A vaccine to prevent initial loss of cognition and eventual Alzheimer's disease in elderly persons

Abstract

Prevention is better than cure and prevention of Alzheimer's disease (AD) may be possible. In elderly persons who are cognitively normal, synaptic hypometabolism as shown by reduced cerebral uptake of fluorodeoxyglucose ( 18 F‐FDG), provides a premonitory signal of potential, future loss of cognition if those individuals also have present evidence of amyloid deposition seen in the Pittsburgh compound B positron emission tomography (PIB‐PET) scan for amyloid. Those are the persons who should be targeted if one aims to prevent AD. The synaptic hypometabolism implies that the brain's availability of adenosine triphosphate (ATP) is inadequate for performance of all required synaptic functions. This review first describes the basis for asserting that reduced cerebral uptake of 18 F‐FDG accurately reflects synaptic hypometabolism; second, explains the basis for asserting that hypometabolism implies inadequate ATP; third, shows that amyloid beta (Aβ) itself, Aβ modified by pyroglutamate to become a molecule termed pE(3)Aβ, and cyclophilin‐D, in concert are the main contributors to inadequate synaptic ATP and that, therefore, reducing all of their levels would neutralize their combined effect and correct the hypometabolism. pE(3)Aβ is more neurotoxic than unmodified Aβ; and cyclophilin D inhibits ATP synthase and reduces ATP formation. Finally, this review describes an mRNA self‐replicating vaccine that will raise brain levels of ATP by reducing Aβ, pyroglutamate‐modified Aβ, and cyclophilin‐D, and thereby—in cognitively normal elderly persons who have synaptic hypometabolism—prevent initiation of the process that terminates in AD.

Mitochondrial Dysfunction as a Driver of Cognitive Impairment in Alzheimer’s Disease

“…Impaired mitochondrial OXPHOS efficiency, dysfunction of mitochondrial respiratory enzymes, and decreased mitochondrial complex (I–V) activities have been detected in the AD brain and various AD models [ 70 ]. For instance, complex IV deficiency has been measured in the platelets, fibroblasts, and postmortem brain tissue samples of patients with mild cognitive impairment (MCI), which often progresses to AD, as well as in diagnosed sporadic sAD patients.…”

Prevention of Alzheimer's dementia may be within reach

“…The details that support use of such a vaccine are described elsewhere. 10 In summary, both supplementary thiamine and a triple mRNA vaccine have good a posteriori potential as prophylaxis against initiation of cognitive loss and the subsequent occurrence of AD. The chances of success would amplify if both approaches were used together.…”

“…Therefore, a self‐replicating mRNA vaccine that reduces levels of all three elements, unmodified Aβ, pyroglutamate modified Aβ, and cyclophilin D, is potentially prophylactic, although its production would be a formidable undertaking. The details that support use of such a vaccine are described elsewhere 10 …”

MicroRNA Networks in Cognition and Dementia

“…The race to find a cure or effective therapeutics has centered around a few key hypotheses with varying success, including formation of brain lesions or plaques from toxic aggregation of beta-amyloid peptides [ 3 ]. More recently, the investigation of mRNA vaccines to slow or prevent cognitive decline is an intensifying focus of the scientific and medical communities [ 4 ].…”