Alzheimer’s disease (AD) is increasingly viewed as a small vessel disease of the brain, as reduced cerebral blood flow not only predates diagnosis but also signifies a more severe phenotype. Blood flow into the brain is controlled by the pial arteries, which contract or dilate to ensure a consistent blood flow, a process known as autoregulation. One of the principle mechanisms of autoregulation is the activation of mechanosensitive, rapid, high amplitude and spatially restricted Ca2+ release events known as Ca2+ sparks in the smooth muscle cells (SMCs). These are functionally coupled to the large conductance Ca2+ activated K+ (BK) channels that hyperpolarise the plasma membrane and promote vasodilation. This project sought to determine the effects of amyloid beta (Aβ) on Ca2+ sparks and cerebral diameter control, in the context of an extensively characterised AD mouse model: APP23, which has a 7-fold overexpression of amyloid precursor protein.   18 month old, male APP23(+/-) and wild-type (Wt) littermates or 10-12 week C57/Bl6 mice were euthanized in adhered to the UK Home Office Guidance on the Operation of the Animals (Scientific Procedures) Act 1986. Pial cerebral arteries from APP23(+/-) and Wt mice were loaded with the Ca2+ indictor Fluo-4-AM and pressurised to 60 mmHg. Arteries from the APP23(+/-) mouse showed a significant reduction in Ca2+ spark frequency compared to Wt controls (9.9 ± 4.3 vs 30.8 ± 6.1, N = 5-7, P < 0.05). This change in Ca2+ spark frequency was associated with a decreased spontaneous transient outward current (STOC) frequency (-30 mV) in freshly isolated SMCs for cerebral arteries from the APP23(+/-) compared to Wt (1.0 ± 0.4 vs 2.7 ± 0.5 Hz, N = 10-14), measured using perforated patch electrophysiology. In pressure myography experiments, this loss in STOC activity translated to an increased myogenic tone at 60 mmHg (27.6 ± 2.1 vs 36.1 ± 2.2 % myogenic tone, N = 25-29) and a reduced contraction to the BK channel inhibitor paxilline (30.5 ± 4.3 vs 12.7 ± 2.1 % constriction, N = 8-12). This pattern of damage to the Ca2+ spark vasoregulation was replicated in cerebral arteries from C57/Bl6 mice through exposure to Aβ. Pre-incubation with Aβ(1-40) (5 nM) for 30 minutes reduced Ca2+ spark frequency compared with arteries incubated with a scrambled control (3.6 ± 1.1 vs 7.8 ± 1.5, N =6-7). Consistent with these observations, the Aβ(1-40) peptide reduced STOC frequency (2.2 ± 1.2 to 0.7 ± 0.8 Hz, N =6), whereas cells exposed to the scrambled control had no effect (1.5 ± 0.4 to 1.8 ± 0.4, N = 7). Finally, incubated with Aβ(1-40) peptide reduced the constriction to paxilline (8.0 ± 1.1 vs 19.2 ± 4.5 % constriction, N = 5) in pressurised arteries. Overall, our data provide the first detailed mechanistic explanation for the development of small vessel disease of the brain in AD and suggest exciting and novel opportunities for future intervention.