**6.3 Role of APOE genotype in the metabolism hypothesis**

If regional brain activity drives amyloid deposition in the pattern seen in AD, then the AD metabolic pattern should arise in those at highest risk for the future development of AD—asymptomatic *APOE\*E4* homozygotes, who have a 12-fold increased risk of LOAD. So far, there are seven such individuals in the Alzheimer's Disease Neuroimaging Initiative's (ADNI) database. Their pattern of amyloid deposition highlights bilateral lenticular nuclei and the ACC/medial prefrontal involvement with the PCC notably unaffected (see **Figure 3**). In fact, the deposition of amyloid in the homozygotes is reminiscent of that seen in Down's syndrome and most mutations found in autosomal dominantly inherited forms of AD arising in APP, PS1, or PS2 [113–115, 117]. This pattern of amyloid deposition in E4 homozygotes is consistent with findings reported previously in an independent group of eight homozygotes [91].

## **6.4 Role of tau in the metabolism hypothesis**

Another difficulty with the metabolism hypothesis of AD is the notable absence of tau involvement in this theory. The role of tau, its modifications, and its etiologic role in neurodegeneration in AD has been reviewed previously [118]. Although the metabolism hypothesis of AD focuses on amyloid deposition, there is increasing evidence that tau plays at least as great if not greater etiopathological role. Of interest in this context, recent studies show tau deposition during preclinical AD in the PCC; the metabolism hypothesis cannot explain this dissociation between PCC and ACC [107].

AD cases with neurofibrillary changes (neuritic plaques, neurofibrillary tangles, neurofibrillary threads, tau tangles) typically show extensive amyloid deposition. However, not all cases with extensive amyloid deposition show neurofibrillary changes [17]. Amyloid deposits and neuritic plaques vary widely across individuals both temporally and regionally; so, they do not provide useful biomarkers for staging of AD [17]. In contrast, the distribution of tau is consistent across individuals and provides useful staging of disease progression [17].

Hyper-phosphorylated intraneuronal tau ("pretangle") has been reported even in young adults in the absence of amyloid particularly in subcortical nuclei such as the locus coeruleus [119]. The significance of these findings in the context of AD remains uncertain as the pretangle material may be transient, related incidentally to other processes (e.g., traumatic brain injury), or the earliest manifestations of AD. Furthermore, studies of transgenic mice with APOE isoform knock-in and APOE knock-out show that even in the absence of amyloid, E4 is particularly neurotoxic in mice with mutant tau transgenes, and this toxicity is in part mediated by neuroinflammation via the innate immune system produced by microglia and type A1 astrocytes [120].

A recent study identified the significant role of tau in the context of amyloid deposition [121]. High resolution fMRI of cerebral blood volume (CBV), coupled to regional metabolism, mapped the earliest changes in preclinical AD to lateral entorhinal (LEC), transentorhinal, and perirhinal cortices, as predicted from neuropathological studies [17]. The former region's CBV correlated significantly with a test of delayed retention. Three lines of mice were generated with differential expression in entorhinal cortex of pathological human APP, tau, or both transgenes.

Mice with mutant entorhinal tau alone, but not mutant APP alone, had diminished CBV in LEC with aging [121]. The double mutant had decreased LEC CBV with aging compared to the single mutants and other controls thereby demonstrating that APP increased tau-related metabolic dysfunction. Decreased CBV in aged double mutant spread even to posterior parietal cortex, a pattern reminiscent of human AD. APP immunohistochemistry of older mice showed no changes between mutant APP and double mutant mice; the label localized mostly to entorhinal cortex. However, tau immunohistochemistry of older mice showed increased signal in the double mutants with the suggestion of relocalization of phospho-tau from neuropil to the somatodendritic compartment.

The differing roles of amyloid and tau in the evolution of AD were recently highlighted in cognitively intact elders [58]. Those positive for amyloid (Aß+) showed hyperconnectivity within DMN and SN when tau deposits were low. In contrast, the Aß + subjects showed decreased FC with increasing tau deposition. Thus, the effects of PET biomarkers on FC appear complex and likely involve multiple neuropathological processes.

These data make clear that tau cannot be ignored in understanding the ontogenesis of AD. The metabolism hypothesis needs modification for relevance beyond amyloid deposition to AD pathophysiology.

### **6.5 Cognitive processing in "real time"**

The biomarkers discussed so far are not dynamic in terms of real time. These scans, even when measured during rest, probe parameters over many minutes totally divorced from cognitive processes that occur at the scale of milliseconds to seconds. Recent studies hint that the metabolism hypothesis has relevance to the latter time scale.

As mentioned in Section 5, lactate is a proxy for neural activation and through regulation of NADH/NAD+ becomes a modulator of rCBF in response to activation [122]. Astrocytes on activation show a metabolic switch toward AG shifting oxygenation from astrocytes to neurons [123]. In turn, lactate produced through AG is critical for memory formation [124]. Because AG can provide reducing equivalents for biosynthesis of macromolecules for plasticity, learning tasks demonstrate focal increases in AG on-line with experience-dependent plasticity [77]. The elevation in AG can persist for many minutes after an activation task [125]. How amyloid impacts real-time learning through changes in AG remains to be elucidated.

Preliminary studies have examined using magnetoencephalography (MEG) oscillatory power in real time in cognitively normal elders either with amyloid deposition ("preclinical AD") or without amyloid deposition [126]. Increases in power in the alpha range in the amyloid-positive preclinical cases at rest localized over the ACC and correlated with increased glucose metabolism. These metabolic changes did not yet correlate with structural atrophy or cognitive decline. The findings begin to define the earliest on-line physiological changes in preclinical AD. Similarly, increased functional connectivity at rest localized to the ACC. Proposed hypotheses include cognitive compensation (i.e., cognitive reserve) or amyloid-related hyper-excitability in preclinical AD [58, 127].

### **7. Concluding remarks about the metabolism hypothesis**

The observations reviewed above argue that even if chronic neural activity in the DMN biases Aß production and clearance toward amyloid deposition, different mechanisms participate in Aß localization in normal elderly, E4 homozygotes,

**25**

**Author details**

José V. Pardo1,2

provided the original work is properly cited.

Health Care System, Minneapolis, USA

\*Address all correspondence to: jvpardo@umn.edu

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 Cognitive Neuroimaging Unit, Mental Health Service Line, Minneapolis Veterans

1 Department of Psychiatry, University of Minnesota, Minneapolis, USA

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

familial dominant AD, and sporadic AD. Further, tau has reached a new level of significance in AD pathophysiology. The cellular and molecular mechanisms of human Aß deposition and the relationship to AD appear pleiomorphic and complex defy so far simplistic explanations for a complex disease. However, given the recent advances in multimodal molecular imaging (amyloid, tau, neuroinflammation,

This work was supported by the Minneapolis Veterans Health Care System; the University of Minnesota Libraries Open Access Fund; and Merit Award

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

etc.), the story is likely to evolve quickly.

The author declares no conflict of interest.

**Acknowledgements**

**Conflict of interest**

I01CX000501 (VA CSR&D).

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

familial dominant AD, and sporadic AD. Further, tau has reached a new level of significance in AD pathophysiology. The cellular and molecular mechanisms of human Aß deposition and the relationship to AD appear pleiomorphic and complex defy so far simplistic explanations for a complex disease. However, given the recent advances in multimodal molecular imaging (amyloid, tau, neuroinflammation, etc.), the story is likely to evolve quickly.
