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1. Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer's disease: a longitudinal observational study

Author

Morenas-Rodríguez, Estrella, Li, Yan, Hassenstab, Jason, Laske, Christoph, Levey, Allan, Lopez, Oscar, Marsh, Jacob, Martinez, Rita, Martins, Ralph, Mason, Neal Scott, Masters, Colin, Mawuenyega, Kwasi, McCullough, Austin, McDade, Eric, Mejia, Arlene, MountzMD, James, Mummery, Cath, Nadkarni, Neelesh, Nagamatsu, Akemi, Neimeyer, Katie, Niimi, Yoshiki, Noble, James, Norton, Joanne, Nuscher, Brigitte, Feederle, Regina, O'Connor, Antoinette, Obermüller, Ulricke, Patira, Riddhi, Perrin, Richard, Ping, Lingyan, Preische, Oliver, Renton, Alan, Ringman, John, Salloway, Stephen, Schofield, Peter, Karch, Celeste M, Senda, Michio, Seyfried, Nick, Shady, Kristine, Shimada, Hiroyuki, Sigurdson, Wendy, Smith, Jennifer, Smith, Lori, Snitz, Beth, Sohrabi, Hamid, Stephens, Sochenda, Schlepckow, Kai, Taddei, Kevin, Thompson, Sarah, Wang, Peter, Wang, Qing, Weamer, Elise, Xu, Jinbin, Xu, Xiong, Morris, John C, Kleinberger, Gernot, Nellgard, Bengt, Vöglein, Jonathan, Blennow, Kaj, Zetterberg, Henrik, Ewers, Michael, Jucker, Mathias, Levin, Johannes, Bateman, Randall J, Haass, Christian, Network, Dominantly Inherited Alzheimer, Adams, Sarah, Allegri, Ricardo, Araki, Aki, Franzmeier, Nicolai, Barthelemy, Nicolas, Bechara, Jacob, Berman, Sarah, Bodge, Courtney, Brandon, Susan, Brooks, William Bill, Brosch, Jared, Buck, Jill, Buckles, Virginia, Carter, Kathleen, Xiong, Chengjie, Cash, Lisa, Chen, Charlie, Chhatwal, Jasmeer, Chrem, Patricio, Chua, Jasmin, Chui, Helena, Cruchaga, Carlos, Day, Gregory S, De La Cruz, Chrismary, Denner, Darcy, Suarez-Calvet, Marc, Diffenbacher, Anna, Dincer, Aylin, Donahue, Tamara, Douglas, Jane, Duong, Duc, Egido, Noelia, Esposito, Bianca, Farlow, Marty, Feldman, Becca, Fitzpatrick, Colleen, Fagan, Anne M, Flores, Shaney, Fox, Nick, Franklin, Erin, Friedrichsen, Nelly, Fujii, Hisako, Gardener, Samantha, Ghetti, Bernardino, Goate, Alison, Goldberg, Sarah, Goldman, Jill, Schultz, Stephanie, Gonzalez, Alyssa, Gräber-Sultan, Susanne, Graff-Radford, Neill, Graham, Morgan, Gray, Julia, Gremminger, Emily, Grilo, Miguel, Groves, Alex, Häsler, Lisa, Hellm, Cortaiga, Gordon, Brian A, Herries, Elizabeth, Hoechst-Swisher, Laura, Hofmann, Anna, Holtzman, David, Hornbeck, Russ, Igor, Yakushev, Ihara, Ryoko, Ikeuchi, Takeshi, Ikonomovic, Snezana, Ishii, Kenji, Benzinger, Tammie L S, Jack, Clifford, Jerome, Gina, Johnson, Erik, Kaeser, Stephan, Kasuga, Kensaku, Keefe, Sarah, Klunk, William Bill, Koeppe, Robert, Koudelis, Deb, and Kuder-Buletta, Elke

Subjects
Adult, Amyloid beta-Peptides, Membrane Glycoproteins, TREM2 protein, human, physiology [Cognition], diagnostic imaging [Cognitive Dysfunction], genetics [Cognitive Dysfunction], genetics [Alzheimer Disease], Middle Aged, United States, Cognition, genetics [Membrane Glycoproteins], Alzheimer Disease, Humans, genetics [Receptors, Immunologic], Cognitive Dysfunction, ddc:610, Neurology (clinical), cerebrospinal fluid [Membrane Glycoproteins], Receptors, Immunologic, diagnostic imaging [Alzheimer Disease], Biomarkers
Abstract

Therapeutic modulation of TREM2-dependent microglial function might provide an additional strategy to slow the progression of Alzheimer's disease. Although studies in animal models suggest that TREM2 is protective against Alzheimer's pathology, its effect on tau pathology and its potential beneficial role in people with Alzheimer's disease is still unclear. Our aim was to study associations between the dynamics of soluble TREM2, as a biomarker of TREM2 signalling, and amyloid β (Aβ) deposition, tau-related pathology, neuroimaging markers, and cognitive decline, during the progression of autosomal dominant Alzheimer's disease.We did a longitudinal analysis of data from the Dominantly Inherited Alzheimer Network (DIAN) observational study, which includes families with a history of autosomal dominant Alzheimer's disease. Participants aged over 18 years who were enrolled in DIAN between Jan 1, 2009, and July 31, 2019, were categorised as either carriers of pathogenic variants in PSEN1, PSEN2, and APP genes (n=155) or non-carriers (n=93). We measured amounts of cleaved soluble TREM2 using a novel immunoassay in CSF samples obtained every 2 years from participants who were asymptomatic (Clinical Dementia Rating [CDR]=0) and annually for those who were symptomatic (CDR>0). CSF concentrations of Aβ40, Aβ42, total tau (t-tau), and tau phosphorylated on threonine 181 (p-tau) were measured by validated immunoassays. Predefined neuroimaging measurements were total cortical uptake of Pittsburgh compound B PET (PiB-PET), cortical thickness in the precuneus ascertained by MRI, and hippocampal volume determined by MRI. Cognition was measured using a validated cognitive composite (including DIAN word list test, logical memory delayed recall, digit symbol coding test [total score], and minimental status examination). We based our statistical analysis on univariate and bivariate linear mixed effects models.In carriers of pathogenic variants, a high amyloid burden at baseline, represented by low CSF Aβ42 (β=-4·28 × 10-2 [SE 0·013], p=0·0012), but not high cortical uptake in PiB-PET (β=-5·51 × 10-3 [0·011], p=0·63), was the only predictor of an augmented annual rate of subsequent increase in soluble TREM2. Augmented annual rates of increase in soluble TREM2 were associated with a diminished rate of decrease in amyloid deposition, as measured by Aβ42 in CSF (r=0·56 [0·22], p=0·011), in presymptomatic carriers of pathogenic variants, and with diminished annual rate of increase in PiB-PET (r=-0·67 [0·25], p=0·0060) in symptomatic carriers of pathogenic variants. Presymptomatic carriers of pathogenic variants with annual rates of increase in soluble TREM2 lower than the median showed a correlation between enhanced annual rates of increase in p-tau in CSF and augmented annual rates of increase in PiB-PET signal (r=0·45 [0·21], p=0·035), that was not observed in those with rates of increase in soluble TREM2 higher than the median. Furthermore, presymptomatic carriers of pathogenic variants with rates of increase in soluble TREM2 above or below the median had opposite associations between Aβ42 in CSF and PiB-PET uptake when assessed longitudinally. Augmented annual rates of increase in soluble TREM2 in presymptomatic carriers of pathogenic variants correlated with decreased cortical shrinkage in the precuneus (r=0·46 [0·22]), p=0·040) and diminished cognitive decline (r=0·67 [0·22], p=0·0020).Our findings in autosomal dominant Alzheimer's disease position the TREM2 response within the amyloid cascade immediately after the first pathological changes in Aβ aggregation and further support the role of TREM2 on Aβ plaque deposition and compaction. Furthermore, these findings underpin a beneficial effect of TREM2 on Aβ deposition, Aβ-dependent tau pathology, cortical shrinkage, and cognitive decline. Soluble TREM2 could, therefore, be a key marker for clinical trial design and interpretation. Efforts to develop TREM2-boosting therapies are ongoing.German Research Foundation, US National Institutes of Health.

Published
2022

2. Predicting brain age from functional connectivity in symptomatic and preclinical Alzheimer disease

Author

Millar, Peter R, Luckett, Patrick H, Lee, Jaehyun, Laske, Christoph, Levey, Allan, Levin, Johannes, Li, Yan, Lopez, Oscar, Marsh, Jacob, Martins, Ralph, Mason, Neal Scott, Masters, Colin, Mawuenyega, Kwasi, Mori, Hiroshi, McCullough, Austin, McDade, Eric, Mejia, Arlene, Morenas Rodriguez, Estrella, Morris, John, Mountz, James, Mummery, Cath, Nadkarni, N Eelesh, Nagamatsu, Akemi, Neimeyer, Katie, Salloway, Stephen P, Niimi, Yoshiki, Noble, James, Norton, Joanne, Nuscher, Brigitte, Obermüller, Ulricke, O'Connor, Antoinette, Patira, Riddhi, Perrin, Richard, Ping, Lingyan, Preische, Oliver, Yakushev, Igor, Renton, Alan, Ringman, John, Salloway, Stephen, Schofield, Peter, Senda, Michio, Seyfried, Nicholas T, Shady, Kristine, Shimada, Hiroyuki, Sigurdson, Wendy, Smith, Jennifer, Morris, John C, Smith, Lori, Snitz, Beth, Sohrabi, Hamid, Stephens, Sochenda, Taddei, Kevin, Thompson, Sarah, Vöglein, Jonathan, Wang, Peter, Wang, Qing, Weamer, Elise, Ances, Beau M, Xiong, Chengjie, Xu, Jinbin, Xu, Xiong, Network, Dominantly Inherited Alzheimer, Adams, Sarah, Allegri, Ricardo, Araki, Aki, Gordon, Brian A, Barthelemy, Nicolas, Bateman, Randall, Bechara, Jacob, Benzinger, Tammie, Berman, Sarah, Bodge, Courtney, Brandon, Susan, Brooks, William Bill, Brosch, Jared, Buck, Jill, Benzinger, Tammie L S, Buckles, Virginia, Carter, Kathleen, Cash, Lisa, Chen, Charlie, Chhatwal, Jasmeer, Mendez, Patricio Chrem, Chua, Jasmin, Chui, Helena, Courtney, Laura, Cruchaga, Carlos, Schindler, Suzanne E, Day, Gregory S, DeLaCruz, Chrismary, Denner, Darcy, Diffenbacher, Anna, Dincer, Aylin, Donahue, Tamara, Douglas, Jane, Duong, Duc, Egido, Noelia, Esposito, Bianca, Fagan, Anne M, Fagan, Anne, Farlow, Marty, Feldman, Becca, Fitzpatrick, Colleen, Flores, Shaney, Fox, Nick, Franklin, Erin, Joseph-Mathurin, Nelly, Fujii, Hisako, Gardener, Samantha, Ghetti, Bernardino, Goate, Alison, Goldberg, Sarah, Goldman, Jill, Gonzalez, Alyssa, Gordon, Brian, Gräber-Sultan, Susanne, Graff-Radford, Neill, Graham, Morgan, Gray, Julia, Bateman, Randall J, Gremminger, Emily, Grilo, Miguel, Groves, Alex, Haass, Christian, Häsler, Lisa, Hassenstab, Jason, Hellm, Cortaiga, Herries, Elizabeth, Hoechst-Swisher, Laura, Hofmann, Anna, Holtzman, David, Hornbeck, Russ, Igor, Yakushev, Ihara, Ryoko, Ikeuchi, Takeshi, Ikonomovic, Snezana, Ishii, Kenji, Jack, Clifford, Jerome, Gina, Jucker, Mathias, Johnson, Erik, Karch, Celeste, Kaeser, Stephan, Kasuga, Kensaku, Keefe, Sarah, Klunk, William, Koeppe, Robert, Koudelis, Deb, and Kuder-Buletta, Elke

Subjects
Adult, Aged, 80 and over, Adolescent, Resting-state functional connectivity, Cognitive Neuroscience, fMRI, Brain, Neuroimaging, Middle Aged, Magnetic Resonance Imaging, pathology [Alzheimer Disease], Young Adult, physiology [Brain], methods [Magnetic Resonance Imaging], Neurology, Brain aging, Alzheimer Disease, Machine learning, Humans, ddc:610, Alzheimer disease, Biomarkers, Aged
Abstract

"Brain-predicted age" quantifies apparent brain age compared to normative neuroimaging trajectories. Advanced brain-predicted age has been well established in symptomatic Alzheimer disease (AD), but is underexplored in preclinical AD. Prior brain-predicted age studies have typically used structural MRI, but resting-state functional connectivity (FC) remains underexplored. Our model predicted age from FC in 391 cognitively normal, amyloid-negative controls (ages 18-89). We applied the trained model to 145 amyloid-negative, 151 preclinical AD, and 156 symptomatic AD participants to test group differences. The model accurately predicted age in the training set. FC-predicted brain age gaps (FC-BAG) were significantly older in symptomatic AD and significantly younger in preclinical AD compared to controls. There was minimal correspondence between networks predictive of age and AD. Elevated FC-BAG may reflect network disruption during symptomatic AD. Reduced FC-BAG in preclinical AD was opposite to the expected direction, and may reflect a biphasic response to preclinical AD pathology or may be driven by inconsistency between age-related vs. AD-related networks. Overall, FC-predicted brain age may be a sensitive AD biomarker.

Published
2022

3. Association ofBDNFVal66Met With Tau Hyperphosphorylation and Cognition in Dominantly Inherited Alzheimer Disease

Author

Lim, Yen Ying, Maruff, Paul, Levin, Johannes, Snitz, Beth, Thompson, Sarah, Weamer, Elise, Mason, Neal Scott, Chui, Helena, Ringman, John, Adams, Sarah, Barthelemy, Nicolas, Bateman, Randall, Benzinger, Tammie, Farlow, Martin R, Brandon, Susan, Buckles, Virginia, Cash, Lisa, Chen, Charlie, Chua, Jasmin, Cruchaga, Carlos, Denner, Darcy, Dincer, Aylin, Donahue, Tamara, Fagan, Anne, Graff-Radford, Neill R, Feldman, Becca, Flores, Shaney, Franklin, Erin, Friedrichsen, Nelly, Gonzalez, Alyssa, Gordon, Brian, Gray, Julia, Gremminger, Emily, Groves, Alex, Hassenstab, Jason, Laske, Christoph, Hellm, Cortaiga, Herries, Elizabeth, Hoechst-Swisher, Laura, Holtzman, David, Hornbeck, Russ, Jerome, Gina, Karch, Celeste, Keefe, Sarah, Koudelis, Deb, Li, Yan, Masters, Colin L, Marsh, Jacob, Martinez, Rita, Mawuenyega, Kwasi, McCullough, Austin, McDade, Eric, Morris, John, Norton, Joanne, Perrin, Richard, Shady, Kristine, Sigurdson, Wendy, Salloway, Stephen, Smith, Jennifer, Wang, Peter, Wang, Qing, Xiong, Chengjie, Xu, Jinbin, Xu, Xiong, Schofield, Peter R, Morris, John C, Bateman, Randall J, Barthélemy, Nicolas R, Network, Dominantly Inherited Alzheimer, Chhatwal, Jasmeer, Fitzpatrick, Colleen, Bodge, Courtney, De La Cruz, Chrismary, Goldman, Jill, Mejia, Arlene, Neimeyer, Katie, Noble, James, Goate, Alison, Gardener, Samantha, Martins, Ralph, Sohrabi, Hamid, Taddei, Kevin, Carter, Kathleen, Duong, Duc, Johnson, Erik, Levey, Allan, Ping, Lingyan, Seyfried, Nick, Gräber-Sultan, Susanne, Häsler, Lisa, Hofmann, Anna, Jucker, Mathias, Kaeser, Stephan, Kuder-Buletta, Elke, Preische, Oliver, Diffenbacher, Anna, Igor, Yakushev, Sato, Chihiro, Vöglein, Jonathan, Obermüller, Ulricke, Esposito, Bianca, Renton, Alan, Brosch, Jared, Buck, Jill, Farlow, Marty, Ghetti, Bernardino, Fagan, Anne M, Allegri, Ricardo, Chrem, Patricio, Egido, Noelia, Haass, Christian, Morenas Rodriguez, Estrella, Nuscher, Brigitte, Day, Gregory S, Graff-Radford, Neill, Graham, Morgan, Stephens, Sochenda, Benzinger, Tammie L S, Jack, Clifford, Bechara, Jacob, Brooks, William Bill, Schofield, Peter, Araki, Aki, Ikeuchi, Takeshi, Kasuga, Kensaku, Ishii, Kenji, Fujii, Hisako, Senda, Michio, Shimada, Hiroyuki, Ihara, Ryoko, Nagamatsu, Akemi, Niimi, Yoshiki, Douglas, Jane, Fox, Nick, Grilo, Miguel, Mummery, Cath, O'Connor, Antoinette, Masters, Colin, Koeppe, Robert, Berman, Sarah, Goldberg, Sarah, Ikonomovic, Snezana, Klunk, William Bill, Lopez, Oscar, Mountz, James, Nadkarni, Neelesh, Patira, Riddhi, and Smith, Lori

Subjects
Adult, Male, Threonine, Memory Disorders, methods [Positron-Emission Tomography], cerebrospinal fluid [Amyloid beta-Peptides], Middle Aged, genetics [Brain-Derived Neurotrophic Factor], cerebrospinal fluid [Alzheimer Disease], Cognition, Cross-Sectional Studies, cerebrospinal fluid [tau Proteins], Humans, Female, ddc:610, Neurology (clinical), Biomarkers, Aged
Abstract

Allelic variation in the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism moderates increases in cerebrospinal fluid (CSF) levels of tau and phosphorylated tau 181 (p-tau181), measured using immunoassay, and cognitive decline in presymptomatic dominantly inherited Alzheimer disease (DIAD). Advances in mass spectrometry show that CSF tau phosphorylation occupancy at threonine 181 and 217 (p-tau181/tau181, p-tau217/tau217) increases with initial β-amyloid (Aβ) aggregation, while phosphorylation occupancy at threonine 205 (p-tau205/tau205) and level of total tau increase when brain atrophy and clinical symptoms become evident.To determine whether site-specific tau phosphorylation occupancy (ratio of phosphorylated to unphosphorylated tau) is associated with BDNF Val66Met in presymptomatic and symptomatic DIAD.This cross-sectional cohort study included participants from the Dominantly Inherited Alzheimer Network (DIAN) and Aβ-positive cognitively normal older adults in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Data were collected from 2009 through 2018 at multicenter clinical sites in the United States, United Kingdom, and Australia, with no follow-up. DIAN participants provided a CSF sample and completed clinical and cognitive assessments. Data analysis was conducted between March 2020 and March 2021.Mass spectrometry analysis was used to determine site-specific tau phosphorylation level; tau levels were also measured using immunoassay. Episodic memory and global cognitive composites were computed.Of 374 study participants, 144 were mutation noncarriers, 156 were presymptomatic mutation carriers, and 74 were symptomatic carriers. Of the 527 participants in the network, 153 were excluded because their CSF sample, BDNF status, or both were unavailable. Also included were 125 Aβ-positive cognitively normal older adults in the ADNI. The mean (SD) age of DIAD participants was 38.7 (10.9) years; 43% were women. The mean (SD) age of participants with preclinical sporadic AD was 74.8 (5.6) years; 52% were women. In presymptomatic mutation carriers, compared with Val66 homozygotes, Met66 carriers showed significantly poorer episodic memory (d = 0.62; 95% CI, 0.28-0.95), lower hippocampal volume (d = 0.40; 95% CI, 0.09-0.71), and higher p-tau217/tau217 (d = 0.64; 95% CI, 0.30-0.97), p-tau181/tau181 (d = 0.65; 95% CI, 0.32-0.99), and mass spectrometry total tau (d = 0.43; 95% CI, 0.10-0.76). In symptomatic mutation carriers, Met66 carriers showed significantly poorer global cognition (d = 1.17; 95% CI, 0.65-1.66) and higher p-tau217/tau217 (d = 0.53; 95% CI, 0.05-1.01), mass spectrometry total tau (d = 0.78; 95% CI, 0.28-1.25), and p-tau205/tau205 (d = 0.97; 95% CI, 0.46-1.45), when compared with Val66 homozygotes. In preclinical sporadic AD, Met66 carriers showed poorer episodic memory (d = 0.39; 95% CI, 0.00-0.77) and higher total tau (d = 0.45; 95% CI, 0.07-0.84) and p-tau181 (d = 0.46; 95% CI, 0.07-0.85).In DIAD, clinical disease stage and BDNF Met66 were associated with cognitive impairment and levels of site-specific tau phosphorylation. This suggests that pharmacological strategies designed to increase neurotrophic support in the presymptomatic stages of AD may be beneficial.

Published
2022

4. Brain network decoupling with increased serum neurofilament and reduced cognitive function in Alzheimer’s disease

Author

Wheelock, Muriah D, Strain, Jeremy F, Fox, Nick C, Graff-Radford, Neill R, Hassenstab, Jason, Jack, Clifford R, Karch, Celeste M, Levin, Johannes, McDade, Eric M, Perrin, Richard J, Schofield, Peter R, Xiong, Chengjie, Mansfield, Patricia, Morris, John C, Bateman, Randal J, Jucker, Mathias, Benzinger, Tammie L S, Ances, Beau M, Eggebrecht, Adam T, Gordon, Brian A, Network, Dominantly Inherited Alzheimer, Tu, Jiaxin Cindy, Tanenbaum, Aaron, Preische, Oliver, Chhatwal, Jasmeer P, Cash, David M, Cruchaga, Carlos, Fagan, Anne M, Johnson, Erik, Jucker, Mathias, Karch, Celeste, Käser, Stephan, Kasuga, Kensaku, Keefe, Sarah, Klunk, William, Koeppe, Robert, Koudelis, Deb, Kuder-Buletta, Elke, Laske, Christoph, Lee, Jae-Hong, Levey, Allan, Levin, Johannes, Li, Yan, Lopez, Oscar, Marsh, Jacob, Martinez, Rita, Martins, Ralph, Mason, Neal Scott, Masters, Colin, Mawuenyega, Kwasi, McCullough, Austin, McDade, Eric, Mejia, Arlene, Morenas-Rodriguez, Estrella, Mori, Hiroshi, Morris, John, Mountz, James, Mummery, Cath, Nadkami, Neelesh, Nagamatsu, Akemi, Neimeyer, Katie, Niimi, Yoshiki, Noble, James, Norton, Joanne, Nuscher, Brigitte, O'Connor, Antoinette, Obermüller, Ulricke, Patira, Riddhi, Perrin, Richard, Ping, Lingyan, Preische, Oliver, Renton, Alan, Ringman, John, Salloway, Stephen, Sanchez-Valle, Raquel, Schofield, Peter, Senda, Michio, Seyfried, Nick, Shady, Kristine, Shimada, Hiroyuki, Sigurdson, Wendy, Smith, Jennifer, Smith, Lori, Snitz, Beth, Sohrabi, Hamid, Stephens, Sochenda, Taddei, Kevin, Thompson, Sarah, Vöglein, Jonathan, Wang, Peter, Wang, Qing, Weamer, Elise, Xiong, Chengjie, Xu, Jinbin, Xu, Xiong, Adams, Sarah, Allegri, Ricardo, Araki, Aki, Barthelemy, Nicolas, Bateman, Randall, Bechara, Jacob, Benzinger, Tammie, Berman, Sarah, Bodge, Courtney, Brandon, Susan, Brooks, William, Brosch, Jared, Buck, Jill, Buckles, Virginia, Carter, Kathleen, Cash, Dave, Cash, Lisa, Chen, Charlie, Chhatwal, Jasmeer, Chrem, Patricio, Chua, Jasmin, Chui, Helena, Cruchaga, Carlos, Day, Gregory S, De La Cruz, Chrismary, Denner, Darcy, Diffenbacher, Anna, Dincer, Aylin, Donahue, Tamara, Douglas, Jane, Duong, Duc, Egido, Noelia, Esposito, Bianca, Fagan, Anne, Farlow, Marty, Feldman, Becca, Fitzpatrick, Colleen, Flores, Shaney, Fox, Nick, Franklin, Erin, Friedrichsen, Nelly, Fujii, Hisako, Gardener, Samantha, Ghetti, Bernardino, Goate, Alison, Goldberg, Sarah, Goldman, Jill, Gonzalez, Alyssa, Gordon, Brian, Gräber-Sultan, Susanne, Graff-Radford, Neill, Graham, Morgan, Gray, Julia, Gremminger, Emily, Grilo, Miguel, Groves, Alex, Haass, Christian, Häsler, Lisa, Hassenstab, Jason, Hellm, Cortaiga, Herries, Elizabeth, Hoechst-Swisher, Laura, Hofmann, Anna, Holtzman, David, Hornbeck, Russ, Igor, Yakushev, Ihara, Ryoko, Ikeuchi, Takeshi, Ikonomovic, Snezana, Ishii, Kenji, Jack, Clifford, and Jerome, Gina

Subjects
enrichment, diagnostic imaging [Nerve Net], functional connectivity, Intermediate Filaments, neurodegeneration, NfL, default mode network, Cross-Sectional Studies, methods [Magnetic Resonance Imaging], Cognition, Alzheimer Disease, Connectome, Humans, Cognitive Dysfunction, ddc:610, Neurology (clinical), diagnostic imaging [Brain], resting state
Abstract

Neurofilament light chain, a putative measure of neuronal damage, is measurable in blood and CSF and is predictive of cognitive function in individuals with Alzheimer’s disease. There has been limited prior work linking neurofilament light and functional connectivity, and no prior work has investigated neurofilament light associations with functional connectivity in autosomal dominant Alzheimer’s disease. Here, we assessed relationships between blood neurofilament light, cognition, and functional connectivity in a cross-sectional sample of 106 autosomal dominant Alzheimer’s disease mutation carriers and 76 non-carriers. We employed an innovative network-level enrichment analysis approach to assess connectome-wide associations with neurofilament light. Neurofilament light was positively correlated with deterioration of functional connectivity within the default mode network and negatively correlated with connectivity between default mode network and executive control networks, including the cingulo-opercular, salience, and dorsal attention networks. Further, reduced connectivity within the default mode network and between the default mode network and executive control networks was associated with reduced cognitive function. Hierarchical regression analysis revealed that neurofilament levels and functional connectivity within the default mode network and between the default mode network and the dorsal attention network explained significant variance in cognitive composite scores when controlling for age, sex, and education. A mediation analysis demonstrated that functional connectivity within the default mode network and between the default mode network and dorsal attention network partially mediated the relationship between blood neurofilament light levels and cognitive function. Our novel results indicate that blood estimates of neurofilament levels correspond to direct measurements of brain dysfunction, shedding new light on the underlying biological processes of Alzheimer’s disease. Further, we demonstrate how variation within key brain systems can partially mediate the negative effects of heightened total serum neurofilament levels, suggesting potential regions for targeted interventions. Finally, our results lend further evidence that low-cost and minimally invasive blood measurements of neurofilament may be a useful marker of brain functional connectivity and cognitive decline in Alzheimer’s disease.

Published
2023

5. First presentation with neuropsychiatric symptoms in autosomal dominant Alzheimer's disease: the Dominantly Inherited Alzheimer's Network Study

Author

O'Connor, Antoinette, Rice, Helen, Hassenstab, Jason, Lee, Jae-Hong, Perrin, Richard J, Xiong, Chengjie, Gordon, Brian, Levey, Allan I, Goate, Alison, Graff-Radford, Neil, Levin, Johannes, Jucker, Mathias, Barnes, Josephine, Benzinger, Tammie, McDade, Eric, Mori, Hiroshi, Noble, James M, Schofield, Peter R, Martins, Ralph N, Salloway, Stephen, Chhatwal, Jasmeer, Morris, John C, Bateman, Randall, Ryan, Natalie S, Howard, Rob, Reeves, Suzanne, Fox, Nick C, Network, Dominantly Inherited Alzheimer, Liu, Kathy Y, Allegri, Ricardo Francisco, Berman, Sarah, Ringman, John M, Cruchaga, Carlos, Farlow, Martin R, Ikeuchi, Takeshi, Ikonomovic, Snezana, Ishii, Kenji, Jack, Clifford, Jerome, Gina, Johnson, Erik, Jucker, Mathias, Karch, Celeste, Käser, Stephan, Kasuga, Kensaku, Keefe, Sarah, Bill Klunk, William, Koeppe, Robert, Koudelis, Deb, Kuder-Buletta, Elke, Laske, Christoph, Levey, Allan, Levin, Johannes, Li, Yan, Lopez, Oscar, Marsh, Jacob, Martinez, Rita, Martins, Ralph, Mason, Neal Scott, Masters, Colin, Mawuenyega, Kwasi, McCullough, Austin, McDade, Eric, Mejia, Arlene, Morenas-Rodriguez, Estrella, Morris, John, MountzMD, James, Mummery, Cath, Nadkarni, Neelesh, Nagamatsu, Akemi, Neimeyer, Katie, Niimi, Yoshiki, Noble, James, Norton, Joanne, Nuscher, Brigitte, O'Connor, Antoinette, Obermüller, Ulricke, Patira, Riddhi, Perrin, Richard, Ping, Lingyan, Preische, Oliver, Renton, Alan, Ringman, John, Salloway, Stephen, Schofield, Peter, Senda, Michio, Seyfried, Nick, Shady, Kristine, Shimada, Hiroyuki, Sigurdson, Wendy, Smith, Jennifer, Smith, Lori, Snitz, Beth, Sohrabi, Hamid, Stephens, Sochenda, Taddei, Kevin, Thompson, Sarah, Vöglein, Jonathan, Wang, Peter, Wang, Qing, Weamer, Elise, Xiong, Chengjie, Xu, Jinbin, Xu, Xiong, Adams, Sarah, Allegri, Ricardo, Araki, Aki, Barthelemy, Nicolas, Bateman, Randall, Bechara, Jacob, Benzinger, Tammie, Berman, Sarah, Bodge, Courtney, Brandon, Susan, Bill Brooks, William, Brosch, Jared, Buck, Jill, Buckles, Virginia, Carter, Kathleen, Cash, Lisa, Chen, Charlie, Chhatwal, Jasmeer, Chrem, Patricio, Chua, Jasmin, Chui, Helena, Cruchaga, Carlos, Day, Gregory S, Cruz, Chrismary De La, Denner, Darcy, Diffenbacher, Anna, Dincer, Aylin, Donahue, Tamara, Douglas, Jane, Duong, Duc, Egido, Noelia, Esposito, Bianca, Fagan, Anne, Farlow, Marty, Feldman, Becca, Fitzpatrick, Colleen, Flores, Shaney, Fox, Nick, Franklin, Erin, Friedrichsen, Nelly, Fujii, Hisako, Gardener, Samantha, Ghetti, Bernardino, Goate, Alison, Goldberg, Sarah, Goldman, Jill, Gonzalez, Alyssa, Gordon, Brian, Gräber-Sultan, Susanne, Graff-Radford, Neill, Graham, Morgan, Gray, Julia, Gremminger, Emily, Grilo, Miguel, Groves, Alex, Haass, Christian, Häsler, Lisa, Hassenstab, Jason, Hellm, Cortaiga, Herries, Elizabeth, Hoechst-Swisher, Laura, Hofmann, Anna, Holtzman, David, Hornbeck, Russ, Igor, Yakushev, and Ihara, Ryoko

Subjects
Arthrogryposis, Psychiatry and Mental health, NEUROPSYCHIATRY, psychology [Alzheimer Disease], ALZHEIMER'S DISEASE, Humans, COGNITION, Surgery, genetics [Alzheimer Disease], Neurology (clinical), ddc:610, BEHAVIOURAL DISORDER, diagnostic imaging [Alzheimer Disease]
Published
2023

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