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Mutations in β-amyloid (Aβ) precursor protein (APP) cause familial Alzheimer's disease (AD) probably by enhancing Aβ peptides production from APP. An antibody targeting Aβ (aducanumab) was approved as an AD treatment; however, some Aβ antibodies have been reported to accelerate, instead of ameliorating, cognitive decline in individuals with AD. Using conditional APP mutations in human neurons for perfect isogenic controls and translational relevance, we found that the APP-Swedish mutation in familial AD increased synapse numbers and synaptic transmission, whereas the APP deletion decreased synapse numbers and synaptic transmission. Inhibition of BACE1, the protease that initiates Aβ production from APP, lowered synapse numbers, suppressed synaptic transmission in wild-type neurons, and occluded the phenotype of APP-Swedish–mutant neurons. Modest elevations of Aβ, conversely, elevated synapse numbers and synaptic transmission. Thus, the familial AD-linked APP-Swedish mutation under physiologically relevant conditions increased synaptic connectivity in human neurons via a modestly enhanced production of Aβ. These data are consistent with the relative inefficacy of BACE1 and anti-Aβ treatments in AD and the chronic nature of AD pathogenesis, suggesting that AD pathogenesis is not simply caused by overproduction of toxic Aβ but rather by a long-term effect of elevated Aβ concentrations. Synapses from Sweden: The so-called Swedish mutation (K595N/M596L) located in exon 16 of the β-amyloid (Aβ) precursor protein (APP) gene causes familial Alzheimer's disease. The mutation has been associated with increased Aβ production due to abnormal APP cleavage. To better understand the role of the mutation in neuronal functions, here, Zhou et al. generated human neurons bearing the Swedish mutation. The mutation caused an increase in the number of functional synapses that was abrogated by inhibition of the APP cleaving enzyme BACE1. Furthermore, whereas APP deletion reduced synapse number, restoring physiological Aβ amounts in APP-deleted neurons elevated synapse number and synaptic transmission, suggesting that at physiological level, Aβ might be synaptogenic. [ABSTRACT FROM AUTHOR]