Elles Konijnenberg1, Jori Tomassen1, Anouk den Braber1,2, Mara Ten Kate1, Maqsood Yaqub3, Sandra D Mulder4, Michel G Nivard2, Hugo Vanderstichele5, Adriaan A Lammertsma3, Charlotte E Teunissen4, Bart N M van Berckel3, Dorret I Boomsma2, Philip Scheltens1, Betty M Tijms1, Pieter Jelle Visser1,6,7. 1. Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands. 2. Department of Biological Psychology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands. 3. Department of Radiology and Nuclear Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands. 4. Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands. 5. Biomarkable bv, working for this study on behalf of ADx NeuroSciences, Ghent, Belgium. 6. Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, the Netherlands. 7. Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Instutet, Stockholm, Sweden.
Abstract
OBJECTIVE: The present work was undertaken to study the genetic contribution to the start of Alzheimer's disease (AD) with amyloid and tau biomarkers in cognitively intact older identical twins. METHODS: We studied in 96 monozygotic twin-pairs relationships between amyloid-beta (Aβ) aggregation as measured by the Aβ1-42/1-40 ratio in cerebrospinal fluid (CSF; n = 126) and positron emission tomography (PET, n = 194), and CSF markers for Aβ production (beta-secretase 1, Aβ1-40, and Aβ1-38) and CSF tau. Associations among markers were tested with generalized estimating equations including a random effect for twin status, adjusted for age, gender, and apolipoprotein E ε4 genotype. We used twin analyses to determine relative contributions of genetic and/or environmental factors to AD pathophysiological processes. RESULTS: Twenty-seven individuals (14%) had an abnormal amyloid PET, and 14 twin-pairs (15%) showed discordant amyloid PET scans. Within twin-pairs, Aβ production markers and total-tau (t-tau) levels strongly correlated (r range = 0.73-0.86, all p < 0.0001), and Aβ aggregation markers and 181-phosphorylated-tau (p-tau) levels correlated moderately strongly (r range = 0.50-0.64, all p < 0.0001). Cross-twin cross-trait analysis showed that Aβ1-38 in one twin correlated with Aβ1-42/1-40 ratios, and t-tau and p-tau levels in their cotwins (r range = -0.28 to 0.58, all p < .007). Within-pair differences in Aβ production markers related to differences in tau levels (r range = 0.49-0.61, all p < 0.0001). Twin discordance analyses suggest that Aβ production and tau levels show coordinated increases in very early AD. INTERPRETATION: Our results suggest a substantial genetic/shared environmental background contributes to both Aβ and tau increases, suggesting that modulation of environmental risk factors may aid in delaying the onset of AD pathophysiological processes. ANN NEUROL 2021;89:987-1000.
OBJECTIVE: The present work was undertaken to study the genetic contribution to the start of Alzheimer's disease (AD) with amyloid and tau biomarkers in cognitively intact older identical twins. METHODS: We studied in 96 monozygotic twin-pairs relationships between amyloid-beta (Aβ) aggregation as measured by the Aβ1-42/1-40 ratio in cerebrospinal fluid (CSF; n = 126) and positron emission tomography (PET, n = 194), and CSF markers for Aβ production (beta-secretase 1, Aβ1-40, and Aβ1-38) and CSF tau. Associations among markers were tested with generalized estimating equations including a random effect for twin status, adjusted for age, gender, and apolipoprotein E ε4 genotype. We used twin analyses to determine relative contributions of genetic and/or environmental factors to AD pathophysiological processes. RESULTS: Twenty-seven individuals (14%) had an abnormal amyloid PET, and 14 twin-pairs (15%) showed discordant amyloid PET scans. Within twin-pairs, Aβ production markers and total-tau (t-tau) levels strongly correlated (r range = 0.73-0.86, all p < 0.0001), and Aβ aggregation markers and 181-phosphorylated-tau (p-tau) levels correlated moderately strongly (r range = 0.50-0.64, all p < 0.0001). Cross-twin cross-trait analysis showed that Aβ1-38 in one twin correlated with Aβ1-42/1-40 ratios, and t-tau and p-tau levels in their cotwins (r range = -0.28 to 0.58, all p < .007). Within-pair differences in Aβ production markers related to differences in tau levels (r range = 0.49-0.61, all p < 0.0001). Twin discordance analyses suggest that Aβ production and tau levels show coordinated increases in very early AD. INTERPRETATION: Our results suggest a substantial genetic/shared environmental background contributes to both Aβ and tau increases, suggesting that modulation of environmental risk factors may aid in delaying the onset of AD pathophysiological processes. ANN NEUROL 2021;89:987-1000.
Authors: Pieter Jelle Visser; Lianne M Reus; Johan Gobom; Iris Jansen; Ellen Dicks; Sven J van der Lee; Magda Tsolaki; Frans R J Verhey; Julius Popp; Pablo Martinez-Lage; Rik Vandenberghe; Alberto Lleó; José Luís Molinuevo; Sebastiaan Engelborghs; Yvonne Freund-Levi; Lutz Froelich; Kristel Sleegers; Valerija Dobricic; Simon Lovestone; Johannes Streffer; Stephanie J B Vos; Isabelle Bos; August B Smit; Kaj Blennow; Philip Scheltens; Charlotte E Teunissen; Lars Bertram; Henrik Zetterberg; Betty M Tijms Journal: Mol Neurodegener Date: 2022-03-28 Impact factor: 14.195
Authors: Sisi Li; Yuhan Qiu; Xi Yuan; Qin Zhang; Mark D Kilby; Richard Saffery; Philip N Baker; Li Wen; Chao Tong; Hongbo Qi Journal: Front Pediatr Date: 2022-08-02 Impact factor: 3.569
Authors: Jori Tomassen; Anouk den Braber; Sophie M van der Landen; Elles Konijnenberg; Charlotte E Teunissen; Lisa Vermunt; Eco J C de Geus; Dorret I Boomsma; Philip Scheltens; Betty M Tijms; Pieter Jelle Visser Journal: Alzheimers Dement (N Y) Date: 2022-09-20
Authors: Olav M Andersen; Nikolaj Bøgh; Anne M Landau; Gro G Pløen; Anne Mette G Jensen; Giulia Monti; Benedicte P Ulhøi; Jens R Nyengaard; Kirsten R Jacobsen; Margarita M Jørgensen; Ida E Holm; Marianne L Kristensen; Aage Kristian O Alstrup; Esben S S Hansen; Charlotte E Teunissen; Laura Breidenbach; Mathias Droescher; Ying Liu; Hanne S Pedersen; Henrik Callesen; Yonglun Luo; Lars Bolund; David J Brooks; Christoffer Laustsen; Scott A Small; Lars F Mikkelsen; Charlotte B Sørensen Journal: Cell Rep Med Date: 2022-09-12