Subjects with aMCI showed decreased DMN activity in memory function related brain regions, such as left medial temporal lobe before atrophy was detectable by sMRI [
86]. Based on a multi-modal imaging approach, including FDG-PET and sMRI and diffusion-weighted MRI results, AD patients revealed decreased structural and functional connections, corresponding consistent reduction of metabolic activity and atrophy within DMN [
90]. The disrupted connectivity in AD turns the high metabolic activity of DMN into hypometabolism [
84]. A 2- to 3- year follow-up study revealed that functional connectivity indices could predict conversion of MCI to AD [
91]. Education, a factor in cognitively demanding tasks, reduces AD risk by reducing neuronal activity and Aβ generation within the default network [
92]. It was observed that in the earliest phase of MCI the individuals exhibited significantly greater hippocampal activation than controls even if two group without difference in hippocampal or entorhinal volumes [
93]. Longitudinal fMRI in cognitively normal elderly participants reveals that subjects with the highest hippocampal activation at baseline and the greatest loss of hippocampal activation demonstrated more rapid cognition decline [
94]. Compensatory efforts as a result of preclinical pathological changes in learning and memory tasks induce enhanced brain activity in some areas in the initial targets of AD, and these changes may precede the diagnosis of AD by 30 years [
95]. Neuronal activity stimulates aerobic glycolysis and increases Aβ production and secretion into the interstitial fluid (ISF). The degree of Aβ aggregation and plaque deposition is directly proportional to ISF Aβ concentrations in vivo [
96]. Factors including elevated endogenous neuronal activity may accelerate the Aβ deposition process. Cognitively normal ApoEε4 carriers show elevated resting-state activity in the default network and increased hippocampal activation in fMRI during a memory-encoding task compared to non-carriers [
97]. Cerebral perfusion abnormalities were evident in AD progression. CBF was a more sensitive parameter than cerebral blood volume for perfusion normalities and appeared before the latter in the progression of AD [
98]. A reduced CBF of the left posterior cingulated gyrus [
99], bilateral prefrontal and frontal, and left parietal [
100], and right parietal and hippocampal regions [
101] evidenced by SPECT could predict the conversion of MCI to AD at least 2 years before clinical AD. But low parietal and medial temporal flow using SPECT demonstrated limited utility in predicting MCI conversion to AD [
102]. Semi-quantitative circumferential-profile analysis of brain SPECT showed that AD patients have more significant reductions in the posterior temporo-parietal regions, and white matter VaD patients have greater reducutions in the frontal brain regions [
103].
Regional CBF measured by Arterial spin-labeling (ASL) magnetic resonance showed that regional CBF of AD patients was significantly lower in both the bilateral frontal and temporal lobes, and the value of VaD patients was significantly in left frontal and temporal white matter [
105]. SPECT imaging of regional benzodiazepine receptors (rBZR) can reflect neuronal integrity in the cerebral cortex. VaD and mixed AD/VaD dementia showed predominant reduction of regional CBF and rBZR in the frontal lobe, and AD in parietotemporal lobe. Furthermore, rBZR images of VaD and mixed dementia showed more extensive and severe defects than CBF images, and CBF images of AD showed more extensive defects than rBZR [
106]. Although the heterogeneity index of the whole brain CBF on SPECT images was not significantly different between the AD and VaD groups, the herogeneity of CBF for AD and VaD was posterior and anterior-dominant respectively [
107].