Sex, amyloid, and <i>APOE</i> ε4 and risk of cognitive decline in preclinical Alzheimer's disease: Findings from three well‐characterized cohorts

Buckley, Rachel F.; Mormino, Elizabeth C.; Amariglio, Rebecca E.; Properzi, Michael J.; Rabin, Jennifer S.; Lim, Yen Ying; Papp, Kathryn V.; Jacobs, Heidi I.L.; Burnham, Samantha; Hanseeuw, Bernard; Doré, Vincent; Dobson, Annette; Masters, Colin L.; Waller, Michael; Rowe, Christopher C.; Maruff, Paul; Donohue, Michael C.; Doré, Vincent; Kirn, Dylan; Hedden, Trey; Chhatwal, Jasmeer P.; Schultz, Aaron P.; Johnson, Keith A.; Villemagne, Victor L.; Sperling, Reisa A.

doi:10.1016/j.jalz.2018.04.010

Cited by 187 publications

(182 citation statements)

References 60 publications

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“…Similarly, we replicated findings from other independent cohorts of the relationship between higher Aβ and increased age [5,6]. Meta‐analyses do not support a relationship between sex and high Aβ [4,31,32], although one observational study reported a female bias [33]. We extend these findings by reporting the magnitude of predictive utility that SCD measurement can provide about the likelihood of Aβ positivity in combination with predominating factors (e.g., age, APOE ).…”

Section: Discussionsupporting

confidence: 82%

Using subjective cognitive decline to identify high global amyloid in community‐based samples: A cross‐cohort study

Buckley

Sikkes

Villemagne

et al. 2019

Alz & Dem Diag Ass & Dis Mo

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Introduction We aimed to examine the contribution of subjective cognitive decline (SCD) to reduce the number of β‐amyloid (Aβ) positron emission tomography scans required for recruiting Aβ+ clinically normal individuals in clinical trials. Methods Three independent cohorts (890 clinically normal: 72 yrs ± 6.7; Female: 43.4%; SCD+: 24%; apolipoprotein E [APOE] ε4+: 28.5%; Aβ+: 32%) were used. SCD was dichotomized from one question. Using logistic regression, we classified Aβ+ using the SCD dichotomy, APOEε4, sex, and age. Results SCD increased odds of Aβ+ by 1.58 relative to non‐SCD. Female APOEε4 carriers with SCD exhibited higher odds of Aβ+ (OR = 3.34), whereas male carriers with SCD showed a weaker, opposing effect (OR = 0.37). SCD endorsement reduces the number of Aβ positron emission tomography scans to recruit Aβ+ individuals by 13% and by 9% if APOEε4 status is known. Conclusion SCD helps to classify those with high Aβ, even beyond the substantial effect of APOE genotype. Collecting SCD is a feasible method for targeting recruitment for those likely on the AD trajectory.

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Section: Discussionsupporting

confidence: 82%

Using subjective cognitive decline to identify high global amyloid in community‐based samples: A cross‐cohort study

Buckley

Sikkes

Villemagne

et al. 2019

Alz & Dem Diag Ass & Dis Mo

Self Cite

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“…However, differences in cognitive test batteries across cohorts required substitution with measures assessing the same cognitive process. The PACC has exhibited relative concordance of the baseline and slopes among these cohorts despite differences in measures. The PACC was computed separately in each cohort by averaging the z‐transformed scores for each measure derived from cohort‐specific sample means and standard deviations.…”

Section: Methodsmentioning

confidence: 94%

Clinical meaningfulness of subtle cognitive decline on longitudinal testing in preclinical AD

Papp

Buckley

Mormino

et al. 2020

Alzheimer's & Dementia

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Introduction Demonstrating the “clinical meaningfulness” of slowing early cognitive decline in clinically normal (CN) older adults with elevated amyloid‐β (Aβ+) is critical for Alzheimer's disease secondary prevention trials and for understanding early cognitive progression. Methods Cox regression analyses were used to determine whether 3‐year slopes on the preclinical Alzheimer's cognitive composite predicted MCI diagnosis and global Clinical Dementia Rating>0 in 267 Aβ+ CN individuals participating in the Harvard Aging Brain Study, Australian Imaging, Biomarker and Lifestyle Study, and Alzheimer's Disease Neuroimaging Initiative. Results Steeper preclinical Alzheimer's cognitive composite decline over 3 years was associated with increased risk for MCI diagnosis and global Clinical Dementia Rating>0 in the following years across all cohorts. Hazard ratios using meta‐analytic estimates were 5.47 (95% CI: 3.25–9.18) for MCI diagnosis and 4.49 (95% CI: 2.84–7.09) for Clinical Dementia Rating>0 in those with subtle decline (>−.14 to −.26 preclinical Alzheimer's cognitive composite standard deviations/year) on longitudinal cognitive testing. Discussion Early “subtle cognitive decline” among Aβ+ CN on a sensitive cognitive composite demonstrably increases risk for imminent clinical disease progression and functional impairment.

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“…Many studies have evaluated the temporal order in which cognitive tests change in biomarker‐defined cohorts. Memory tests, such as the Free and Cued Selective Reminding Test (FCSRT) and CVLT‐2, are among the most sensitive [26,35]. When we examined the relationship between different CSF markers of neurodegeneration and standardized measures of cognition, we found that ratios of candidate synaptic biomarkers to Tau correlated strongly with sensitive measures from the CVLT that probe memory acquisition and retention or the MDRS that assesses more general cognitive function.…”

Section: Discussionmentioning

confidence: 99%

Synaptic biomarkers in CSF aid in diagnosis, correlate with cognition and predict progression in MCI and Alzheimer's disease

Galasko

Xiao

et al. 2019

A&D Transl Res & Clin Interv

102

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Introduction Amyloid, Tau, and neurodegeneration biomarkers can stage Alzheimer's Disease (AD). Synaptic biomarkers may help track cognition. Methods In cognitively normal controls, Mild Cognitive Impairment (MCI) and AD, we investigated CSF biomarkers in relation to cognitive measures and as predictors of cognitive and global decline. Results There were 90 normal controls (mean age 73.0, 58% women), 57 MCI (mean age 74.3, 35% women), and 46 AD (mean age 70.7, 41% women). CSF Aβ1‐42 and Neuronal Pentraxin 2 (NPTX2) were decreased, and CSF Tau, neurogranin, and SNAP25 increased in AD versus controls. Aβ1‐42/Tau or NPTX2/Tau discriminated AD and controls best. NPTX2/Tau correlated strongly with cognition in AD and MCI and predicted a 2–3‐year decline. We replicated findings in the ADNI cohort. Discussion CSF synaptic biomarkers, particularly NPTX2, which regulates synaptic homeostasis, relate to cognition and predict progression in AD beyond Aβ1‐42 and Tau. This is relevant for prognosis and clinical trials.

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Sex, amyloid, and APOE ε4 and risk of cognitive decline in preclinical Alzheimer's disease: Findings from three well‐characterized cohorts

Abstract: Although Aβ did not differ by sex, cognitive decline was greater in females with higher Aβ. Our findings suggest that sex may play a modifying role on risk of Alzheimer's disease-related cognitive decline.

Cited by 187 publications

References 60 publications

Using subjective cognitive decline to identify high global amyloid in community‐based samples: A cross‐cohort study

Using subjective cognitive decline to identify high global amyloid in community‐based samples: A cross‐cohort study

Clinical meaningfulness of subtle cognitive decline on longitudinal testing in preclinical AD

Synaptic biomarkers in CSF aid in diagnosis, correlate with cognition and predict progression in MCI and Alzheimer's disease

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