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Since the pathological profiles of FDG and hippocampus suggest that the hypo-metabolism and the hippocampal atrophy appear before the AD symptoms emerge, both of FDG-PET and the volume of hippocampus could be presymptomatic biomarkers. This finding is consistent with the literature. For examples, Mistur et al. (2009) suggested that the hy- pometabolism occurs in the preclinical stage of AD and the FDG-PET could be a pathologi- cal biomarker for early detection of AD. The presymptomatic biomarkers such as FDG-PET are critical for developing potential treatments of AD in presymptomatic or minimally symp- tomatic populations (Cummings and Jeste, 2007).Andrews et al. (2016) suggested that the volume of hippocampus is one of presymptomatic biomarkers which is related to Amyloid-β. Based on our findings, we may suggest that FDG and the volume of hippocampus can serve as important biomarkersfor the early detection of AD.

5.3

Limitation and future study

Overall, this study revealed the existence of two different progression profiles of Alzheimers disease, suggesting a new way to evaluate the disease progression.

The parameters in our study are estimated by EM algorithm. However, the latent tran- sition analysis may contain some unusual features that can cause difficulties in the EM algorithm especially when with small samples (Chung et al., 2008).

In addition, the model selection methods AIC and BIC can be highly unstable over repeated sampling (Preacher and Merkle, 2012). Thus, selecting model by AIC and BIC

should be more cautious.

The screening test for AD early detection is critical for the prevention of AD. For this, it is essential to identify the most sensitive presymptomatic biomarkers that can detect the early symptoms of AD or clinical impairment. This is the subject of future study.

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Appendix A

SAS code

/*LTA with AOPE4 covariates*/ proc lta data=ADfinal ;

title1 ’Model1’; nstatus 6; ntimes 2;

items FDG00ca MMSE00ca Hippocampus00ca FDG24ca MMSE24ca Hippocampus24ca; categories 3 3 3; measurement times; covariates1 APOE4x ; reference1 1 ; seed 592667; run;