The first drugs approved for treating Alzheimer’s disease (AD) were the acetyl-cholinesterase inhibitors, which were modestly beneficial toward retaining cognitive function and provided approximately 6 months of benefit during the AD clinical course. Later in 2003, memantine, a glutamate NMDA-receptor modulator was approved. Memantine was more beneficial later in the disease course. However, since the year 2003, the overwhelming majority of clinical trials conducted on putative Alzheimer’s disease drugs have failed. Part of the high failure rate can be attributed to the dominant and overly simplistic amyloid-β (Abeta) hypothesis which posits a causal role for extracellular Abeta plaques. The weight-of-the-evidence suggests that the actual cause of the dementia associated with Alzheimer’s is a disruption of neuroplasticity, with a failure to produce new synapses for encoding new information, with a net loss of synapses corresponding to dementia severity. The human brain forms over one trillion new synapses per day and also removes the same number as part of normal learning and memory. In contrast to conceptualizing Abeta as a pathogenic entity, the amyloid precursor protein (APP) may play a central role in neuroplasticity, with Abeta playing an important homeostatic role by sequestering potentially neurotoxic free iron and copper and in removing old synapses. Based on the flawed Abeta hypothesis, a series of monoclonal antibody drugs that bind and remove Abeta protein have been developed and recently approved by both the US Food and Drug Administration (FDA) and the Veterans Administration. Results from trials on these drugs demonstrate that carriers of the high-risk apolipoprotein-ϵ4 allele are at elevated risk for developing hemorrhages and edema at sites where Abeta plaques have been removed by the monoclonal antibodies. Homozygous ϵ4/ϵ4 carriers are at even higher risk than heterozygous ϵ3/ϵ4 carriers. Given that the patient population at highest risk for development of Alzheimer’s (i.e., ϵ4 carriers) are also at highest risk for serious adverse events following administration of this new class of drugs, the clinical utility of these expensive and only marginally efficacious new therapeutics is questionable. The results from these recent trials emphasize the necessity of determining whether research subject volunteers are carriers of either the ϵ2, ϵ3, or ϵ4 allele prior to enrollment.