Cognitive Decline in Alzheimer’s Disease Is Not Associated with APOE

Katzourou, Ioanna; Leonenko, Ganna; Ivanov, Dobril; Meggy, Alun; Marshall, Rachel; Sims, Rebecca; Williams, Julie; Holmans, Peter; Escott‐Price, Valentina; Initiative, Alzheimer’s Disease Neuroimaging

doi:10.3233/jad-210685

Cited by 7 publications

(6 citation statements)

References 46 publications

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“…28 Furthermore, recent evidence suggests the APOE ε4 allele has no effect on disease progression. 29,30 Results on sex have been mixed, in one study shown to influence only baseline scores, 2 but not slope, and in another shown only to significantly influence slope. 4 These differences may be due to different male/female distributions within the trials.…”

Section: Resultsmentioning

confidence: 99%

“…This may be because most participants were amyloid positive, so APOE ε4 status may not be adding more to the model, given the strong association between APOE ε4 status and amyloid positivity 28 . Furthermore, recent evidence suggests the APOE ε4 allele has no effect on disease progression 29,30 . Results on sex have been mixed, in one study shown to influence only baseline scores, 2 but not slope, and in another shown only to significantly influence slope 4 .…”

Section: Discussionmentioning

confidence: 99%

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Disease progression model using the integrated Alzheimer's Disease Rating Scale

Gueorguieva

Chua

Willis

et al. 2022

Alzheimer's & Dementia

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Introduction An Alzheimer's disease (AD) dementia disease progression model was developed based on the integrated Alzheimer's Disease Rating Scale (iADRS). Methods Data from 3483 placebo participants in six AD trials were used to develop the disease progression model with NONMEM (version 7.4.2) and examined for mild cognitive impairment, and mild and moderate dementia due to AD. Results Baseline iADRS score was significantly influenced by AD symptomatic medication use, EXPEDITION2 enrollment (included moderate AD participants), age, and baseline Mini‐Mental State Examination (MMSE) score. Rate of disease progression increased across disease stage and was significantly influenced by AD medication use, age, and baseline MMSE score. Apolipoprotein E ε4 carrier status did not influence baseline iADRS score or disease progression. Discussion These results demonstrate a disease progression model describing the time course of the iADRS across the AD severity spectrum. This model can assist future clinical trials in study design optimization and treatment effect interpretation. Highlights A disease progression model described the integrated Alzheimer's Disease Rating Scale (iADRS) time course in mild cognitive impairment to moderate Alzheimer's disease. Using the linear regression model, iADRS scores can be calculated for Mini‐Mental State Examination scores. Results can help optimize future clinical trial design and aid in understanding treatment effects.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Disease progression model using the integrated Alzheimer's Disease Rating Scale

Gueorguieva

Chua

Willis

et al. 2022

Alzheimer's & Dementia

View full text Add to dashboard Cite

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“…For example, for Huntington's disease, which is caused by a CAG repeat expansion in the Huntingtin gene, HTT , genome‐wide association studies of Huntington's disease progression (Moss et al., 2017 ) and age at onset of motor signs (Correia et al., 2015 ) have reported novel genetic variants associated with the disease subphenotypes rather than overall risk. Similarly, it has been observed that the rate of cognitive decline in AD is often reported as not associated to APOE (Katzourou et al., 2021 ), however no powerful GWAS of rate of decline in AD exist as yet to generate a PRS for rate of decline prediction. PRS derived from GWAS using biomarkers of neurodegeneration such as amyloid positron emission tomography (amyloid‐beta PET) (Yan et al., 2021 ) or plasma biomarkers (Bradley et al., 2023 ; Stevenson‐Hoare et al., 2022 ) may have more useful applications for treatment, especially as newer therapies are developed which have very specific mechanisms of action (e.g., anti‐amyloid antibodies).…”

Section: Discussionmentioning

confidence: 99%

Pitfalls of predicting age‐related traits by polygenic risk scores

Escott‐Price

Schmidt

2023

Annals of Human Genetics

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Polygenic risk scores (PRS) are a method increasingly used to capture the combined effect of genome‐wide significant variants and those which individually do not show genome‐wide significant association but are likely to contribute to the risk of developing diseases. However, their practical use incurs complications and inconsistencies that so far limit their clinical applicability. The aims of the present review are to discuss the PRS for age‐related diseases and to highlight pitfalls and limitations of PRS prediction accuracy due to ageing and mortality effects. We argue that the PRS is widely used but the individual's PRS values differ substantially depending on the number of genetic variants included, the discovery GWAS and the method employed to generate them. Moreover, for neurodegenerative disorders, although an individual's genetics do not change with age, the actual score depends on the age of the sample used in the discovery GWAS and is likely to reflect the individual's disease risk at this particular age. Improvement of PRS prediction accuracy for neurodegenerative disorders will come from two sides, both the precision of clinical diagnoses, and a careful attention to the age distribution in the underlying samples and validation of the prediction in longitudinal studies.

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“…While APOE ε4 as a risk factor is well established, the role of apoE4 in progression after controlling for the presence of amyloid is more uncertain. Conflicting studies suggest that the APOE ε4 allele has no effect on disease progression even without accounting for the presence or absence of amyloid pathology 11,12 . Currently, trials on amyloid‐targeting drugs, particularly antibody‐based therapies, generally enroll only amyloid‐positive participants.…”

Section: Introductionmentioning

confidence: 99%

“…Conflicting studies suggest that the APOE ε4 allele has no effect on disease progression even without accounting for the presence or absence of amyloid pathology. 11,12 Currently, trials on amyloid-targeting drugs, particularly antibody-based therapies, generally enroll only amyloidpositive participants. So, it is important to understand the role of the APOE ε4 allele in a pathology-selected population.…”

Section: Introductionmentioning

confidence: 99%

APOE ε4's impact on response to amyloid therapies in early symptomatic Alzheimer's disease: Analyses from multiple clinical trials

Evans

Sparks

Andersen

et al. 2023

Alzheimer's & Dementia

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INTRODUCTIONApolipoprotein E (APOE) ε4 may interact with response to amyloid‐targeting therapies.METHODSAggregate data from trials enrolling participants with amyloid‐positive, early symptomatic Alzheimer's disease (AD) were analyzed for disease progression.RESULTSPooled analysis of potentially efficacious antibodies lecanemab, aducanumab, solanezumab, and donanemab shows slightly better efficacy in APOE ε4 carriers than in non‐carriers. Carrier and non‐carrier mean (95% confidence interval) differences from placebo using Clinical Dementia Rating Scale–Sum of Boxes (CDR‐SB) were –0.30 (–0.478, –0.106) and –0.20 (–0.435, 0.042) and AD Assessment Scale–Cognitive subscale (ADAS‐Cog) values were –1.01 (–1.577, –0.456) and –0.80 (–1.627, 0.018), respectively. Decline in the APOE ε4 non‐carrier placebo group was equal to or greater than that in carriers across multiple scales. Probability of study success increases as the representation of the carrier population increases.DISCUSSIONWe hypothesize that APOE ε4 carriers have same or better response than non‐carriers to amyloid‐targeting therapies and similar or less disease progression with placebo in amyloid‐positive trials.HIGHLIGHTS Amyloid‐targeting therapies had slightly greater efficacy in apolipoprotein E (APOE) ε4 carriers. Clinical decline is the same/slightly faster in amyloid‐positive APOE ε4 non‐carriers. Prevalence of non‐carriers in trial populations could impact outcomes.

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Cognitive Decline in Alzheimer’s Disease Is Not Associated with APOE

Cited by 7 publications

References 46 publications

Disease progression model using the integrated Alzheimer's Disease Rating Scale

Disease progression model using the integrated Alzheimer's Disease Rating Scale

Pitfalls of predicting age‐related traits by polygenic risk scores

APOE ε4's impact on response to amyloid therapies in early symptomatic Alzheimer's disease: Analyses from multiple clinical trials

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