**6. AD risk factors**

Several risk factors for AD have been indicated. Genetic factors are increasingly recognized as major risk factors for dementia. The most remarkable factor for AD from numerous studies is the ApoE gene on chromosome 19. ApoE, which is a major component of lipoproteins with 299 amino acid residues, plays a role in the metabolism and redistribution of cholesterol [61]. ApoE constitutes three major common isoforms, designated ApoE2, ApoE3, and ApoE4. ApoE isoforms interact differently with Aβ isoform-specific effects on Aβ-clearance. In ApoE4, domain interaction occurs as a result of a putative salt bridge, leading to tight structural formation. This interaction is unlikely to take place with ApoE2 and ApoE3 [62, 63]. ApoE4 is associated with an increased risk for AD along with early onset of the disease [64]. It was reported that ApoE4 carrier frequency was the highest in AD among AD, DLB, and control groups, and it was also higher in DLB than in the control groups [65]. Other findings have shown that ApoE4 carrier and allelic frequencies were comparable for those with AD and DLB with respect to Japanese subjects [57, 66].

Recently, a single nucleotide polymorphism in triggering receptor expressed on myeloid cells 2 (TREM2), an innate immune receptor expressed on the surface of microglia, were associated with both reduced hippocampal volume in healthy older adults and MCI [67, 68]. It was also shown that increased CSF sTREM2 levels were associated with higher CSF total TAU and phospho-TAU181P [69].

### **7. Future prospect**

Biomarkers are usually employed as an indicator of processes related to the onset of a disease, specific disease conditions or response to therapeutic interventions [70]. However, it is clear that at present no single biomarker plays a sufficient discrimination role in screening for future development of late-onset AD or dementia. During development of the disease, the time when each unique biomarker becomes elevated will vary. Therefore, it is imperative to be able to determine when specific biomarkers need to be measured in order to provide timely thera‐ peutic intervention.

Blood testing for measuring biomarkers will be easy and widely accepted due to the ease of collection and low cost. Moreover, the increasing availability of large sample sets obtained from a variety of technologies might contribute to diagnosis, prediction, and monitoring the progression of AD [71]. If a standardization of sample collection, standard operating proce‐ dures, comprehensive data management, and exchange of scientific findings is established, and if collaborative studies continue to progress, these should lead to a reduction in the variability and fragmentation of data. It is very likely that we may see plasma biomarkers become a reliable indicator for diagnosing AD.

Biomarkers of disease presence, subtypes (i.e., endophenotypes), treatment response, and progression are needed to advance therapeutic and preventative opportunities for this rapidly growing health care crisis.
