**1. Introduction**

Hoyer et al. proposed the metabolism hypothesis of AD based on observations of normal aging and early AD focusing on the relationships between CMRglu, CMRO, and CBF [1–3]. This hypothesis has both weak and strong versions. The weak version, not of interest here, suggests that amyloid deposition is an epiphenomenon, potentially unrelated to AD; the causative pathophysiology must lay elsewhere—perhaps a primary mitochondrial failure. The more interesting hypothesis relies on a stronger version: neural activity sustained during resting and introspection (i.e., wakefulness [4]) over a lifetime (i.e., the "autobiographical self") drives AD pathology.

A more recent model of the strong version posited sustained metabolic activity in the default mode network (DMN) is a substrate for amyloid deposition through the mediation of some process related to neural activity [5]. CMRglu declined with aging. Since oxidative metabolism was largely preserved, a primary abnormality in

the handling of glucose was posited with the observation that aerobic glycolysis (AG) declined precipitously during normal aging [6, 7]. Concomitantly, molecular imaging of critical biomarkers in AD identified for the first time the distribution of proteins such as fibrillar amyloid and tau in the brain, both in asymptomatic healthy elderly and in patients with various neurodegenerative disorders including AD [8–10].

Such progress led to the definition and characterization of preclinical and clinical AD based on biomarkers for staging [11–14]. To understand the pathophysiology of the hypothesized metabolic dysfunction, understanding the relationships between brain metabolism and these neuropathological biomarkers became critical during both normal aging and AD. These advances detail the evolution of imaging biomarkers along with their relationship to the brain's structural, metabolic, and cognitive dysfunction.

Here, recent findings relevant to aging and AD are reviewed briefly as background. Current understanding of the development and ontogenesis of biomarkers for AD are summarized. Data are integrated with advances in neuroimaging and brain metabolism as well as in preclinical models mostly focusing on the resting state. These results bear on the metabolism hypothesis of AD. Notable gaps in this hypothesis and its relationship to cognitive aging highlight avenues requiring further research for progress in the field.

## **2. Amyloid and tau in aging and AD**

Several studies of patients developing dementia (both early and late-onset sporadic AD; familial AD) as well as Down's syndrome show amyloid deposition begins decades before overt symptoms of dementia arise [11, 15, 16]. Amyloid deposition of plaques, particularly the diffuse type, in AD begins in inferior neocortex with spread to other neocortical regions including precuneus, lateral parietal, and frontal association neocortices [17, 18]. Amyloid positivity predicts past and future progressive cognitive decline [19]. Glucose metabolism tends to decline where amyloid localizes; it is first seen in preclinical AD, mild cognitive impairment (MCI), and early AD using fluorodeoxyglucose (FDG) positron emission tomography (PET) in the posterior cingulate cortex (PCC) followed by biparietal involvement [20–22]. The steepest increases in amyloid deposition during healthy aging according to amyloid PET, thought to measure fibrillar amyloid or neuritic plaques, occurs in anterior cingulate cortex (ACC), PCC, precuneus, and temporal cortices [23]. The earliest detectable amyloid deposits by PET localize to precuneus, PCC, and medial orbitofrontal cortex; these deposits were not associated with atrophy or hypometabolism despite changes in functional connectivity [24].

Although there is some overlap between amyloid deposition and cortical hypometabolism [22], other factors such as APOE genotype and tau deposition affect the distribution of amyloid. Whole-brain amyloid positivity appears a greater determinant of gross cognitive dysfunction compared to the precise areal distribution; however, measures of non-crystallized intelligence (e.g., executive functions, reasoning, problem solving) are sensitive to the amount deposited [19]. It is not unusual to find a dissociation between amyloid deposition and metabolic hypometabolism or between amyloid deposition and cortical thinning [25–27]. As discussed below (Section 6.1), while clinically normal elders can show significant correlation between thinning and amyloid deposition in the PCC, they do not show a significant association between these biomarkers in the ACC [28]. Amyloid deposition although predictive of future cognitive decline correlates poorly with actual cognitive status: the number of neurofibrillary tangles (NFTs), not senile amyloid plaques, correlates with cognitive status before death [29]. Classically, amyloid

**17**

**Figure 1.**

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

is necessary but not sufficient for the diagnosis of AD; tau with neurofibrillary changes is also required [30, 31]. However, over one-third of patients with clinically diagnosed mild to moderate AD who do not carry an APOE4 allele show minimal amyloid yet extensive neurofibrillary degeneration on autopsy [32]. Whether this group is pathophysiologically an AD variant or a tauopathy remains unclear [32, 33]. Deposits of tau generally follow amyloid. Immunohistochemical studies of tau and neuroimaging of humans using tau radiotracers converge on tau's more restricted involvement in the temporal lobe in early AD [17, 34, 35]. Tau does not follow the global miliary pattern of amyloid neocortical involvement with disease progression. Tau's presence more directly correlates with cognitive dysfunction and cortical thinning than does amyloid [14, 36]. These changes reflect presumably the final stages of neurodegeneration. Unlike amyloid deposition, the localization of tau mirrors the clinical and neuroanatomical phenotypic variability of AD [37, 38]. Longitudinal data of both amyloid and tau have enabled assessment of directionality of biomarker spread as well as potential relationships with gene expression [39]. APOE played a central role in the lipid interactome affecting both Aß and tau spread, while tau- and Aß-risk genes differentially contributed to the specific spread of each biomarker.

The distribution of amyloid has been noted to overlap with the neural system related to the default mode of brain function [5]. The observation has prompted hypotheses about the relationship of neural activity, the default mode network, and

PET studies have shown a broad region of relative deactivation in resting states

The deactivation in the VMPFC during rest was shown not to reflect a relative activation as the OEF did not change significantly from whole-brain (e.g., **Figure 1**;

*Transverse sections (z = −6) of stereotactically normalized parametric data showing convergence across studies between CBF change and FC as well as relative stability of OEF. Left: Region of common relative CBF deactivation (VMPFC) in mega image contrast between active scans and passive scans (peak Z-score − 7.7; modified from [40]); middle: Default mode oxygen extraction fraction during rest with eyes closed; uniform OEF; no OEF increase in VMPFC [41]. Right: Resting state FC of the VMPFC with the DMN [49]. Middle* 

&

compared to active states with greatest deactivation within the ventromedial prefrontal cortex (VMPFC) with peak minimum at Brodmann area 10 (BA10; **Figure 1**) [40]. Additional regions showing deactivations localized bilaterally to the inferior and superior frontal cortex, PCC/precuneus, prefrontal cortex, inferior

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

**3. The default mode network (DMN)**

parietal cortex, and several temporal areas.

*left: Copyright (2003) National Academy of Sciences, U.S.A.*

AD that continue to evolve.

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

*Redirecting Alzheimer Strategy - Tracing Memory Loss to Self Pathology*

cognitive dysfunction.

further research for progress in the field.

**2. Amyloid and tau in aging and AD**

tabolism despite changes in functional connectivity [24].

Although there is some overlap between amyloid deposition and cortical hypometabolism [22], other factors such as APOE genotype and tau deposition affect the distribution of amyloid. Whole-brain amyloid positivity appears a greater determinant of gross cognitive dysfunction compared to the precise areal distribution; however, measures of non-crystallized intelligence (e.g., executive functions, reasoning, problem solving) are sensitive to the amount deposited [19]. It is not unusual to find a dissociation between amyloid deposition and metabolic hypometabolism or between amyloid deposition and cortical thinning [25–27]. As discussed below (Section 6.1), while clinically normal elders can show significant correlation between thinning and amyloid deposition in the PCC, they do not show a significant association between these biomarkers in the ACC [28]. Amyloid deposition although predictive of future cognitive decline correlates poorly with actual cognitive status: the number of neurofibrillary tangles (NFTs), not senile amyloid plaques, correlates with cognitive status before death [29]. Classically, amyloid

the handling of glucose was posited with the observation that aerobic glycolysis (AG) declined precipitously during normal aging [6, 7]. Concomitantly, molecular imaging of critical biomarkers in AD identified for the first time the distribution of proteins such as fibrillar amyloid and tau in the brain, both in asymptomatic healthy elderly and in patients with various neurodegenerative disorders including AD [8–10]. Such progress led to the definition and characterization of preclinical and clinical AD based on biomarkers for staging [11–14]. To understand the pathophysiology of the hypothesized metabolic dysfunction, understanding the relationships between brain metabolism and these neuropathological biomarkers became critical during both normal aging and AD. These advances detail the evolution of imaging biomarkers along with their relationship to the brain's structural, metabolic, and

Here, recent findings relevant to aging and AD are reviewed briefly as background. Current understanding of the development and ontogenesis of biomarkers for AD are summarized. Data are integrated with advances in neuroimaging and brain metabolism as well as in preclinical models mostly focusing on the resting state. These results bear on the metabolism hypothesis of AD. Notable gaps in this hypothesis and its relationship to cognitive aging highlight avenues requiring

Several studies of patients developing dementia (both early and late-onset sporadic AD; familial AD) as well as Down's syndrome show amyloid deposition begins decades before overt symptoms of dementia arise [11, 15, 16]. Amyloid deposition of plaques, particularly the diffuse type, in AD begins in inferior neocortex with spread to other neocortical regions including precuneus, lateral parietal, and frontal association neocortices [17, 18]. Amyloid positivity predicts past and future progressive cognitive decline [19]. Glucose metabolism tends to decline where amyloid localizes; it is first seen in preclinical AD, mild cognitive impairment (MCI), and early AD using fluorodeoxyglucose (FDG) positron emission tomography (PET) in the posterior cingulate cortex (PCC) followed by biparietal involvement [20–22]. The steepest increases in amyloid deposition during healthy aging according to amyloid PET, thought to measure fibrillar amyloid or neuritic plaques, occurs in anterior cingulate cortex (ACC), PCC, precuneus, and temporal cortices [23]. The earliest detectable amyloid deposits by PET localize to precuneus, PCC, and medial orbitofrontal cortex; these deposits were not associated with atrophy or hypome-

**16**

is necessary but not sufficient for the diagnosis of AD; tau with neurofibrillary changes is also required [30, 31]. However, over one-third of patients with clinically diagnosed mild to moderate AD who do not carry an APOE4 allele show minimal amyloid yet extensive neurofibrillary degeneration on autopsy [32]. Whether this group is pathophysiologically an AD variant or a tauopathy remains unclear [32, 33].

Deposits of tau generally follow amyloid. Immunohistochemical studies of tau and neuroimaging of humans using tau radiotracers converge on tau's more restricted involvement in the temporal lobe in early AD [17, 34, 35]. Tau does not follow the global miliary pattern of amyloid neocortical involvement with disease progression. Tau's presence more directly correlates with cognitive dysfunction and cortical thinning than does amyloid [14, 36]. These changes reflect presumably the final stages of neurodegeneration. Unlike amyloid deposition, the localization of tau mirrors the clinical and neuroanatomical phenotypic variability of AD [37, 38]. Longitudinal data of both amyloid and tau have enabled assessment of directionality of biomarker spread as well as potential relationships with gene expression [39]. APOE played a central role in the lipid interactome affecting both Aß and tau spread, while tau- and Aß-risk genes differentially contributed to the specific spread of each biomarker.
