A mutation in the BRI2/ITM2b gene causes loss of BRI2 protein leading to familial Danish dementia (FDD). BRI2 deficiency of FDD provokes an increase in amyloid‐β precursor protein (APP) processing since BRI2 is an inhibitor of APP proteolysis, and APP mediates the synaptic/memory deficits in FDD. APP processing is linked to Alzheimer disease (AD) pathogenesis, which is consistent with a common mechanism involving toxic APP metabolites in both dementias. We show that inhibition of APP cleavage by β‐secretase rescues synaptic/memory deficits in a mouse model of FDD. β‐cleavage of APP yields amino‐terminal‐soluble APPβ (sAPPβ) and β‐carboxyl‐terminal fragments (β‐CTF). Processing of β‐CTF by γ‐secretase releases amyloid‐β (Aβ), which is assumed to cause AD. However, inhibition of γ‐secretase did not ameliorate synaptic/memory deficits of FDD mice. These results suggest that sAPPβ and/or β‐CTF, rather than Aβ, are the toxic species causing dementia, and indicate that reducing β‐cleavage of APP is an appropriate therapeutic approach to treating human dementias. Our data and the failures of anti‐Aβ therapies in humans advise against targeting γ‐secretase cleavage of APP and/or Aβ.