Inverse association between CSF Aβ 42 levels and years of education in mild form of Alzheimer's disease: The cognitive reserve theory

Dumurgier, Julien; Paquet, Claire; Benisty, Sarah; Kiffel, Claire; Lidy, Claude; Mouton-Liger, François; Chabriat, Hugues; Laplanche, Jean‐Louis; Hugon, Jacques

doi:10.1016/j.nbd.2010.07.007

Cited by 36 publications

(23 citation statements)

References 24 publications

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“…These findings are consistent with cross-sectional studies suggesting that cognitively normal individuals with higher CR are able to tolerate higher levels of AD-pathology, as measured by levels of ;CSF Aβ 1–42 (Arenaza-Urquijo, et al, 2013; Vemuri, et al, 2011), CSF tau (Vemuri, et al, 2011), amyloid imaging (Rentz, et al, 2010), or FDG-PET metabolism (Ewers, et al, 2013). They are also consistent with studies of individuals with MCI or AD dementia, which have reported that, after controlling for neuropsychological test performance or disease severity, individuals with high-CR have lower levels of CSF Aβ 1–42 compared to individuals with low CR (Dumurgier, et al, 2010; Rolstad, et al, 2009a, 2009b). Moreover, these results converge with recent neuropathological findings showing that asymptomatic individuals with AD pathology (i.e., tau tangles and amyloid plaques) tend to have higher levels of education than symptomatic individuals (Monsell, et al, 2013).…”

Section: Discussionsupporting

confidence: 89%

Relationship of cognitive reserve and cerebrospinal fluid biomarkers to the emergence of clinical symptoms in preclinical Alzheimer's disease

Soldan

Pettigrew

et al. 2013

Neurobiology of Aging

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Levels of β-amyloid and phosphorylated tau (p-tau), as measured in cerebrospinal fluid (CSF), have been associated with risk of progressing from normal cognition to onset of clinical symptoms during preclinical Alzheimer’s disease (AD). We examined whether cognitive reserve (CR) modifies this association. CSF was obtained at baseline from 239 participants (mean age 57.2 years) who had been followed for up to 17 years with clinical and cognitive assessments (mean follow-up 8 years). A composite score based on the National Adult Reading Test (NART), vocabulary, and years of education at baseline was used as an index of CR. Cox regression models showed that increased risk of progressing from normal cognition to symptom onset was associated with lower CR, lower baseline β-amyloid, and higher baseline p-tau. There was no interaction between CR and β-amyloid, suggesting that the protective effects of higher CR are equivalent across the observed range of amyloid levels. By contrast, both tau and p-tau interacted with CR, indicating that CR was more protective at lower levels of tau and p-tau.

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Section: Discussionsupporting

confidence: 89%

Relationship of cognitive reserve and cerebrospinal fluid biomarkers to the emergence of clinical symptoms in preclinical Alzheimer's disease

Soldan

Pettigrew

et al. 2013

Neurobiology of Aging

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“…Second, our cohort contains a large proportion of participants more highly educated than the general population. The likely higher cognitive reserve in this population may alter the association of these biomarkers and cognition, and limits the generalizability of the findings [42]. Third, despite the finding of statistically significant associations between CSF and neuroimaging biomarkers and cognitive change at the group level in this study, the predictive value of these biomarkers, alone or in combination, to discriminate decliners from non-decliners at the individual level remained quite modest (as characterized by a low AUC) after 3-year follow-up.…”

Section: Discussionmentioning

confidence: 99%

Alzheimer’s Disease Biomarkers and Future Decline in Cognitive Normal Older Adults

Dumurgier

Hanseeuw

Hatling

et al. 2017

JAD

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Background Identifying older adults at risk of cognitive decline represents a challenge as Alzheimer’s disease (AD) modifying therapies move towards preclinical stages. Objective To investigate the relationship between AD biomarkers and subsequent change in cognition in a cohort of cognitively intact older adults. Methods 84 cognitively normal subjects (mean age 72.0 years, 59% women) were recruited through the Massachusetts Alzheimer’s Disease Research Center and the Harvard Aging Brain Study and followed over 3 years. Measurements of beta-amyloid 1-42 (Ab42), total Tau (t-Tau) and Tau phosphorylated at threonine 181 (p-Tau181) in the CSF at study entry were available in all cases. Baseline brain MRI, FDG-PET and PiB-PET data were available in the majority of participants. Relationship between baseline AD biomarkers and longitudinal change in cognition was assessed using Cox proportional hazard regression and linear mixed models. Results 14% participants increased their global Clinical Dementia Rating (CDR) score from 0 to 0.5 during follow-up. A CDR score increase was associated with higher baseline CSF t-Tau and p-Tau181, higher global cortical PiB retention and lower hippocampal volume. The combination of high CSF t-Tau and low Aβ42 or low hippocampal volume was more strongly related to cognitive outcome than each single biomarker. Higher CSF t-Tau was the only biomarker associated with subsequent decline in MMSE score. Conclusions Baseline CSF t-Tau and p-Tau181, in vivo amyloid load and hippocampal volume were all independently associated with future decline in cognition. The discriminatory ability of these biomarkers to predict risk of cognitive decline, however, was only modest.

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“…Factors such as ApoE status, gender, age, education, and brain size appear associated with differences in CSF Aβ 42 levels [87], with education inversely correlated with CSF Aβ 42 in early disease [88]. Such findings suggest that, at least in the case of CSF Aβ 42 , biomarkers must be interpreted in the context of phenotype.…”

Section: Future Directionsmentioning

confidence: 99%

Clinical, imaging, and pathological heterogeneity of the Alzheimer's disease syndrome

Lam

Masellis

Freedman

et al. 2013

Alzheimers Res Ther

319

239

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With increasing knowledge of clinical in vivo biomarkers and the pathological intricacies of Alzheimer's disease (AD), nosology is evolving. Harmonized consensus criteria that emphasize prototypic illness continue to develop to achieve diagnostic clarity for treatment decisions and clinical trials. However, it is clear that AD is clinically heterogeneous in presentation and progression, demonstrating variable topographic distributions of atrophy and hypometabolism/hypoperfusion. AD furthermore often keeps company with other conditions that may further nuance clinical expression, such as synucleinopathy exacerbating executive and visuospatial dysfunction and vascular pathologies (particularly small vessel disease that is increasingly ubiquitous with human aging) accentuating frontal-dysexecutive symptomatology. That some of these atypical clinical patterns recur may imply the existence of distinct AD variants. For example, focal temporal lobe dysfunction is associated with a pure amnestic syndrome, very slow decline, with atrophy and neurofibrillary tangles limited largely to the medial temporal region including the entorhinal cortex. Left parietal atrophy and/or hypometabolism/hypoperfusion are associated with language symptoms, younger age of onset, and faster rate of decline - a potential 'language variant' of AD. Conversely, the same pattern but predominantly affecting the right parietal lobe is associated with a similar syndrome but with visuospatial symptoms replacing impaired language function. Finally, the extremely rare frontal variant is associated with executive dysfunction out of keeping with degree of memory decline and may have prominent behavioural symptoms. Genotypic differences may underlie some of these subtypes; for example, absence of apolipoprotein E e4 is often associated with atypicality in younger onset AD. Understanding the mechanisms behind this variability merits further investigation, informed by recent advances in imaging techniques, biomarker assays, and quantitative pathological methods, in conjunction with standardized clinical, functional, neuropsychological and neurobehavioral evaluations. Such an understanding is needed to facilitate 'personalized AD medicine', and eventually allow for clinical trials targeting specific AD subtypes. Although the focus legitimately remains on prototypic illness, continuing efforts to develop disease-modifying therapies should not exclude the rarer AD subtypes and common comorbid presentations, as is currently often the case. Only by treating them as well can we address the full burden of this devastating dementia syndrome.

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Inverse association between CSF Aβ 42 levels and years of education in mild form of Alzheimer's disease: The cognitive reserve theory

Cited by 36 publications

References 24 publications

Relationship of cognitive reserve and cerebrospinal fluid biomarkers to the emergence of clinical symptoms in preclinical Alzheimer's disease

Relationship of cognitive reserve and cerebrospinal fluid biomarkers to the emergence of clinical symptoms in preclinical Alzheimer's disease

Alzheimer’s Disease Biomarkers and Future Decline in Cognitive Normal Older Adults

Clinical, imaging, and pathological heterogeneity of the Alzheimer's disease syndrome

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