Combination therapy targeting Alzheimer's disease risk factors is associated with a significant delay in Alzheimer's disease–related cognitive decline

IF 4.9 Q1 CLINICAL NEUROLOGY

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Pub Date : 2025-03-27 DOI:10.1002/trc2.70074

Yuan Shang, Georgina Torrandell-Haro, Francesca Vitali, Roberta Diaz Brinton, The Alzheimer's Disease Neuroimaging Initiative (ADNI)

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Abstract

BACKGROUND

Alzheimer's disease (AD) cognitive decline can be a major contributor to loss of independent living. Therapeutic strategies that alter the course of cognitive deterioration have the potential to sustain activities of daily living, promote quality of life, and delay transition to nursing-home care.

METHODS

We performed longitudinal linear regression analysis of National Alzheimer's Coordinating Center (NACC) cognitive data from 7653 mild dementia AD participants at baseline with at least one medication for diabetes (DBMD), lipid-lowering (LIPL), anti-hypertensive (AHTN), and non-steroidal anti-inflammatory (NSD) medications or any combination in 5684 (74%) participants and in 1969 (26%) participants with no study-relevant prescriptions over 10 years. Change in cognitive function was determined by Mini-Mental State Examination (MMSE) and CDR® Dementia Staging Instrument Sum of Boxes (CDR-SB) scores relative to non-treated participants stratified by sex and apolipoprotein E (APOE) genotype. Validation analysis was performed using Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset.

RESULTS

Combination of DBMD+LIPL+AHTN+NSD (QuadRx) resulted in a significant 46% MMSE and 32% CDR-SB delay in cognitive decline at 5 years, which was sustained at 10 years with a delay in decline of 47% MMSE and 33% CDR-SB. QuadRx was equally effective for the delay of cognitive decline in both females and males at 5 and 10 years. QuadRx mitigated the impact of the APOE ε4 genotype. Findings were validated in ADNI AD participants in which QuadRx was associated with a significant 60% MMSE delay in cognitive decline at 1 and 2 years.

CONCLUSIONS

Combination therapy was associated with a significant delay in cognitive decline in NACC AD participants at a magnitude comparable to or greater than amyloid beta immunomodulators. Further, the delay in decline was sustained for 10 years. The impact of QuadRx to delay cognitive decline was validated in deeply characterized ADNI participants. These data support combination therapy in persons with AD risk factors to alter the course of AD that persists for a decade, enabling cognitive function at a magnitude associated with independent living.

Highlights

QuadRx slowed Alzheimer's disease (AD) cognitive decline by 47% in the National Alzheimer's Coordinating Center NACC and 60% in Alzheimer's Disease Neuroimaging Initiative ADNI participants.
Combination therapy exhibited additive and synergistic slowing of cognitive decline.
QuadRx was equally effective in females and males at 5 and 10 years.
QuadRx mitigated the impact of the apolipoprotein E ε4 genotype.
QuadRx was effective in AD participants reporting drug use for their AD risk factor.

Abstract Image

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针对阿尔茨海默病危险因素的联合治疗与阿尔茨海默病相关认知衰退的显著延迟相关

阿尔茨海默病（AD）认知能力下降可能是丧失独立生活能力的主要原因。改变认知退化过程的治疗策略有可能维持日常生活活动，提高生活质量，并延迟向养老院护理的过渡。方法：我们对美国国家阿尔茨海默病协调中心（NACC） 7653名轻度痴呆性AD患者的认知数据进行纵向线性回归分析，这些患者在基线时至少服用了一种糖尿病（DBMD）、降脂（LIPL）、降压（AHTN）和非甾体抗炎（NSD）药物或任何组合，其中5684名（74%）参与者和1969名（26%）参与者在10年内没有服用与研究相关的处方。认知功能的变化通过迷你精神状态检查（MMSE）和CDR®痴呆分期工具盒和（CDR- sb）评分来确定，这些评分相对于按性别和载脂蛋白E （APOE）基因型分层的未接受治疗的参与者。使用阿尔茨海默病神经影像学倡议（ADNI）数据集进行验证分析。结果DBMD+LIPL+AHTN+NSD （QuadRx）联合治疗可导致认知衰退在5年时显著延迟46% MMSE和32% CDR-SB，这种延迟持续到10年时，延迟47% MMSE和33% CDR-SB。QuadRx对于延迟5岁和10岁时女性和男性的认知衰退同样有效。QuadRx减轻了APOE ε4基因型的影响。研究结果在ADNI AD参与者中得到了验证，在1年和2年的认知衰退中，QuadRx与显著60%的MMSE延迟相关。结论：联合治疗与NACC AD患者认知能力下降的显著延迟相关，其延迟程度与淀粉样蛋白免疫调节剂相当或更大。此外，衰退的延迟持续了10年。QuadRx延缓认知衰退的影响在深度特征的ADNI参与者中得到了验证。这些数据支持对AD危险因素患者进行联合治疗，以改变持续10年的AD病程，使认知功能在一定程度上与独立生活相关。在国家阿尔茨海默病协调中心（NACC）和阿尔茨海默病神经影像学倡议（ADNI）参与者中，QuadRx延缓了阿尔茨海默病（AD）认知能力下降47%和60%。联合治疗显示出认知衰退的累加和协同减缓。在5岁和10岁时，QuadRx对雌性和雄性同样有效。QuadRx减轻了载脂蛋白ε4基因型的影响。QuadRx对报告药物使用的AD参与者的AD风险因素有效。

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来源期刊

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Medicine-Psychiatry and Mental Health

CiteScore

10.10

自引率

2.10%

发文量

134

审稿时长

10 weeks

期刊介绍： Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.