The amyloid-β (Aβ) oligomer hypothesis of Alzheimer's disease (AD) still 
dominates the field, yet the clinical trial evidence does not robustly support 
it. A falsifiable prediction of the hypothesis is that Aβ oligomer levels should 
be elevated in the brain regions and at the disease stages where and when neuron 
death and synaptic protein loss begin and are the most severe, but we review 
previous evidence to demonstrate that this is not consistently the case. To 
rescue the Aβ oligomer hypothesis from falsification, we propose the novel 
ad-hoc hypothesis that the exceptionally vulnerable hippocampus may normally 
produce Aβ peptides even in healthily aging individuals, and hippocampal 
oxidatively damaged DNA, pathogen DNA, and metal ions such as zinc may initiate 
and drive Aβ peptide aggregation into oligomers and spreading, neuron death, 
synaptic dysfunction, and other aspects of AD neurodegeneration. We highlight 
additional evidence consistent with the underwhelming efficacy of Aβ 
oligomer-lowering agents, such as aducanumab, and of antioxidants, such as 
vitamin E, versus the so far isolated case report that DNase-I treatment for 2 
months resulted in a severe AD patient's Mini-Mental State Exam score increasing 
from 3 to 18, reversing his diagnosis to moderate AD, according to the 
Mini-Mental State Exam.