**5. Role of DMN and amyloid**

The default network shows overlap with brain regions high in AG which in turn show overlap with areas of amyloid deposition in AD [74]. Unlike oxidative phosphorylation used to generate energy, AG proceeds less efficiently energetically (2 ATP vs. 38 ATP per glucose molecule) but more suitably for reduction of biomolecules for anabolism [75]. Anabolism that appears to play a much greater role in early human development could also provide, albeit to a lesser extent, the substrates for plasticity related to learning and memory in adults [76, 77]. The metabolism hypothesis is important because it motivates the search for AD pathophysiology beyond amyloid deposition to some aspect of cerebral metabolism particularly AG. Normal aging is associated with the loss of AG in regions which sustain higher levels of AG in youth; these are the very regions showing susceptibility to amyloid deposition [7]. The metabolism hypothesis could help explain why the frequency of AD rises relentlessly with aging and oxidative stress.

Several lines of evidence support the metabolism hypothesis of AD through altered processing of Aß [78]. The processing pathways include both increased production and decreased clearance. Most AD-causing dominant mutations in APP, PSEN1, and PSEN2 increase Aß production [79]. One mutation that is protective for AD occurs near the APP BACE1 cleavage site impairing γ cleavage; it is associated in vitro with decreased amyloidogenic peptides [80]. Likewise, vibrissal stimulation of APP transgenic mice increases Aß in interstitial CSF and amyloid plaques while decreasing lactate, a proxy for neural activity [81]. In-vitro mouse slice preparations show based on microdialysis rapid increases in Aß correlated with synaptic activity [82]. In cognitively normal older adults, greater hippocampal activity during encoding at baseline correlates with longitudinal amyloid deposition and diminished cognitive performance [83]. APOE, the major risk locus for AD, plays a key role in Aß aggregation, fibrillogenesis, and maturation of neuritic plaques [84]. AD patients relative to controls have decreased clearance of CSF Aß with normal rate of Aß production [85].

### **6. Gaps in the metabolism hypothesis**

Here, issues informing discussions about the amyloid hypothesis of AD and relationships to cerebral metabolism are outlined. These raise questions about the strong version of the metabolism hypothesis and its implications, or at least suggest a need for revision. Significant circumstantial evidence centers on several

**21**

**Figure 3.**

*Fact, Fiction, or Evolution: Mechanism Hypothesis of Alzheimer's Disease*

observations: (1) normal cognitive aging; (2) familial AD; (3) healthy individuals at very high risk of AD (*APOE\*E4* homozygotes); (4) the evolving role of tau in AD; (5) interrelationships between amyloid and tau in AD pathology; and (6) the

The metabolism hypothesis suggests that if chronically elevated levels of resting brain activity over the lifetime drive Aß deposition with attendant cognitive dysfunction leading to AD, there should be amyloid deposition during healthy aging as well. Based on this mechanism, the PCC region should show major hypometabo-

Yet, this phenomenon is not observed. The PCC in normal aging shows relative preservation (**Figure 3**). Among the regions showing the least decline in metabolism with aging is the PCC. Older healthy adults show minimal PCC atrophy rates over 12 months [89]. Older healthy adults, especially E4 non-carriers, do not show amyloid deposition in the PCC [90–92]. Young adult E4 carriers with positive family history of AD and at high risk of future AD already show PCC hypometabolism implying DMN hyperactivity related to AD must have occurred before then [93]. Of note, older healthy E4 non-carriers begin to show amyloid positivity at around 71 years of age, while the E4 carriers develop amyloid positivity about 20 years earlier. Interestingly, when separating the independent effects of aging vs. E4 load, amyloid deposition shows a more frontal involvement. Of note, the effects of aging and E4 load interact: the peak hazard ratio occurs ~60 years of age and declines thereafter; E4 is a risk factor for AD even for younger adults (<65 years) [94]. Furthermore, resting connectivity of the PCC/precuneus region to the ACC is reduced in older healthy adults who carry E4 even in the absence of detectable fibrillar amyloid or decreased CSF Aß42 suggesting both Aß-dependent and

The principal locus of declining metabolism in healthy elders does not map to the PCC but localizes instead to the ACC (**Figure 3**) [96–101]. ACC hypometabolism correlates also with aging-related decline in cognitive function [99]. Whereas

*Decline of brain activity with aging in healthy volunteers. Voxel-wise Pearson correlation (r) map of glucose uptake vs. age in stereotactically normalized brain (3D-SSP; S. Minoshima, University of Utah). A, lateral; B, medial; C, dorsal (left)/ventral (right). Color scale shows peak r = −0.8. Note the greatest decline in glucose uptake with age localizes to the ACC (BA 32/9; region 1). A midline circuit (regions 1-3) includes dorsomedial thalamus and basal forebrain/subgenual cingulate; the metabolism in this circuit correlates with declining executive function (verbal fluency). Other regions with lower correlations are not associated with cognitive performance. Reprinted from Neuroimage, Vol 35(3), Pardo JV et al., Where the brain grows old: Decline in anterior cingulate and medial* 

*prefrontal function with normal aging. Copyright (2007), with permission from Elsevier.*

lism, atrophy, and amyloid deposition as seen in early AD [21, 86–88].

*DOI: http://dx.doi.org/10.5772/intechopen.83824*

implications for cognitive function in "real time."

Aß-independent aging-related mechanisms [95].

**6.1 The metabolism hypothesis and cognitive aging**

## *Fact, Fiction, or Evolution: Mechanism Hypothesis of Alzheimer's Disease DOI: http://dx.doi.org/10.5772/intechopen.83824*

observations: (1) normal cognitive aging; (2) familial AD; (3) healthy individuals at very high risk of AD (*APOE\*E4* homozygotes); (4) the evolving role of tau in AD; (5) interrelationships between amyloid and tau in AD pathology; and (6) the implications for cognitive function in "real time."
