**8. Conclusions**

reagent (EDTA or others), needle gauge, and 6-h fasting, standards should be proposed. For plasma preparation, a time limit until plasma separation after blood sampling may be critical to avoid induction of unwanted component leakage. Centrifugation speed (gravity force), duration, temperature, and number of spins, sample storage conditions may also require specification, though most common plasma samples are stored immediately at a temperature of –80°C for long-term storage. There will also be a number of factors that apply to subjects (patients and other participants involved): such as demographics (age, sex, and race/ethnicity), life style, overall health conditions (chronic drug administration, dietary supplements),

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

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

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‐

smoking, and alcohol consumption.

with respect to Japanese subjects [57, 66].

phospho-TAU181P [69].

**7. Future prospect**

peutic intervention.

**6. AD risk factors**

76 Update on Dementia

In spite of the fact that reliable biomarkers have been established in CSF, no blood-based biomarker has been fully validated or qualified, even though an increasing number of plasma biomarker candidates have been reported. However, promising candidates have been emerging due to the progress in the field. Longitudinal studies from collaborative research and from the use of a variety of technologies and study designs are expected.
