Timely and accurate diagnosis of early Alzheimer's disease (AD) is critical to maximizing the potential benefits of disease-modifying therapies; however, it remains a challenge in clinical practice.
A double-blind survey was conducted among general practitioners (GPs; n = 52) and AD specialists (neurologists, psychiatrists, geriatricians, and others; n = 75) across five European countries to evaluate healthcare practitioners’ (HCPs) perceptions of diagnosing AD. Data from all countries were pooled and presented overall.
GPs are usually the first point of contact for patients with mild cognitive impairment (MCI)/AD. Only 30% of patients received a formal diagnosis of AD during the MCI stage, and it took patients 15.2 months from symptom onset to their first primary care visit. The most common challenges identified by HCPs were referral times, lack of effective treatment, and resource and time constraints.
Systemic reforms are required to remove barriers in early AD diagnosis, including tailored training and coordinated care between GPs and AD specialists.
Efficacy outcomes in clinical trials are based on well-powered analyes of the entire participating population. Trial populations will comprise many types of demographic and biological subgroups, including individuals of different sexes, groups of older and younger individuals, participants with or without the apolipoprotein E ε4 (APOE) genotype, ethnoracial groups, participants from urban versus rural communities, participants with lower and higher educational levels, or individuals who have or have not undergone previous therapies such as anti-amyloid monoclonal antibodies (MABs). Each subgroups is underpowered to draw definitive outcomes, and analyses can lead to inaccurate conclusions. Disciplined subgroup analysis can be hypothesis generating and can help guide drug development decision-making. The risks associated with subgroup analysis can be mitigated by using standard terminology, prespecifying outcomes of interest, stratifying randomization, conducting interaction analyses to identify confounds, and limiting the number of subgroup comparisons. Alternative efficacy and safety analyses such as the interaction test and non-inferiority analyses may yield important insights. Together, these design and analytic straegies may allow trialists to avoid spurious interpretations and derive more informative conclusions regarding the impact of therapy on subgroups in Alzheimer's disease (AD) clinical trials. Greater understanding of safety and efficacy in the subgroups participating in trials is crtically important for indicating what conclusions can be generalized if the candidate therapy is approved.
Amyloid beta (Aβ)-directed antibodies have shown varying degrees of efficacy against Alzheimer's disease (AD). This study explored the relationship between targeting of Aβ molecular species and therapeutic efficacy/adverse effects.
Surface plasmon resonance was used to measure binding of various Aβ-directed antibodies to monomers and soluble oligomers from AD brains. Plaque reactivity was assessed by immunohistochemistry and immunofluorescence. Antibody PMN310 was tested in AD mouse models.
Pan-Aβ reactive antibodies that failed in the clinic lost the ability to bind AD brain oligomers when competing with monomers. Lecanemab, aducanumab, and donanemab, which slowed cognitive decline, and early stage PMN310 and ACU193 showed a greater ability to withstand monomer competition. All antibodies bound plaque except for PMN310. In mouse models, PMN310 protected cognition and was not associated with microhemorrhages.
These results suggest that selectivity for soluble toxic oligomers correlates with clinical efficacy, potentially attenuating monomer competition and amyloid-related imaging abnormalities (ARIA).
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