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CALHM1 P86L polymorphism modulates CSF A? levels in cognitively healthy individuals at risk for Alzheimer's disease.

ABSTRACT: The calcium homeostasis modulator 1 (CALHM1) gene codes for a novel cerebral calcium channel controlling intracellular calcium homeostasis and amyloid-? (A?) peptide metabolism, a key event in the etiology of Alzheimer's disease (AD). The P86L polymorphism in CALHM1 (rs2986017) initially was proposed to impair CALHM1 functionally and to lead to an increase in A? accumulation in vitro in cell lines. Recently, it was reported that CALHM1 P86L also may influence A? metabolism in vivo by increasing A? levels in human cerebrospinal fluid (CSF). Although the role of CALHM1 in AD risk remains uncertain, concordant data have now emerged showing that CALHM1 P86L is associated with an earlier age at onset of AD. Here, we have analyzed the association of CALHM1 P86L with CSF A? in samples from 203 AD cases and 46 young cognitively healthy individuals with a positive family history of AD. We failed to detect an association between the CALHM1 polymorphism and CSF A? levels in AD patients. Our data, however, revealed a significant association of CALHM1 P86L with elevated CSF A?42 and A?40 in the normal cohort at risk for AD. This work shows that CALHM1 modulates CSF A? levels in presymptomatic individuals, strengthening the notion that CALHM1 is involved in AD pathogenesis. These data further demonstrate the utility of endophenotype-based approaches focusing on CSF biomarkers for the identification or validation of risk factors for AD.

SUBMITTER: Koppel J

PROVIDER: S-EPMC3188873 | biostudies-literature | 2011 Sep-Oct

REPOSITORIES: biostudies-literature

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CALHM1 P86L polymorphism modulates CSF Aβ levels in cognitively healthy individuals at risk for Alzheimer's disease.

Koppel Jeremy J Campagne Fabien F Vingtdeux Valérie V Dreses-Werringloer Ute U Ewers Michael M Rujescu Dan D Hampel Harald H Gordon Marc L ML Christen Erica E Chapuis Julien J Greenwald Blaine S BS Davies Peter P Marambaud Philippe P

Molecular medicine (Cambridge, Mass.) 20110524 9-10

The calcium homeostasis modulator 1 (CALHM1) gene codes for a novel cerebral calcium channel controlling intracellular calcium homeostasis and amyloid-β (Aβ) peptide metabolism, a key event in the etiology of Alzheimer's disease (AD). The P86L polymorphism in CALHM1 (rs2986017) initially was proposed to impair CALHM1 functionally and to lead to an increase in Aβ accumulation in vitro in cell lines. Recently, it was reported that CALHM1 P86L also may influence Aβ metabolism in vivo by increasing ...[more]

PMID: 21629967

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Project description:Research shows that gamma activity changes in Alzheimer's disease (AD), revealing synaptic pathology and potential therapeutic applications. We aim to explore whether cognitive challenge combined with quantitative EEG (qEEG) can unmask abnormal gamma frequency power in healthy individuals at high risk of developing AD. We analyzed low (30-50 Hz) and high gamma (50-80 Hz) power over six brain regions at EEG sensor level (frontal/central/parietal/left temporal/right temporal/occipital) in a dataset collected from an aging cohort during N-back working memory (WM) testing at two different load conditions (N = 0 or 2). Cognitively healthy (CH) study participants (≥60 years old) of both sexes were divided into two subgroups: normal amyloid/tau ratios (CH-NAT, n = 10) or pathological amyloid/tau (CH-PAT, n = 14) in cerebrospinal fluid (CSF). During low load (0-back) challenge, low gamma is higher in CH-PATs than CH-NATs over frontal and central regions (p = 0.014∼0.032, effect size (Cohen's d) = 0.95∼1.11). However, during high load (2-back) challenge, low gamma is lower in CH-PATs compared to CH-NATs over the left temporal region (p = 0.045, Cohen's d = -0.96), and high gamma is lower over the parietal region (p = 0.035, Cohen's d = -1.02). Overall, our studies show a medium to large negative effect size across the scalp (Cohen's d = -0.51∼-1.02). In addition, low gamma during 2-back is positively correlated with 0-back accuracy over all regions except the occipital region only in CH-NATs (r = 0.69∼0.77, p = 0.0098∼0.027); high gamma during 2-back correlated positively with 0-back accuracy over all regions in CH-NATs (r = 0.68∼0.78, p = 0.007∼0.030); high gamma during 2-back negatively correlated with 0-back response time over parietal, right temporal, and occipital regions in CH-NATs (r = -0.70∼-0.66, p = 0.025∼0.037). We interpret these preliminary results to show: (1) gamma power is compromised in AD-biomarker positive individuals, who are otherwise cognitively healthy (CH-PATs); (2) gamma is associated with WM performance in normal aging (CH-NATs) (most significantly in the frontoparietal region). Our pilot findings encourage further investigations in combining cognitive challenges and qEEG in developing neurophysiology-based markers for identifying individuals in the prodromal stage, to help improving our understanding of AD pathophysiology and the contributions of low- and high-frequency gamma oscillations in cognitive functions.

Dataset Information

CALHM1 P86L polymorphism modulates CSF A? levels in cognitively healthy individuals at risk for Alzheimer's disease.

Publications

CALHM1 P86L polymorphism modulates CSF Aβ levels in cognitively healthy individuals at risk for Alzheimer's disease.

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