Alzheimer's disease (AD) pathogenesis involves chronic cerebral hypoperfusion predicted to create sustained mild tissue acidosis (pH 7.0–7.2) in vulnerable brain regions, particularly the anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC). Acid-sensing ion channel 1a (ASIC1a), a proton-gated calcium-permeable channel highly expressed in these regions, has an activation threshold near pH 7.0, placing it at the boundary of AD-associated acidosis, and is predicted to generate recurrent, activity-driven calcium influx as normal synaptic pH transients repeatedly breach the narrowed threshold margin, predicted to drive tau hyperphosphorylation via the proposed CaMKII–PP2A–GSK3β cascade through cumulative calcium burden over years of neural activity. Recent work by Gupta et al. (2026) demonstrates that carbonic anhydrase 4 (CA4) controls ASIC1a activation thresholds in rodent nucleus accumbens medium spiny neurons, and that acetazolamide (AZD), an FDA-approved, blood–brain barrier (BBB)-penetrant CA4 inhibitor, can modulate ASIC1a-mediated synaptic plasticity through this pathway in that circuit. This identifies the CA4–ASIC1a axis as pharmacologically accessible and positions AZD as a repurposing candidate, but with a critical mechanistic paradox that must be acknowledged at the outset: CA4 inhibition reduces synaptic pH buffering, directly potentiating ASIC1a calcium entry, which is the opposite of what the proposed AD pathology requires. Resolution of this paradox is stage-dependent: in early AD, AZD's established cerebral blood flow (CBF) enhancing properties are predicted to raise tissue pH and reduce ASIC1a threshold-crossing, outweighing the local synaptic potentiation effect; in late disease, depleted vascular reserve eliminates the CBF benefit while ASIC1a potentiation persists, reversing the risk–benefit balance. Whether this competition resolves in favor of benefit at any disease stage is the central empirical question this hypothesis generates. This framework's central empirical premise, that ACC/PCC tissue pH is chronically 7.0–7.2 in early AD, is supported by postmortem data and metabolic inference but has not been confirmed by in-vivo regional measurement; Prediction 1 provides this direct test; if ACC/PCC pH in early AD does not fall within this range, the mechanistic chain proposed here requires fundamental revision regardless of the pharmacological outcome of Prediction 2. This paper proposes the CA4–ASIC1a–vascular competition as a mechanistic hypothesis warranting empirical investigation, identifies AZD as the pharmacological tool to test it — with the direct CBF-versus-ASIC1a-potentiation experiment (Prediction 2) as the prerequisite experimental gate before any clinical application is justified — defines the proposed beneficial window and its closing signals, and generates testable predictions using an already approved drug with decades of human safety data. Management of patients outside this window, whether through combination therapy at the MCI stage or alternative mechanisms at the dementia stage, is beyond the scope of this paper and addressed in subsequent work.
Arthur Stewart (Mon,) studied this question.