Thus far a tight coupling has

Thus far, a tight coupling has been observed between mAbs that target aggregated Aβ and the occurrence of ARIA. If ARIA-E is caused by increased trafficking to and clearance of fibrillar Aβ from cerebral vessels (20), mAbs could be designed with conformationally specific epitopes selective for soluble aggregated species (oligomers and protofibrils) and avoid ARIA-E. Alternatively, if ARIA-E has an inflammatory component (14), antibodies may be designed to avoid inflammation. In this regard, it is unclear whether the infrequency of ARIA-E with crenezumab is related to its IgG4 structure or its mid-domain epitope. Preclinical studies have suggested that it binds all forms of Aβ, including fibrils (36). However, more clinical testing is needed to see if it clears plaques. If, in fact, ARIA-E is more related to inflammation, single-chain variable fragments and other structures lacking the microglia-activating Fc fragment could emerge as promising therapies 59, 60. They may offer an alternative, noninflammatory approach to the clearance of Aβ, potentially avoiding ARIA that occurs with complete antibodies.
Mechanism of Aβ Clearance by mAbs: Brain Entry Versus Peripheral Sink Not fully resolved is whether brain entry of anti-Aβ mAbs is necessary, although many experts have attributed the failure of these agents to poor central nervous system penetration (only approximately 0.1% cross the blood-brain barrier) (11). Novel attempts to improve antibody penetration into brain have included targeting receptors on the blood-brain barrier to induce TCS 2002 sale of antibodies into the central nervous system or delivering the genes encoding antibodies and inducing expression in the subject (8). The peripheral sink hypothesis of mAbs is based on transport of Aβ across the blood-brain barrier as well as an equilibrium between Aβ in brain and periphery 61, 62. By draining plasma Aβ, this equilibrium can be altered to leach Aβ from brain without any direct action of antibodies. Ponezumab exploited the peripheral sink effect—at least for plasma Aβ40—but failed to meet clinical end points. Solanezumab continues to test this hypothesis (62), which may still have hope if instituted in preclinical stages (A4 and DIAN-TU) 31, 32.
Importance of Higher Doses The failure of anti-Aβ mAb trials has raised questions about the need for higher doses. For solanezumab, the combination of insignificant efficacy and excellent safety begs the question of whether higher doses would have yielded significant effects for the primary outcomes (30) and whether these should still be considered for ongoing studies in preclinical AD 31, 32. Similarly, the encouraging results with aducanumab pose a conundrum following disappointing results with other N-terminal antibodies—bapineuzumab and gantenerumab. Both antibodies share with aducanumab similar pharmacodynamic effects of fibrillar Aβ clearance on PET scans and ARIA-E, although at lower rates than aducanumab. Would higher doses of these drugs produce similar effects (35)?
Importance of Stage of Disease An often-cited explanation for the failure of anti-Aβ immunotherapy trials is that they are set too late in the disease process 9, 30. Obviously, earlier intervention with a disease-modifying treatment, including anti-Aβ mAbs, is advantageous. Less clear is whether early intervention is necessary for any treatment benefit—i.e., whether an Aβ cascade is initiated such that deterioration can no longer be slowed, or whether, in the setting of advanced Aβ deposition, modest Aβ clearance is simply irrelevant. If Aβ accumulation largely precedes cognitive impairment and is nearly complete by the dementia stage 63, 64, 65, later intervention with Aβ-lowering therapies may prove ineffective. Empirical trial evidence for this viewpoint is quite sparse and perhaps limited to the post hoc analyses from the phase 3 solanezumab trial (23) and the phase 2 crenezumab trial 38, 40, suggesting clinical efficacy restricted to mild AD subgroups. Unquestionably, the field is moving earlier, as a number of ongoing trials are evaluating treatment effects in prodromal (gantenerumab) or prodromal and mild (aducanumab, crenezumab, gantenerumab, BAN2401) AD. Moreover, we should expect additional studies of preclinical AD to join the ongoing secondary prevention trials: A4 (solanezumab) (31), Alzheimer Prevention Initiative (crenezumab) (10), and DIAN-TU (solanezumab, gantenerumab) (32).