Age and the association between apolipoprotein E genotype and Alzheimer disease: A cerebrospinal fluid biomarker–based case–control study

Saddiki, Hana; Fayossé, Aurore; Cognat, Emmanuel; Sabia, Séverine; Engelborghs, Sebastiaan; Wallon, David; Alexopoulos, Panagiotis; Blennow, Kaj; Zetterberg, Henrik; Parnetti, Lucilla; Zerr, Inga; Hermann, Péter; Gabelle, Audrey; Boada, Merçé; Orellana, Adelina; Rojas, Itziar de; Lilamand, Matthieu; Bjerke, Maria; Broeckhoven, Christine Van; Farotti, Lucia; Salvadori, Nicola; Diehl‐Schmid, Janine; Grimmer, Timo; Hourrègue, Claire; Dugravot, Aline; Nicolas, Gaël; Laplanche, Jean‐Louis; Lehmann, Sylvain; Bouaziz‐Amar, Elodie; Initiative, Alzheimer’s Disease Neuroimaging; Hugon, Jacques; Tzourio, Christophe; Singh‐Manoux, Archana; Paquet, Claire; Dumurgier, Julien

doi:10.1371/journal.pmed.1003289

Cited by 50 publications

(57 citation statements)

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“…The ε4 allele of the Apolipoprotein E (APOE) gene is the strongest genetic risk factor for late onset Alzheimer's disease (AD) [1]. Around 25% of the Caucasian population carries at least one ε4 allele [2], with a 3-fold increased risk of AD for heterozygotes and a nearly 15fold increased risk for homozygotes compared to the ε3 homozygotes, the most common genotype [3]. APOE ε2 is less common and appears to have a protective effect on AD [4].…”

Section: Introductionmentioning

confidence: 99%

The association of APOE ε4 with cognitive function over the adult life course and incidence of dementia: 20 years follow-up of the Whitehall II study

et al. 2021

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Background Approximately 25% of the general population carries at least one ε4 allele of the Apolipoprotein E (APOE ε4), the strongest genetic risk factor for late onset Alzheimer’s disease. Beyond its association with late-onset dementia, the association between APOE ε4 and change in cognition over the adult life course remains uncertain. This study aims to examine whether the association between Apolipoprotein E (APOE) ε4 zygosity and cognition function is modified between midlife and old age. Methods A cohort study of 5561 participants (mean age 55.5 (SD = 5.9) years, 27.1% women) with APOE genotyping and repeated cognitive tests for reasoning, memory, and semantic and phonemic fluency, during a mean (SD) follow-up of 20.2 (2.8) years (the Whitehall II study). We used joint models to examine the association of APOE genotype with cognitive function trajectories between 45 and 85 years taking drop-out, dementia, and death into account and Fine and Gray models to examine associations with dementia. Results Compared to non-carriers, heterozygote (prevalence 25%) and homozygote (prevalence 2%) APOE ε4 carriers had increased risk of dementia, sub-distribution hazard ratios 2.19 (95% CI 1.73, 2.77) and 5.97 (95% CI 3.85, 9.28) respectively. Using data spanning 45–85 years with non-ε4 carriers as the reference, ε4 homozygotes had poorer global cognitive score starting from 65 years; ε4 heterozygotes had better scores between 45 and 55 years, then no difference until poorer cognitive scores from 75 years onwards. In analysis of individual cognitive tests, better cognitive performance in the younger ε4 heterozygotes was primarily attributable to executive function. Conclusions Both heterozygous and homozygous ε4 carriers had poorer cognition and greater risk of dementia at older ages. Our findings show some support for a complex antagonist pleiotropic effect of APOE ε4 heterozygosity over the adult life course, characterized by cognitive advantage in midlife.

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Section: Introductionmentioning

confidence: 99%

The association of APOE ε4 with cognitive function over the adult life course and incidence of dementia: 20 years follow-up of the Whitehall II study

et al. 2021

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“…In fact, the predictive model with driving behaviour and age alone achieved an F1 score of 0.88 (95% CI 0.86–0.91), and the model with driving behaviour, age, and APOE ε4 status achieved an F1 score of 0.91 (95% CI 0.89–0.94). This improvement is unsurprising since age and APOE ε4 are among the strongest risk factors for AD [ 36 ]. Others have shown that the ability of novel AD biomarkers to predict preclinical AD (generally indicated by abnormality of PET or CSF amyloid biomarkers) may be improved by including age and APOE ε4 status in models [ 34 , 37 , 38 ].…”

Section: Discussion/conclusionmentioning

confidence: 99%

GPS driving: a digital biomarker for preclinical Alzheimer disease

et al. 2021

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Background Alzheimer disease (AD) is the most common cause of dementia. Preclinical AD is the period during which early AD brain changes are present but cognitive symptoms have not yet manifest. The presence of AD brain changes can be ascertained by molecular biomarkers obtained via imaging and lumbar puncture. However, the use of these methods is limited by cost, acceptability, and availability. The preclinical stage of AD may have a subtle functional signature, which can impact complex behaviours such as driving. The objective of the present study was to evaluate the ability of in-vehicle GPS data loggers to distinguish cognitively normal older drivers with preclinical AD from those without preclinical AD using machine learning methods. Methods We followed naturalistic driving in cognitively normal older drivers for 1 year with a commercial in-vehicle GPS data logger. The cohort included n = 64 individuals with and n = 75 without preclinical AD, as determined by cerebrospinal fluid biomarkers. Four Random Forest (RF) models were trained to detect preclinical AD. RF Gini index was used to identify the strongest predictors of preclinical AD. Results The F1 score of the RF models for identifying preclinical AD was 0.85 using APOE ε4 status and age only, 0.82 using GPS-based driving indicators only, 0.88 using age and driving indicators, and 0.91 using age, APOE ε4 status, and driving. The area under the receiver operating curve for the final model was 0.96. Conclusion The findings suggest that GPS driving may serve as an effective and accurate digital biomarker for identifying preclinical AD among older adults.

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“…CSF t-tau, p-tau, Abeta 42, and Abeta 40 were quantified using ELISA kits from Fujirebio (Fujirebio, Ghent, Belgium). The established lab-specific cut-offs indicating pathological levels t-tau > 449 pg/ml, p-tau > 60 pg/ml, Abeta 1-42 < 450 pg/ml, and Abeta ratio [(abeta1-42/abeta1-40)*10)] <0.975 were applied as previously reported [ 30 ]. Test performers were blind to clinical information and clinical investigators vice versa.…”

Section: Methodsmentioning

confidence: 99%

Plasma Lipocalin 2 in Alzheimer’s disease: potential utility in the differential diagnosis and relationship with other biomarkers

et al. 2022

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Background Lipocalin-2 is a glycoprotein that is involved in various physiological and pathophysiological processes. In the brain, it is expressed in response to vascular and other brain injury, as well as in Alzheimer’s disease in reactive microglia and astrocytes. Plasma Lipocalin-2 has been proposed as a biomarker for Alzheimer’s disease but available data is scarce and inconsistent. Thus, we evaluated plasma Lipocalin-2 in the context of Alzheimer’s disease, differential diagnoses, other biomarkers, and clinical data. Methods For this two-center case-control study, we analyzed Lipocalin-2 concentrations in plasma samples from a cohort of n = 407 individuals. The diagnostic groups comprised Alzheimer’s disease (n = 74), vascular dementia (n = 28), other important differential diagnoses (n = 221), and healthy controls (n = 84). Main results were validated in an independent cohort with patients with Alzheimer’s disease (n = 19), mild cognitive impairment (n = 27), and healthy individuals (n = 28). Results Plasma Lipocalin-2 was significantly lower in Alzheimer’s disease compared to healthy controls (p < 0.001) and all other groups (p < 0.01) except for mixed dementia (vascular and Alzheimer’s pathologic changes). Areas under the curve from receiver operation characteristics for the discrimination of Alzheimer’s disease and healthy controls were 0.783 (95%CI: 0.712–0.855) in the study cohort and 0.766 (95%CI: 0.627–0.905) in the validation cohort. The area under the curve for Alzheimer’s disease versus vascular dementia was 0.778 (95%CI: 0.667–0.890) in the study cohort. In Alzheimer’s disease patients, plasma Lipocalin2 did not show significant correlation with cerebrospinal fluid biomarkers of neurodegeneration and AD-related pathology (total-tau, phosphorylated tau protein, and beta-amyloid 1-42), cognitive status (Mini Mental Status Examination scores), APOE genotype, or presence of white matter hyperintensities. Interestingly, Lipocalin 2 was lower in patients with rapid disease course compared to patients with non-rapidly progressive Alzheimer’s disease (p = 0.013). Conclusions Plasma Lipocalin-2 has potential as a diagnostic biomarker for Alzheimer’s disease and seems to be independent from currently employed biomarkers.

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Age and the association between apolipoprotein E genotype and Alzheimer disease: A cerebrospinal fluid biomarker–based case–control study

Cited by 50 publications

References 46 publications

The association of APOE ε4 with cognitive function over the adult life course and incidence of dementia: 20 years follow-up of the Whitehall II study

The association of APOE ε4 with cognitive function over the adult life course and incidence of dementia: 20 years follow-up of the Whitehall II study

GPS driving: a digital biomarker for preclinical Alzheimer disease

Plasma Lipocalin 2 in Alzheimer’s disease: potential utility in the differential diagnosis and relationship with other biomarkers

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