Abstract The amyloid cascade hypothesis assumes that the development of Alzheimer’s disease (AD) is driven by a self-perpetuating cycle, in which β-amyloid (Aβ) accumulation leads to Tau pathology and neuronal damages. A particular mutation (A673T) of the amyloid precursor protein (APP) was identified among Icelandic population. It provides a protective effect against Alzheimer- and age-related cognitive decline. This APP mutation leads to the reduced production of Aβ with A2T (position in peptide sequence) change (Aβ ice ). In addition, Aβ ice has the capacity to form protective heterodimers in association with wild-type Aβ. Despite the emerging interest in Aβ ice during the last decade, the impact of Aβ ice on events associated with the amyloid cascade has never been reported. First, the effects of Aβ ice were evaluated in vitro by electrophysiology on hippocampal slices and by studying synapse morphology in cortical neurons. We showed that Aβ ice protects against endogenous Aβ-mediated synaptotoxicity. Second, as several studies have outlined that a single intracerebral administration of Aβ can worsen Aβ deposition and cognitive functions several months after the inoculation, we evaluated in vivo the long-term effects of a single inoculation of Aβ ice or Aβ-wild-type (Aβ wt ) in the hippocampus of transgenic mice (APP swe /PS1 dE9 ) over-expressing Aβ 1-42 peptide. Interestingly, we found that the single intra-hippocampal inoculation of Aβ ice to mice rescued synaptic density and spatial memory losses four months post-inoculation, compared with Aβ wt inoculation. Although Aβ load was not modulated by Aβ ice infusion, the amount of Tau-positive neuritic plaques was significantly reduced. Finally, a lower phagocytosis by microglia of post-synaptic compounds was detected in Aβ ice -inoculated animals, which can partly explain the increased density of synapses in the Aβ ice animals. Thus, a single event as Aβ ice inoculation can improve the fate of AD-associated pathology and phenotype in mice several months after the event. These results open unexpected fields to develop innovative therapeutic strategies against AD.