White Matter Hyperintensity Volume and Amyloid-PET Synergistically Impact Memory Independent of Tau-PET in Older Adults Without Dementia

Background: Alzheimer’s disease (AD) and cerebrovascular disease are common, co-existing pathologies in older adults. Whether the effects of cerebrovascular disease and AD biomarkers on cognition are additive or synergistic remains unclear. Objective: To examine whether white matter hyperintensity (WMH) volume moderates the independent association between each AD biomarker and cognition. Methods: In 586 older adults without dementia, linear regressions tested the interaction between amyloid-β (Aβ) positron emission tomography (PET) and WMH volume on cognition, independent of tau-PET. We also tested the interaction between tau-PET and WMH volume on cognition, independent of Aβ-PET. Results: Adjusting for tau-PET, the quadratic effect of WMH interacted with Aβ-PET to impact memory. There was no interaction between either the linear or quadratic effect of WMH and Aβ-PET on executive function. There was no interaction between WMH volume and tau-PET on either cognitive measure. Conclusion: Results suggest that cerebrovascular lesions act synergistically with Aβ to affect memory, independent of tau, highlighting the importance of incorporating vascular pathology into biomarker assessment of AD.

[1]  M. Bondi,et al.  Interactive Effects of Pulse Pressure and Tau Imaging on Longitudinal Cognition. , 2022, Journal of Alzheimer's disease : JAD.

[2]  Keith A. Johnson,et al.  Association of β-Amyloid and Vascular Risk on Longitudinal Patterns of Brain Atrophy , 2022, Neurology.

[3]  Christopher E. Bauer,et al.  Instrumental validation of free water, peak‐width of skeletonized mean diffusivity, and white matter hyperintensities: MarkVCID neuroimaging kits , 2022, Alzheimer's & dementia.

[4]  A. Mauleon,et al.  Combination of white matter hyperintensities and Aβ burden is related to cognitive composites domain scores in subjective cognitive decline: the FACEHBI cohort , 2021, Alzheimer's research & therapy.

[5]  C. Rosano,et al.  Differences in Alzheimer’s Disease and Related Dementias Pathology Among African American and Hispanic Women: A Qualitative Literature Review of Biomarker Studies , 2021, Frontiers in Systems Neuroscience.

[6]  J. Gallacher,et al.  Prediction of Alzheimer’s disease biomarker status defined by the ‘ATN framework’ among cognitively healthy individuals: results from the EPAD longitudinal cohort study , 2020, Alzheimer's research & therapy.

[7]  J. Gallacher,et al.  Prediction of Alzheimer’s disease biomarker status defined by the ‘ATN framework’ among cognitively healthy individuals: results from the EPAD longitudinal cohort study , 2020, Alzheimer's Research & Therapy.

[8]  W. M. van der Flier,et al.  Brain amyloid β, cerebral small vessel disease, and cognition , 2020, Neurology.

[9]  G. Chételat,et al.  White matter hyperintensities across the adult lifespan: relation to age, Aβ load, and cognition , 2020, Alzheimer's Research & Therapy.

[10]  C. DeCarli,et al.  The Impact of Amyloid-β or Tau on Cognitive Change in the Presence of Severe Cerebrovascular Disease. , 2020, Journal of Alzheimer's disease : JAD.

[11]  N. Kandiah,et al.  Small Vessel Disease and Associations with Cerebrospinal Fluid Amyloid, Tau, and Neurodegeneration (ATN) Biomarkers and Cognition in Young Onset Dementia. , 2020, Journal of Alzheimer's disease : JAD.

[12]  H. Aizenstein,et al.  Cognitive Reserve Moderates Effects of White Matter Hyperintensity on Depressive Symptoms and Cognitive Function in Late-Life Depression , 2020, Frontiers in Psychiatry.

[13]  M. Albert,et al.  White matter hyperintensities and CSF Alzheimer disease biomarkers in preclinical Alzheimer disease , 2019, Neurology.

[14]  C. Rowe,et al.  Influence of Comorbidity of Cerebrovascular Disease and Amyloid-β on Alzheimer's Disease. , 2019, Journal of Alzheimer's disease : JAD.

[15]  P. Scheltens,et al.  Comorbid amyloid-β pathology affects clinical and imaging features in VCD , 2019, Alzheimer's & Dementia.

[16]  Paul E. Gilbert,et al.  APOE interacts with tau PET to influence memory independently of amyloid PET in older adults without dementia , 2019, Alzheimer's & dementia : the journal of the Alzheimer's Association.

[17]  H. Chertkow,et al.  Amyloid burden and white matter hyperintensities mediate age-related cognitive differences , 2019, Neurobiology of Aging.

[18]  Eric E. Smith,et al.  Vascular dysfunction—The disregarded partner of Alzheimer's disease , 2019, Alzheimer's & Dementia.

[19]  Keith A. Johnson,et al.  Interactive Associations of Vascular Risk and &bgr;-Amyloid Burden With Cognitive Decline in Clinically Normal Elderly Individuals: Findings From the Harvard Aging Brain Study , 2018, JAMA Neurology.

[20]  J. Whitwell,et al.  Alzheimer's disease neuroimaging , 2018, Current opinion in neurology.

[21]  W. M. van der Flier,et al.  Cerebrovascular and amyloid pathology in predementia stages: the relationship with neurodegeneration and cognitive decline , 2017, Alzheimer's Research & Therapy.

[22]  Daniel R. Schonhaut,et al.  Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer’s disease , 2017, Brain : a journal of neurology.

[23]  W. Jagust,et al.  Considerations and code for partial volume correcting [18F]-AV-1451 tau PET data , 2017, Data in brief.

[24]  C. DeCarli,et al.  Baseline White Matter Hyperintensities and Hippocampal Volume are Associated With Conversion From Normal Cognition to Mild Cognitive Impairment in the Framingham Offspring Study , 2017, Alzheimer disease and associated disorders.

[25]  Alan J. Thomas,et al.  Parietal white matter lesions in Alzheimer’s disease are associated with cortical neurodegenerative pathology, but not with small vessel disease , 2017, Acta Neuropathologica.

[26]  W. M. van der Flier,et al.  White Matter Hyperintensities Potentiate Hippocampal Volume Reduction in Non-Demented Older Individuals with Abnormal Amyloid-β. , 2016, Journal of Alzheimer's disease : JAD.

[27]  Nick C Fox,et al.  White matter hyperintensities are a core feature of Alzheimer's disease: Evidence from the dominantly inherited Alzheimer network , 2016, Annals of neurology.

[28]  Yi Su,et al.  Tau and Aβ imaging, CSF measures, and cognition in Alzheimer's disease , 2016, Science Translational Medicine.

[29]  Daniel R. Schonhaut,et al.  Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease. , 2016, Brain : a journal of neurology.

[30]  M. Weiner,et al.  Effects of amyloid and vascular markers on cognitive decline in subcortical vascular dementia , 2015, Neurology.

[31]  Alexander Leemans,et al.  Decoupling of structural and functional brain connectivity in older adults with white matter hyperintensities , 2015, NeuroImage.

[32]  D. Y. Lee,et al.  Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. , 2015, JAMA.

[33]  Brian A. Gordon,et al.  The effects of white matter hyperintensities and amyloid deposition on Alzheimer dementia , 2015, NeuroImage: Clinical.

[34]  Jens C. Pruessner,et al.  Operationalizing protocol differences for EADC-ADNI manual hippocampal segmentation , 2015, Alzheimer's & Dementia.

[35]  C. Jack,et al.  Vascular and amyloid pathologies are independent predictors of cognitive decline in normal elderly , 2015, Brain : a journal of neurology.

[36]  Miranka Wirth,et al.  Vascular risk and Aβ interact to reduce cortical thickness in AD vulnerable brain regions , 2014, Neurology.

[37]  Jae Seung Kim,et al.  Synergistic effects of ischemia and β-amyloid burden on cognitive decline in patients with subcortical vascular mild cognitive impairment. , 2014, JAMA psychiatry.

[38]  M. Weiner,et al.  Effects of cerebrovascular disease and amyloid beta burden on cognition in subjects with subcortical vascular cognitive impairment , 2014, Neurobiology of Aging.

[39]  W. Klunk,et al.  Cognitive aging in persons with minimal amyloid-β and white matter hyperintensities , 2013, Neuropsychologia.

[40]  Jordan Muraskin,et al.  White matter hyperintensities and cerebral amyloidosis: necessary and sufficient for clinical expression of Alzheimer disease? , 2013, JAMA neurology.

[41]  Paul A. Yushkevich,et al.  Multi-Atlas Segmentation with Joint Label Fusion , 2013, IEEE Transactions on Pattern Analysis and Machine Intelligence.

[42]  A. Brickman,et al.  Regional white matter hyperintensity volume, not hippocampal atrophy, predicts incident Alzheimer disease in the community. , 2012, Archives of neurology.

[43]  Evan Fletcher,et al.  Adaptive image segmentation for robust measurement of longitudinal brain tissue change , 2012, 2012 Annual International Conference of the IEEE Engineering in Medicine and Biology Society.

[44]  Lotte Gerritsen,et al.  Loss of entorhinal cortex and hippocampal volumes compared to whole brain volume in normal aging: The SMART-Medea study , 2012, Psychiatry Research: Neuroimaging.

[45]  Philip S. Insel,et al.  A composite score for executive functioning, validated in Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants with baseline mild cognitive impairment , 2012, Brain Imaging and Behavior.

[46]  K. Jellinger,et al.  Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature , 2012, Journal of neuropathology and experimental neurology.

[47]  Cindee M. Madison,et al.  Cerebrovascular disease, beta-amyloid, and cognition in aging , 2012, Neurobiology of Aging.

[48]  T. Iwatsubo.  [Alzheimer's disease Neuroimaging Initiative (ADNI)]. , 2011, Nihon rinsho. Japanese journal of clinical medicine.

[49]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease: Report of the NINCDS—ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease , 2011, Neurology.

[50]  B Fischl,et al.  Correlations between MRI white matter lesion location and executive function and episodic memory , 2011, Neurology.

[51]  W. M. van der Flier,et al.  Heterogeneity of small vessel disease: a systematic review of MRI and histopathology correlations , 2010, Journal of Neurology, Neurosurgery & Psychiatry.

[52]  C. Jack,et al.  Alzheimer's Disease Neuroimaging Initiative (ADNI) , 2010, Neurology.

[53]  Nick C Fox,et al.  The Alzheimer's disease neuroimaging initiative (ADNI): MRI methods , 2008, Journal of magnetic resonance imaging : JMRI.

[54]  Charles DeCarli,et al.  White Matter Hyperintensities and Subclinical Infarction: Associations With Psychomotor Speed and Cognitive Flexibility , 2008, Stroke.

[55]  David A. Bennett,et al.  Mixed brain pathologies account for most dementia cases in community-dwelling older persons , 2007, Neurology.

[56]  Nicholas Ayache,et al.  Non-parametric Diffeomorphic Image Registration with the Demons Algorithm , 2007, MICCAI.

[57]  C. Jack,et al.  Alzheimer's Disease Neuroimaging Initiative , 2008 .

[58]  J. Mazziotta,et al.  Regional Spatial Normalization: Toward an Optimal Target , 2001, Journal of computer assisted tomography.

[59]  B L Miller,et al.  Neuropsychological correlates of white-matter lesions in healthy elderly subjects. A threshold effect. , 1992, Archives of neurology.

[60]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease , 1984, Neurology.

[61]  C. D. Beaumont,et al.  Regression Diagnostics — Identifying Influential Data and Sources of Collinearity , 1981 .

[62]  W. W. Muir,et al.  Regression Diagnostics: Identifying Influential Data and Sources of Collinearity , 1980 .

[63]  Clifford R. Jack,et al.  EADC-ADNI Working Group on The Harmonized Protocol for Manual Hippocampal Segmentation and for the Alzheimer ’ s Disease Neuroimaging Initiative , 2015 .

[64]  D. Salmon,et al.  Neuropsychological criteria for mild cognitive impairment improves diagnostic precision, biomarker associations, and progression rates. , 2014, Journal of Alzheimer's disease : JAD.

[65]  D. Salmon,et al.  Antemortem pulse pressure elevation predicts cerebrovascular disease in autopsy-confirmed Alzheimer's disease. , 2012, Journal of Alzheimer's disease : JAD.

[66]  Shuangzhe Liu,et al.  Regression diagnostics , 2020, Applied Quantitative Analysis for Real Estate.