Alzheimers: Enigmatic Conclusions from Science

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

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**12**

**15**

**Chapter 2**

*José V. Pardo*

biology of cerebral metabolism.

**1. Introduction**

self") drives AD pathology.

**Abstract**

Fact, Fiction, or Evolution:

Mechanism Hypothesis of

The metabolism hypothesis of Alzheimer's disease (AD) was first proposed in 1975. In normal aging and very mild AD, the cerebral metabolic rate for oxygen (CMRO2) and cerebral blood flow (CBF) remained approximately constant, but the metabolism of glucose (CMRglu) declined markedly. This decline in CMRglu identified a specific and primary metabolic defect that triggered downstream cellular cascades evolving into AD and its characteristic neuropathological lesions. These findings led research about AD into the role of insulin resistance that foresaw modern trials of insulin for AD treatment. The metabolism hypothesis evolved over subsequent decades with improved in-vivo measurement of metabolic parameters and AD biomarkers in humans. A more recent model highlights the interrelationships between the default mode network (DMN) and biomarkers such as CMRglu, amyloid, and tau. In other words, metabolic conditions related to sustained cortical activity during aging throughout the lifetime are conducive to the deposition of amyloid. This activity is thought to underlie the "autobiographical self." These ideas and findings motivate aging and AD-research focus on the biochemistry and cell

**Keywords:** dementia, amyloid, tau, cerebral metabolism, default mode networks, cerebral energetics, aerobic glycolysis, cognitive aging, functional connectivity

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

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

Alzheimer's Disease
