participants. Subjects between the ages of 20 and 65 were recruited in their study, while we recruited AC aged 50–74 years old. The older age of our participants could increase the risk of amyloid deposition having started, which could present as a decline in the plasma Aβ_1–42 and Aβ_1–42/Aβ_1–40 ratio (Song et al., 2011; Hendrix et al., 2021). Our results were compatible with the CSF finding in the ACS (aged 43–76 years old) conducted at Washington University, where a positive FH for AD was associated with a decrease in Aβ_1–42 (Xiong et al., 2011). Further longitudinal studies are required to follow the trajectory of Aβ and the clinical cognitive function of cognitively intact AC.

In our study, elevated levels of Aβ_1–40, P-tau, and P-tau/T-tau ratio were noted in the AD and AC groups compared with the NC group. These results were in line with previous studies (Ertekin-Taner et al., 2008; Janelidze et al., 2020). Increased P-tau is thought to reflect Aβ and tau pathologies in AD, while increased T-tau is a more non-specific marker of neuronal injury (Blennow et al., 2010). Therefore, P-tau and the P-tau/T-tau ratio, but not T-tau alone, may be more suitable as antecedent biomarkers of AD. Meanwhile, the fact that the AD and AC groups had similar findings, compared with the NC group, indicates the potential for AC to develop AD.

The correlation between the level of Aβ_1–42 and Aβ_1–40 and the level of T-tau and P-tau, only existed in AC but was lost in the AD group. Amyloid peptides are formed via amyloid precursor protein (APP) cleavage at several enzyme sites. Physiologically, the non-amyloidogenic and amyloidogenic pathways characterize the amyloid peptide formation process by APP at a dynamically steady state. The amyloidogenic pathway leads to AD. After APP cleavage by β-secretase to release β-APP, the remaining membrane-bound APP C-terminal is subsequently cleaved by γ-secretase, to release Aβ_1–40 (90%) and Aβ_1–42 (10%) peptide into the extracellular space (Mokhtar et al., 2013). Disruption of this steady state could lead to subsequent pathological changes in dementia. The loss of correlation between the plasma level of Aβ_1–42 and Aβ_1–40 in AD patients may be related to progressive Aβ_1–42 deposition, while the correlation still exists in the preclinical stage or high potential AC. Tau protein is an integral component of the neuronal cytoskeleton and is responsible for the promotion of microtubule assembly in the normal brain. In the AD brain, tau exists in a hyperphosphorylated state, which leads to aberrant secondary structures and loss of function, resulting in a reduced ability to bind to microtubules and to promote their assembly (Mokhtar et al., 2013). Over- and hyper-phosphorylated tau may disrupt the correlation between the level of T-tau and P-tau in the AD group.

There were some limitations to the current study. First, although we have demonstrated innovative findings, they are based on a limited sample size with different demographic characteristics in each group; future studies utilizing larger samples are recommended. Most of the participants in our study were female. However, sex differences in AD plasma biomarkers during the preclinical stage is still unknown (Jack et al., 2017; Nebel et al., 2018). In addition, we did not perform a brain amyloid and Fluorodeoxyglucose (FDG) positron emission tomography (PET) scan for the AC participants to detect brain amyloid deposition and assess the presence of brain hypometabolism for confirming the role of possible pre-clinical AD; we will have to track their clinical course to determine if they are given a diagnosis of AD in the future. Besides, FDG PET may be useful to differential early onset (aged ≤65 years) and late-onset AD (aged >65 years). As compared to late-onset AD, early onset AD patients showed a significant decrease in glucose consumption in a wide portion of the left parietal lobe (Chiaravalloti et al., 2016). We should especially pay attention to those with this hypometabolism pattern for the possibility of developing AD symptoms earlier. Moreover, we did not survey all of the cardiovascular risk factors which inconclusively but might alter the result of biomarkers for AD. However, the prevalence of hypertension and diabetes are similar between AC and NC group and even higher prevalence of hypercholesterolemia and higher CAIDE dementia risk score in NC group. The possible influence of these vascular risk factors on plasma biomarkers may be minored. Family history of AD still be the major factor to influence them in our study. Finally, this was a cross-sectional examination of these biomarkers, especially focusing on whether there was a loss of correlation between the level of Aβ_1–42 and Aβ_1–40 and the level of T-tau and P-tau in AD. Longitudinal studies to track how these biomarkers relate to clinical presentation are encouraged.

In conclusion, we reported the influence of FH for AD on a wide array of plasma biomarkers in the AC cohort of cognitively normal middle to older age individuals. Changes in the correlation between the levels of Aβ_1–42 and Aβ_1–40, and that of T-tau and P-tau in AC may be a biomarker for the development of AD. Further longitudinal studies following the trajectory of clinical information, plasma and CSF biomarkers, structural and functional neuroimaging, such as Aβ, tau and FDG PET scans, are required to better understand the pathogenesis of AD.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Kaohsiung Medical University Hospital Institutional Review Board [KMUHIRB-SV(I)-20190025 and KMUHIRB-G(I)-20210026]. The patients/participants provided their written informed consent to participate in this study.

T-CH and Y-HY contributed to the study conception and design. L-CH, K-YL, and Y-HY contributed to the acquisition of data. M-HC, L-CH, C-PC, and Y-HY analyzed and interpreted the data. M-HC and L-CH conducted the statistical analyses and involved in writing the initial draft of the manuscript. All authors reviewed and revised the manuscript and approved the submitted version.