Alzheimer''s and Dementia: Translational Research and Clinical Interventions最新文献

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.

Highlights

INTRODUCTION

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.

METHODS

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.

RESULTS

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.

DISCUSSION

These results suggest that selectivity for soluble toxic oligomers correlates with clinical efficacy, potentially attenuating monomer competition and amyloid-related imaging abnormalities (ARIA).

Highlights

INTRODUCTION

Effect on amyloid plaque as measured by positron emission tomography imaging with Centiloid standardization of two therapeutic approaches targeting amyloid beta (Aβ) was investigated using exposure-response modeling.

METHODS

Individual-level verubecestat data from the APECS trial were pooled with summary-level data from the literature for amyloid monoclonal antibodies (mAbs) and fitted in a joint non-linear mixed-effects model.

RESULTS

An indirect-response (turnover) model with verubecestat inhibiting plaque formation and mAbs stimulating plaque removal well represented the data. The estimated plaque elimination half-life was 6.4 years. Daily verubecestat 40 mg was estimated to reduce formation by 91.8%. Aducanumab 10 mg/kg every 4 weeks (Q4W), donanemab 1400 mg Q4W, gantenerumab 1200 mg Q4W, and lecanemab 10 mg/kg Q2W were estimated to increase the removal rate by 9.3-, 18.6-, 5.3-, and 13.8-fold, respectively.

DISCUSSION

The model provides a fundamental measure of drug effects on plaque, independent of disease stage and study-design factors, improving cross-study comparisons and enabling predictions.

Highlights

The ongoing conversations surrounding the importance of minimal clinically important differences and descriptions of meaningful impacts must include the voices of those living with Alzheimer's disease and related dementias. To provide this perspective, members of the Alzheimer's Association Early Stage Advisory Group were asked to describe what matters most to them, their experiences with treatment, how they define meaningful care, and what would provide them with feelings of progress and hope. Responses offer differing yet complementary definitions of a quality life, ways in which clinicians and providers can recognize and support the person behind the diagnosis, and how participating in clinical trials can bring hope – both now and for the future. By centering on the lived experiences and perspectives of those people living with dementia, this article provides insight for those seeking to develop novel treatments and provide care and support, both now and in the future.

Highlights

The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a landmark 2-year randomized clinical trial evaluating multidomain lifestyle interventions for dementia prevention in older adults at elevated risk. Its effectiveness and national reach represent an important step towards scaling prevention science in diverse, real-world settings. However, the trial also underscores a persistent challenge in lifestyle medicine: the prioritization of feasibility over optimization. In this commentary, we review U.S. POINTER through a precision medicine lens and outline strategies to integrate standardized core elements with flexible, individualized components that can amplify both potency and applicability. We emphasize three priorities: (1) tailoring interventions to drive physiological adaptations; (2) leveraging the synergistic potential of related behavioral domains; and (3) targeting sleep and circadian health as central intervention components. While U.S. POINTER advances feasibility and community participation, a more tailored, mechanistically informed approach could increase effect sizes and extend benefits to populations historically excluded in prevention research. Personalized strategies should not be confined to pharmacology—they must also guide behavioral interventions. Designing lifestyle programs that stimulate measurable adaptations, leverage behavioral synergy, and align with circadian biology offers the potential to produce greater and more durable cognitive benefits.

Highlights

INTRODUCTION

Polypharmacy is common in older adults with mild cognitive impairment (MCI), but its impact on cognitive decline is unclear. Studies on the association between polypharmacy and cognitive outcomes have yielded inconsistent evidence. The objective of this study was to assess the association between polypharmacy and the risk of progression from MCI to dementia.

METHODS

We conducted a longitudinal cohort study of 237 older adults with MCI in Taiwan. Polypharmacy was defined as the concurrent use of ≥5 prescription medications. Cognitive function was assessed annually using the Clinical Dementia Rating scale. Cox proportional hazards regression models were used to evaluate the association between polypharmacy and dementia risk, adjusting for demographic and clinical covariates. Subgroup analyses examined the effects of different medication counts and specific medications on dementia progression.

RESULTS

Among 237 participants, 108 (45.6%) had polypharmacy, and 89 were diagnosed with dementia during a median follow-up of 34 months (interquartile range: 16.7 to 52.6 months). Kaplan–Meier analysis showed a higher dementia-free survival probability in the polypharmacy group (p = 0.005). Cox regression analysis revealed that polypharmacy was significantly associated with a reduced risk of MCI progression to dementia (hazard ratio [HR] = 0.49, 95% confidence interval [CI]: 0.31 to 0.78) after adjusting for covariates. Medication counts ranging from ≥5 to ≥8 were significantly associated with a reduced dementia risk, without a clear cut-off. Further analysis suggested that antihypertensive and lipid-modifying drugs were associated with a reduced risk of dementia progression.

CONCLUSION

Our findings suggest that polypharmacy is associated with a lower risk of progression to dementia in people with MCI, highlighting the importance of medication appropriateness over medication count. Future research should optimize pharmacological strategies to balance the risks and benefits of polypharmacy in older adults with MCI.

Highlights