Is Brain Amyloid Production a Cause or a Result of Dementia of The Alzheimer's Type?

Abstract

The amyloid cascade hypothesis has guided much of research into Alzheimer disease (AD) over the last 25 years. We argue that the hypothesis of beta amyloid (Aβ) as the primary cause of dementia may not be fully correct. Rather, we propose that decline in brain metabolic activity, which is tightly linked to synaptic activity, actually underlies both the cognitive decline and the deposition of Aβ. Aβ may further exacerbate metabolic decline and result in a downward spiral of cognitive function, leading to dementia. This novel interpretation can tie the disparate risk factors for dementia to a unifying hypothesis and present a roadmap for interventions to decrease the prevalence of dementia in the elderly population.

γ-Secretase Inhibitors and Modulators for the Treatment of Alzheimer's Disease: Disappointments and Hopes

“…Collectively, these obvservations question the hypothesis that A is the key pathologic factor affecting AD process. It has been recently proposed that a decline in brain metabolic activity or synaptic activity is the underlying cause of the disease [99]. Decreased metabolic activity, which can be consequent to decreased synaptic activity, increasessecretase expression or activity which, in turn, increases A deposition as a secondary response [99].…”

“…It has been recently proposed that a decline in brain metabolic activity or synaptic activity is the underlying cause of the disease [99]. Decreased metabolic activity, which can be consequent to decreased synaptic activity, increasessecretase expression or activity which, in turn, increases A deposition as a secondary response [99]. If this is true we should assist to other failures of -secretase inhibitors or other A -lowering agents, especially those for which no proofs of neuronal rescue and attenuation of memory deficit have been documented in preclinical model of AD.…”

Aging in Down Syndrome and the Development of Alzheimer's Disease Neuropathology

“…Despite the fact that extensive extracellular Aβ accumulation is a feature of AD in both the general population and DS, inconsistent associations between Aβ and dementia severity have been reported [28]. The hypothesis that brain amyloid is the cause of dementia in sporadic AD has also been questioned [29]. Transgenic mice overexpressing mutant human APP show signs of cognitive dysfunction prior to the accumulation of insoluble and extracellular Aβ[30], suggesting that earlier more soluble forms of Aβ may be important [31].…”

Preventing Alzheimer's disease by means of natural selection

“…sporadic AD [19,20], but proponents of the model have altered some of its basic premises in an effort to align prediction with empirical observation. For example, it is now postulated that neuronal loss derives from the toxicity of tau, the accumulation of which is assumed to be triggered by overproduction of amyloid [4].…”