Alzheimer's disease as homeostatic responses to age-related myelin breakdown

Abstract

The amyloid hypothesis (AH) of Alzheimer's disease (AD) posits that the fundamental cause of AD is the accumulation of the peptide amyloid beta (Aβ) in the brain. This hypothesis has been supported by observations that genetic defects in amyloid precursor protein (APP) and presenilin increase Aβ production and cause familial AD (FAD). The AH is widely accepted but does not account for important phenomena including recent failures of clinical trials to impact dementia in humans even after successfully reducing Aβ deposits. Herein, the AH is viewed from the broader overarching perspective of the myelin model of the human brain that focuses on functioning brain circuits and encompasses white matter and myelin in addition to neurons and synapses. The model proposes that the recently evolved and extensive myelination of the human brain underlies both our unique abilities and susceptibility to highly prevalent age-related neuropsychiatric disorders such as late onset AD (LOAD). It regards oligodendrocytes and the myelin they produce as being both critical for circuit function and uniquely vulnerable to damage. This perspective reframes key observations such as axonal transport disruptions, formation of axonal swellings/sphenoids and neuritic plaques, and proteinaceous deposits such as Aβ and tau as by-products of homeostatic myelin repair processes. It delineates empirically testable mechanisms of action for genes underlying FAD and LOAD and provides "upstream" treatment targets. Such interventions could potentially treat multiple degenerative brain disorders by mitigating the effects of aging and associated changes in iron, cholesterol, and free radicals on oligodendrocytes and their myelin.

Fig. 1

Quadratic (Inverted U) Trajectories of Human Brain Myelination Over the Lifespan. Myelination (Y-axis) versus age (X-axis) in frontal lobes of normal individuals. Left panel: in vivo MRI data (Bartzokis et al., 2001) using inversion recovery images that are most sensitive to the high cholesterol levels in myelin and are optimal for tracking myelination. Right panel: postmortem myelin stain data of frontal lobe cortex depicting intracortical myelination (from Kaes, 1907 adapted and reproduced in Kemper, 1994). The data were acquired 100 years apart yet the two samples of normal individuals show remarkably similar frontal lobe myelination trajectories, both reaching a peak at age 45. A very similar matching pattern (not shown—see Bartzokis, 2007) is observed in temporal lobe.

Fig. 2

Myelin repair. (A) Myelin is “cut” to reveal normal fast axonal transport (FAT). (B) Myelin damage, FAT disruption, and axonal swelling phenotype of repair process.

Fig. 3

Progressive age-related cognitive decline into AD with early loss of memory encoding.