Amyloid-β, Tau, and Cognition in Cognitively Normal Older Individuals: Examining the Necessity to Adjust for Biomarker Status in Normative Data

International audienceWe investigated whether amyloid-β (Aβ) and tau affected cognition in cognitively normal (CN) individuals, and whether norms for neuropsychological tests based on biomarker-negative individuals would improve early detection of dementia. We included 907 CN individuals from 8 European cohorts and from the Alzheimer's disease Neuroimaging Initiative. All individuals were aged above 40, had Aβ status and neuropsychological data available. Linear mixed models were used to assess the associations of Aβ and tau with five neuropsychological tests assessing memory (immediate and delayed recall of Auditory Verbal Learning Test, AVLT), verbal fluency (Verbal Fluency Test, VFT), attention and executive functioning (Trail Making Test, TMT, part A and B). All test except the VFT were associated with Aβ status and this influence was augmented by age. We found no influence of tau on any of the cognitive tests. For the AVLT Immediate and Delayed recall and the TMT part A and B, we calculated norms in individuals without Aβ pathology (Aβ-norms), which we validated in an independent memory-clinic cohort by comparing their predictive accuracy to published norms. For memory tests, the Aβ-norms rightfully Bos et al. Biomarker Adjusted Norms for Cognitive Tests identified an additional group of individuals at risk of dementia. For non-memory test we found no difference. We confirmed the relationship between Aβ and cognition in cognitively normal individuals. The Aβ-norms for memory tests in combination with published norms improve prognostic accuracy of dementia

Table_3_Amyloid-β, Tau, and Cognition in Cognitively Normal Older Individuals: Examining the Necessity to Adjust for Biomarker Status in Normative Data.DOCX

<p>We investigated whether amyloid-β (Aβ) and tau affected cognition in cognitively normal (CN) individuals, and whether norms for neuropsychological tests based on biomarker-negative individuals would improve early detection of dementia. We included 907 CN individuals from 8 European cohorts and from the Alzheimer's disease Neuroimaging Initiative. All individuals were aged above 40, had Aβ status and neuropsychological data available. Linear mixed models were used to assess the associations of Aβ and tau with five neuropsychological tests assessing memory (immediate and delayed recall of Auditory Verbal Learning Test, AVLT), verbal fluency (Verbal Fluency Test, VFT), attention and executive functioning (Trail Making Test, TMT, part A and B). All test except the VFT were associated with Aβ status and this influence was augmented by age. We found no influence of tau on any of the cognitive tests. For the AVLT Immediate and Delayed recall and the TMT part A and B, we calculated norms in individuals without Aβ pathology (Aβ- norms), which we validated in an independent memory-clinic cohort by comparing their predictive accuracy to published norms. For memory tests, the Aβ- norms rightfully identified an additional group of individuals at risk of dementia. For non-memory test we found no difference. We confirmed the relationship between Aβ and cognition in cognitively normal individuals. The Aβ- norms for memory tests in combination with published norms improve prognostic accuracy of dementia.</p

Table_4_Amyloid-β, Tau, and Cognition in Cognitively Normal Older Individuals: Examining the Necessity to Adjust for Biomarker Status in Normative Data.DOCX

<p>We investigated whether amyloid-β (Aβ) and tau affected cognition in cognitively normal (CN) individuals, and whether norms for neuropsychological tests based on biomarker-negative individuals would improve early detection of dementia. We included 907 CN individuals from 8 European cohorts and from the Alzheimer's disease Neuroimaging Initiative. All individuals were aged above 40, had Aβ status and neuropsychological data available. Linear mixed models were used to assess the associations of Aβ and tau with five neuropsychological tests assessing memory (immediate and delayed recall of Auditory Verbal Learning Test, AVLT), verbal fluency (Verbal Fluency Test, VFT), attention and executive functioning (Trail Making Test, TMT, part A and B). All test except the VFT were associated with Aβ status and this influence was augmented by age. We found no influence of tau on any of the cognitive tests. For the AVLT Immediate and Delayed recall and the TMT part A and B, we calculated norms in individuals without Aβ pathology (Aβ- norms), which we validated in an independent memory-clinic cohort by comparing their predictive accuracy to published norms. For memory tests, the Aβ- norms rightfully identified an additional group of individuals at risk of dementia. For non-memory test we found no difference. We confirmed the relationship between Aβ and cognition in cognitively normal individuals. The Aβ- norms for memory tests in combination with published norms improve prognostic accuracy of dementia.</p

Effect of CALHM1 on <b>Aβ</b>_1-42- induced cell toxicity.

<p>HEK-293 cells over-expressing CALHM1-WT, CALHM1-G330D and CALHM1-P86L were treated with 2 μM Aβ_1-42 oligomers for 24h. Cell viability was measured by MTT reduction. Data are the mean ± SEM of three independent experiments performed in triplicate. * <i>P</i><0.05 vs untreated cells by student t test.</p

Effect of CALHM1 mutations on Ca²⁺ influx.

<p><b>A</b>. HEK-293 cells transfected with GFP, CALHM1-WT, CALHM1-P86L, CALHM1-R154H, CALHM1-A213T and CALHM1-G330D were loaded with Fura-2 and tested for Ca²⁺ influx into the cytoplasm following the removal of Ca²⁺ from the extracellular media. Time course of Ca²⁺ signals normalized to the value before the addition of Ca²⁺ and expressed as the mean±S.E.M. are shown. <b>B</b>. Mean peak Ca²⁺ signals for the different conditions are shown. Number of cells analysed are given for each condition. * <i>P</i><0.05 <i>vs</i> GFP; ** <i>P</i><0.01 <i>vs</i> GFP, one-way ANOVA and Bonferroni <i>post </i><i>hoc</i>.</p