Acetazolamide as an Acute-to-Subacute Intervention for Early-Stage Alzheimer's Disease A Cerebrovascular-Reactivity-Defined Treatment Window for Carbonic Anhydrase 4 Inhibition

This paper proposes that acetazolamide (AZD), an FDA-approved blood-brain barrier-penetrant carbonic anhydrase 4 (CA4) inhibitor, has a defined beneficial therapeutic window in early-stage Alzheimer's disease, identifiable by a validated cerebrovascular reactivity (CVR) challenge (>20% CBF increase to weight-adjusted intravenous AZD), within which CBF-mediated tissue pH normalization is predicted to outweigh AZD's direct synaptic potentiation of ASIC1a calcium entry; outside this window the same competition reverses and AZD is predicted to be net harmful by the identical mechanism. The mechanistic chain that generates this window operates as follows. Chronic cerebral hypoperfusion in vulnerable regions, particularly the anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC), is predicted to create sustained mild tissue acidosis (pH 7.0–7.2); acid-sensing ion channel 1a (ASIC1a), a proton-gated calcium-permeable channel highly expressed in these regions with an activation threshold near pH 7.0, is predicted to generate recurrent activity-driven calcium influx as normal synaptic pH transients repeatedly breach the narrowed threshold margin, driving tau hyperphosphorylation via the proposed CaMKII-PP2A-GSK3β cascade through cumulative burden over years of neural activity. Gupta et al. (2026) demonstrates that CA4 controls ASIC1a activation thresholds in rodent nucleus accumbens medium spiny neurons and that AZD modulates this in a living brain circuit, identifying the CA4-ASIC1a axis as pharmacologically accessible but generating a mechanistic paradox: CA4 inhibition at the synapse potentiates ASIC1a calcium entry, the opposite of what the proposed AD pathology requires, while CA4 inhibition at the capillary endothelium produces the documented 38-75% CBF increase that raises tissue pH and reduces threshold-crossing. The paradox resolves stage-dependently through the relative dominance of these two effects: in preserved vascular reserve, CBF enhancement outweighs synaptic potentiation; in depleted reserve, the same drug produces steal-phenomenon CBF reduction while synaptic potentiation persists. The 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. The direct CBF-versus-ASIC1a-potentiation experiment (Prediction 2) is the prerequisite experimental gate before clinical application is justified. Management of patients outside the beneficial window, 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. **Keywords:** acetazolamide, ASIC1a, carbonic anhydrase 4, Alzheimer's disease, preclinical Alzheimer's disease, drug repurposing, cerebrovascular reactivity, AZD-CVR challenge, vascular reserve, cerebral hypoperfusion, chronic mild acidosis, synaptic pH, tau hyperphosphorylation, calcium signaling, CaMKII, GSK3β, PP2A, anterior cingulate cortex, posterior cingulate cortex, stage-dependent treatment window, blood-brain barrier penetrance