**Acknowledgements**

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

neuropil to the somatodendritic compartment.

amyloid deposition to AD pathophysiology.

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

neuropathological processes.

latter time scale.

regulation of NADH/NAD+

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

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

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

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

As mentioned in Section 5, lactate is a proxy for neural activation and through

[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,

becomes a modulator of rCBF in response to activation

**24**

This work was supported by the Minneapolis Veterans Health Care System; the University of Minnesota Libraries Open Access Fund; and Merit Award I01CX000501 (VA CSR&D).
