Factors that cause the initial metabolic decline could include maturational changes, cerebral vascular aging, chronic diseases (e.g., diabetes), injury or sedentary lifestyle selection. Since none of these conditions acts in isolation, we would expect synergistic effects on metabolism/synaptic activity and cognitive function decline, progressing to dementia.
Maturational changes would be characterized by declines of metabolic activity that occur with normal maturation [36
], which could underlie the onset of autosomal dominant forms of AD. Chronic diseases, such as Type I and type II diabetes would also be a logical etiology for cognitive compromise if they chronically decrease CNS metabolic activity [45
]. Of note are studies that propose a decrease of brain glucose utilization in long-term diabetics [48
], decreased brain metabolic activity during mild hyperglycemia [49
] and cognitive compromise in Type I diabetics [50
]. Moreover, the increased risk for cognitive decline in type II diabetes is not associated with a greater density of Aβ deposition than non-diabetics but with evidence for more small strokes [51
Acute injuries, such as stroke, can result in both local and remote changes. Local effects occur in response to vascular insufficiency and from resulting neuronal death. Brain-wide effects (diaschisis), represent decreased brain activity remote from the infarct [52
]. Decreased metabolic activity could start a progressive decline leading to further decline. Even the role of apolipoprotein E, apart from its role in transport of Aβ, fits this schema, since the ε4 isoform of apoE is less effective than either the ε2 or ε3 isoforms in facilitating neuronal process regeneration [33
]. If neurite regeneration and synaptogenesis are slowed, then recovery from insults (e.g., strokes) would be impeded and synaptic activity/metabolic activity may not recover. Delayed regeneration/restoration of function would leave neurons deafferented and dysfunctional for longer periods and would further exacerbate decreased metabolic/synaptic activity.
Finally, lifestyle factors would fit into this scenario. Educational achievement and cognitive/social engagement seem to decrease the risk for dementia [54
]. Physical exercise, which has been shown to increase brain activity, and diet can be protective against onset/progression of dementia [56
]. Even estradiol replacement in the perimenopausal period appears to decrease the risk of developing dementia later in life [59
], and estradiol replacement increases synaptic activity [60
]. Hence, lifestyle choices influence the production of BACE and Aβ.