Abstract
Alzheimer's disease (AD) is the most common cause of dementia and is characterized
by progressive neurodegeneration and cognitive decline. Understanding the pathophysiology
underlying AD is paramount for the management of individuals at risk of and suffering
from AD. The vascular hypothesis stipulates a relationship between cardiovascular
disease and AD-related changes although the nature of this relationship remains unknown.
In this review, we discuss several potential pathological pathways of vascular involvement
in AD that have been described including dysregulation of neurovascular coupling,
disruption of the blood brain barrier, and reduced clearance of metabolite waste such
as beta-amyloid, a toxic peptide considered the hallmark of AD. We will also discuss
the two-hit hypothesis which proposes a 2-step positive feedback loop in which microvascular
insults precede the accumulation of Aß and are thought to be at the origin of the
disease development. At neuroimaging, signs of vascular dysfunction such as chronic
cerebral hypoperfusion have been demonstrated, appearing early in AD, even before
cognitive decline and alteration of traditional biomarkers. Cerebral small vessel
disease such as cerebral amyloid angiopathy, characterized by the aggregation of Aß
in the vessel wall, is highly prevalent in vascular dementia and AD patients. Current
data is unclear whether cardiovascular disease causes, precipitates, amplifies, precedes,
or simply coincides with AD. Targeted imaging tools to quantitatively evaluate the
intracranial vasculature and longitudinal studies in individuals at risk for or in
the early stages of the AD continuum could be critical in disentangling this complex
relationship between vascular disease and AD.
Abbreviations:
Aß (beta-amyloid), AD (Alzheimer's disease), APP (amyloid precursor protein), AQP4 (aquaporin-4), ASL (arterial spin labeling), BBB (blood brain barrier), CAA (cerebral amyloid angiopathy), CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), CBF (cerebral blood flow), CCH (chronic cerebral hypoperfusion), cfPWV (carotid-to-femoral pulse wave velocity), CSF (cerebrospinal fluid), CSVD (cerebral small vessel disease), CVD (cerebrovascular disease), CVR (cerebrovascular reactivity), CVRF (cardiovascular risk factors), DCE (dynamic contrast enhanced), GLUT1 (glucose transporter 1), ICA (internal carotid artery), MCA (middle cerebral artery), MCI (mild cognitive impairment), MRI (magnetic resonance imaging), NFT (neurofibrillary tangles), NO (nitric oxide), NVU (neurovascular unit), PET (positron emission tomography), PSEN (presenilin), PWV (pulse wave velocity), RAGE (receptor for advanced glycation end products), VCID (vascular cognitive impairment and dementia), VHAD (vascular hypothesis for Alzheimer's disease), vSMC (vascular smooth muscular cells), WMH (white matter hyperintensity)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Translational ResearchAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- 2021 Alzheimer's disease facts and figures.Alzheimers Dement. 2021; 17: 327-406
- World Alzheimer Report 2021: Journey through the diagnosis of dementia.Alzheimer's Disease International, London, England2021
- Alzheimer's disease: as it was in the beginning.Rev Neurosci. 2017; 28: 825-843
- The amyloid hypothesis on trial.Nature. 2018; 559: S4-s7
- The amyloid hypothesis of Alzheimer's disease at 25 years.EMBO Mol Med. 2016; 8: 595-608
- Emerging concepts in Alzheimer's disease.Annu Rev Pathol. 2015; 10: 291-319
- Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.Alzheimers Dement. 2011; 7: 280-292
- The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics.Science. 2002; 297: 353-356
- Neurovascular dysfunction and faulty amyloid β-peptide clearance in Alzheimer disease.Cold Spring Harb Perspect Med. 2012; 2
- Alzheimer's disease.N Engl J Med. 2004; 351: 56-67
- Alzheimer's disease: the amyloid cascade hypothesis.Science. 1992; 256: 184-185
- APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: a genetic screening study of familial and sporadic cases.PLoS Med. 2017; 14e1002270
- Treatment combinations for Alzheimer's disease: current and future pharmacotherapy options.J Alzheimers Dis. 2019; 67: 779-794
- Failure to demonstrate efficacy of aducanumab: an analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019.Alzheimers Dement. 2021; 17: 696-701
- Aging and Alzheimer's disease: lessons from the Nun Study.Gerontologist. 1997; 37: 150-156
- Propagation of tau misfolding from the outside to the inside of a cell.J Biol Chem. 2009; 284: 12845-12852
- The pathobiology of vascular dementia.Neuron. 2013; 80: 844-866
- Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory.The J Neurosci. 2005; 25: 7709-7717
- Vascular cognitive impairment and dementia: JACC scientific expert panel.J Am Coll Cardiol. 2019; 73: 3326-3344
- Epidemiology of vascular dementia.Arterioscler Thromb Vasc Biol. 2019; 39: 1542-1549
- The vascular hypothesis of Alzheimer's disease: a key to preclinical prediction of dementia using neuroimaging.J Alzheimers Dis. 2018; 63: 35-52
- Can disturbed brain microcirculation cause Alzheimer's disease?.Neurol Res. 1993; 15: 146-153
- Pathologic sequelae of vascular cognitive impairment and dementia sheds light on potential targets for intervention.Cerebral Circulation - Cognition and Behav. 2021; 2100030
- Cerebrovascular atherosclerosis correlates with Alzheimer pathology in neurodegenerative dementias.Brain. 2012; 135: 3749-3756
- Vascular contributions to cognitive impairment, clinical Alzheimer's disease, and dementia in older persons.Biochim Biophys Acta. 2016; 1862: 878-886
- Mixed brain pathologies account for most dementia cases in community-dwelling older persons.Neurology. 2007; 69: 2197-2204
- Risk of incident clinical diagnosis of Alzheimer's disease-type dementia attributable to pathology-confirmed vascular disease.Alzheimers Dement. 2017; 13: 613-623
- Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer's Coordinating Centre.Brain: A Journal of Neurology. 2013; 136: 2697-2706
- Coronary artery disease is associated with Alzheimer disease neuropathology in APOE4 carriers.Neurology. 2006; 66: 1399-1404
- Cardiovascular risk factors and future risk of Alzheimer's disease.BMC Med. 2014; 12: 130
- Risk factors for vascular dementia and Alzheimer disease.Stroke. 2004; 35: 2620-2622
- Ankle-to-brachial index and dementia: the Honolulu-Asia Aging Study.Circulation. 2007; 116: 2269-2274
- Dementia and Alzheimer's disease incidence in relationship to cardiovascular disease in the Cardiovascular Health Study cohort.J Am Geriatr Soc. 2005; 53: 1101-1107
- Heart failure and risk of dementia and Alzheimer disease: a population-based cohort study.Arch Intern Med. 2006; 166: 1003-1008
- Pathophysiologic relationship between Alzheimer's disease, cerebrovascular disease, and cardiovascular risk: a review and synthesis.Alzheimers Dement (Amst). 2017; 7: 69-87
- Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam Study.Ann Neurol. 2005; 57: 789-794
- Relation of cerebral vessel disease to Alzheimer's disease dementia and cognitive function in elderly people: a cross-sectional study.The Lancet Neurol. 2016; 15: 934-943
- Alzheimer's disease neuroimaging I. Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis.Nat Commun. 2016; 7: 11934
- Blood-brain barrier breakdown in the aging human hippocampus.Neuron. 2015; 85: 296-302
- Zlokovic BV. Brain imaging of neurovascular dysfunction in Alzheimer's disease.Acta Neuropathol. 2016; 131: 687-707
- Zlokovic BV. Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease.Biochim Biophys Acta. 2016; 1862: 887-900
- Blood-brain barrier permeability in aging and Alzheimer's disease.The J Prevention of Alzheimer's Dis. 2014; 1: 138-139
- Cerebrospinal fluid biomarkers of neurovascular dysfunction in mild dementia and Alzheimer's disease.J Cerebral Blood Flow and Metabolism: Off J Int Soc Cerebral Blood Flow and Metabolism. 2015; 35: 1055-1068
- Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders.Natr Rev Neurol. 2018; 14: 133-150
- Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders.Natr Rev Neurosci. 2011; 12: 723-738
- Vascular risk factors promote conversion from mild cognitive impairment to Alzheimer disease.Neurology. 2011; 76: 1485-1491
- The Science of Vascular Contributions to Cognitive Impairment and Dementia (VCID): A framework for advancing research priorities in the cerebrovascular biology of cognitive decline.Cell Mol Neurobiol. 2016; 36: 281-288
- Preventing dementia by preventing stroke: the Berlin Manifesto.Alzheimers Dement. 2019; 15: 961-984
Govindpani K, McNamara LG, Smith NR, et al. Vascular dysfunction in Alzheimer’s disease: a prelude to the pathological process or a consequence of it? J Clin Med 2019;8:651.
- Vascular contributions to cognitive impairment and dementia (VCID): a report from the 2018 National Heart, Lung, and Blood Institute and National Institute of Neurological Disorders and Stroke Workshop, Alzheimers Dement. 2020; 16: 1714-1733
- Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers.Lancet Neurol. 2013; 12: 207-216
- NIA-AA research framework: toward a biological definition of Alzheimer's disease.Alzheimers Dement. 2018; 14: 535-562
- Vascular dysfunction-the disregarded partner of Alzheimer's disease.Alzheimers Dement. 2019; 15: 158-167
- The impact of neurovascular, blood-brain barrier, and glymphatic dysfunction in neurodegenerative and metabolic diseases.Int Rev Neurobiol. 2020; 154: 413-436
- Alzheimer's disease and the blood-brain barrier.Curr Alzheimer Res. 2013; 10: 1015-1033
- Neurovascular Unit Dysfunction and Neurodegenerative Disorders.Front Neurosci. 2020; 14: 334
- P-glycoprotein (ABCB1) and Oxidative Stress: Focus on Alzheimer's Disease.Oxid Med Cell Longev. 2017; 20177905486
- Clearance of beta-amyloid in the brain.Curr Med Chem. 2014; 21: 4085-4090
- Neurovascular regulation in the normal brain and in Alzheimer's disease.Nat Rev Neurosci. 2004; 5: 347-360
- Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease.Nat Rev Neurosci. 2017; 18: 419-434
- Pericytes of the neurovascular unit: key functions and signaling pathways.Nat Neurosci. 2016; 19: 771-783
- Looking at the blood-brain barrier: molecular anatomy and possible investigation approaches.Brain Res Rev. 2010; 64: 328-363
- Blood-brain barrier dysfunction and the pathogenesis of Alzheimer’s disease.Int J Mol Sci. 2017; 18: 1965
- Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice.J Cell Biol. 2003; 161: 653-660
- The role of adherens junctions and VE-cadherin in the control of vascular permeability.J Cell Sci. 2008; 121: 2115-2122
- VE-cadherin: the major endothelial adhesion molecule controlling cellular junctions and blood vessel formation.Arterioscler Thromb Vasc Biol. 2008; 28: 223-232
- Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis.Cell. 1999; 98: 147-157
- Vascular endothelial-cadherin is an important determinant of microvascular integrity in vivo.Proc Natl Acad Sci U S A. 1999; 96: 9815-9820
- Amyloid Beta induces oxidative stress-mediated blood-brain barrier changes in capillary amyloid angiopathy.Antioxid Redox Signal. 2011; 15: 1167-1178
- Neuroinflammation and blood-brain barrier changes in capillary amyloid angiopathy.Neurodegener Dis. 2012; 10: 329-331
- Aβ(1-42) oligomer-induced leakage in an in vitro blood-brain barrier model is associated with up-regulation of RAGE and metalloproteinases, and down-regulation of tight junction scaffold proteins.J Neurochem. 2015; 134: 382-393
- Aβ₁₋₄₂-RAGE interaction disrupts tight junctions of the blood-brain barrier via Ca²⁺-calcineurin signaling.J Neurosci. 2012; 32: 8845-8854
- Morphometric analysis of CNS microvascular endothelium.Microvasc Res. 1985; 30: 99-115
- Transcytosis: crossing cellular barriers.Physiol Rev. 2003; 83: 871-932
- Targeted delivery of protein and gene medicines through the blood-brain barrier.Clin Pharmacol Ther. 2015; 97: 347-361
- The blood-brain barrier: an engineering perspective.Front Neuroeng. 2013; 6: 7
- Blood-brain barrier dysfunction as a cause and consequence of Alzheimer's disease.J Cereb Blood Flow Metab. 2013; 33: 1500-1513
- Amyloid beta deposition is related to decreased glucose transporter-1 levels and hippocampal atrophy in brains of aged APP/PS1 mice.Brain Res. 2007; 1181: 93-103
- GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration.Nat Neurosci. 2015; 18: 521-530
- Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer's disease.Acta Neuropathol. 2009; 118: 103-113
- Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease.Curr Alzheimer Res. 2007; 4: 191-197
- Decreased clearance of CNS beta-amyloid in Alzheimer's disease.Science. 2010; 330: 1774
- Transport pathways for clearance of human Alzheimer's amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system.J Cereb Blood Flow Metab. 2007; 27: 909-918
- Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier.J Clin Invest. 2000; 106: 1489-1499
- The brain's glymphatic system: current controversies.Trends Neurosci. 2020; 43: 458-466
- Interactions between Amyloid-Β proteins and human brain pericytes: implications for the pathobiology of Alzheimer’s disease.J Clin Med. 2020; 9: 1490
- Pericyte coverage of retinal and cerebral capillaries.Invest Ophthalmol Vis Sci. 1990; 31: 999-1007
- Pericyte physiology.FASEB J. 1993; 7: 1031-1038
- Central nervous system pericytes in health and disease.Nat Neurosci. 2011; 14: 1398-1405
- The CNS microvascular pericyte: pericyte-astrocyte crosstalk in the regulation of tissue survival.Fluids Barriers CNS. 2011; 8: 8
- What is a pericyte?.J Cereb Blood Flow Metab. 2016; 36: 451-455
- The role of pericytes in neurovascular unit remodeling in brain disorders.Int J Mol Sci. 2014; 15: 6453-6474
- Pericytes regulate the blood-brain barrier.Nature. 2010; 468: 557-561
Hamilton NB, Attwell D, Hall CN. Pericyte-mediated regulation of capillary diameter: a component of neurovascular coupling in health and disease. Front Neuroenergetics 2010;2:5.
- Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging.Neuron. 2010; 68: 409-427
- Pericytes are required for blood–brain barrier integrity during embryogenesis.Nature. 2010; 468: 562-566
- Pericyte loss influences Alzheimer-like neurodegeneration in mice.Nat Commun. 2013; 4: 2932
- Clearance systems in the brain-implications for Alzheimer disease.Nat Rev Neurol. 2015; 11: 457-470
- Pericyte degeneration causes white matter dysfunction in the mouse central nervous system.Nat Med. 2018; 24: 326-337
- Pericytes in Alzheimer's disease: novel clues to cerebral amyloid angiopathy pathogenesis.Adv Exp Med Biol. 2019; 1147: 147-166
- The pericyte: a forgotten cell type with important implications for Alzheimer's disease?.Brain Pathol. 2014; 24: 371-386
- Rapid degeneration of cultured human brain pericytes by amyloid beta protein.J Neurochem. 1997; 68: 1135-1141
- Amyloid-beta-induced degeneration of human brain pericytes is dependent on the apolipoprotein E genotype.Ann N Y Acad Sci. 2000; 903: 187-199
- Deficiency in mural vascular cells coincides with blood-brain barrier disruption in Alzheimer's disease.Brain Pathol. 2013; 23: 303-310
- Lipoprotein receptor-related protein-1 mediates amyloid-beta-mediated cell death of cerebrovascular cells.Am J Pathol. 2007; 171: 1989-1999
- The contribution of astrocytes to the regulation of cerebral blood flow.Front Neurosci. 2014; 8: 103
- Glial and neuronal control of brain blood flow.Nature. 2010; 468: 232-243
- Astrocytes and the regulation of cerebral blood flow.Trends Neurosci. 2009; 32: 160-169
- Uniquely hominid features of adult human astrocytes.J Neurosci. 2009; 29: 3276-3287
- Astrocyte-endothelial interactions at the blood-brain barrier.Nat Rev Neurosci. 2006; 7: 41-53
- Astrocyte control of synaptic transmission and neurovascular coupling.Physiol Rev. 2006; 86: 1009-1031
- Glial influences on BBB functions and molecular players in immune cell trafficking.Biochim Biophys Acta. 2016; 1862: 472-482
- The blood-brain barrier in Alzheimer's disease.Neurobiol Dis. 2017; 107: 41-56
- A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β.Sci Transl Med. 2012; 4 (147ra11)
- Vascular amyloid alters astrocytic water and potassium channels in mouse models and humans with Alzheimer's disease.Neuroscience. 2009; 159: 1055-1069
- Association of Perivascular Localization of Aquaporin-4 With Cognition and Alzheimer Disease in Aging Brains.JAMA Neurol. 2017; 74: 91-99
- Loss of astrocyte polarization in the tg-ArcSwe mouse model of Alzheimer's disease.J Alzheimers Dis. 2011; 27: 711-722
- Ischemic cell death in brain neurons.Physiol Rev. 1999; 79: 1431-1568
- Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain.Nat Neurosci. 2017; 20: 406-416
Zhu WM, Neuhaus A, Beard DJ, Sutherland BA, DeLuca GC. Neurovascular coupling mechanisms in health and neurovascular uncoupling in Alzheimer’s disease. Brain 2022;145:2276–2292.
- What is the key mediator of the neurovascular coupling response?.Neurosci Biobehav Rev. 2019; 96: 174-181
- Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease.J Appl Physiol. 2006; 100 (1985): 328-335
- Decrease in parietal cerebral hemoglobin oxygenation during performance of a verbal fluency task in patients with Alzheimer's disease monitored by means of near-infrared spectroscopy (NIRS)–correlation with simultaneous rCBF-PET measurements.Brain Res. 1997; 755: 293-303
- Demonstration of impaired neurovascular coupling responses in TG2576 mouse model of Alzheimer's disease using functional laser speckle contrast imaging.Geroscience. 2017; 39: 465-473
- Impaired neurovascular coupling in aging and Alzheimer's disease: Contribution of astrocyte dysfunction and endothelial impairment to cognitive decline.Exp Gerontol. 2017; 94: 52-58
- Regulation of cerebral blood flow in humans: physiology and clinical implications of autoregulation.Physiol Rev. 2021; 101: 1487-1559
- Dynamic regulation of cerebral blood flow in patients with Alzheimer disease.Hypertension. 2018; 72: 139-150
- The interaction of dynamic cerebral autoregulation and neurovascular coupling in cognitive impairment.Curr Alzheimer Res. 2021; 18: 1067-1076
- Capillary pericytes regulate cerebral blood flow in health and disease.Nature. 2014; 508: 55-60
- Attwell D. Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles.Nat Neurosci. 2016; 19: 1619-1627
- Channelrhodopsin excitation contracts brain pericytes and reduces blood flow in the aging mouse brain in vivo.Front Aging Neurosci. 2020; 12: 108
- Contractile pericytes determine the direction of blood flow at capillary junctions.Proc Natl Acad Sci U S A. 2020; 117: 27022-27033
- Brain capillary pericytes exert a substantial but slow influence on blood flow.Nat Neurosci. 2021; 24: 633-645
- Brain capillary pericytes and neurovascular coupling.Comp Biochem Physiol A Mol Integr Physiol. 2021; 254110893
- Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes.Science. 2019; : 365
- Serum response factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in Alzheimer's phenotype.Proc Natl Acad Sci U S A. 2007; 104: 823-828
- Soluble amyloid-beta, effect on cerebral arteriolar regulation and vascular cells.Mol Neurodegener. 2010; 5: 15
- The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease.Neuron. 2017; 96: 17-42
- Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice.Science. 2009; 323: 1211-1215
- Impaired Hippocampal Neurovascular Coupling in a Mouse Model of Alzheimer's Disease.Front Physiol. 2021; 12715446
- Alzheimer's disease: the link between Amyloid-β and neurovascular dysfunction.J Alzheimers Dis. 2020; 76: 1179-1198
- Blood-brain barrier permeability precedes senile plaque formation in an Alzheimer disease model.Microcirculation. 2003; 10: 463-470
- MRI morphometry in Alzheimer's disease.Ageing Res Rev. 2016; 30: 17-24
- Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis.JAMA. 2015; 313: 1939-1949
- The bidirectional association between reduced cerebral blood flow and brain atrophy in the general population.J Cereb Blood Flow Metab. 2015; 35: 1882-1887
- Intracranial arterial 4D-flow is associated with metrics of brain health and Alzheimer's disease.Alzheimers Dement (Amst). 2015; 1: 420-428
- 4D flow MRI for intracranial hemodynamics assessment in Alzheimer's disease.J Cerebral Blood Flow and Metabolism: Off J Int Soc Cerebral Blood Flow and Metabolism. 2016; 36: 1718-1730
- The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia.Acta Neuropathol. 2010; 120: 287-296
- Cullum CM. FMRI of working memory in patients with mild cognitive impairment and probable Alzheimer's disease.Eur Radiol. 2006; 16: 193-206
- ASL perfusion MRI predicts cognitive decline and conversion from MCI to dementia.Alzheimer Dis Assoc Disord. 2010; 24: 19-27
- The concept of sporadic cerebral small vessel disease: a road map on key definitions and current concepts.Int J Stroke. 2016; 11: 6-18
- Clinical Significance of magnetic resonance imaging markers of vascular brain injury: a systematic review and meta-analysis.JAMA Neurol. 2019; 76: 81-94
- Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the american heart association/american stroke association.Stroke. 2011; 42: 2672-2713
- Cerebral small vessel disease in sporadic and familial alzheimer disease.Am J Pathol. 2021; 191: 1888-1905
- Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges.Lancet Neurol. 2010; 9: 689-701
- Interaction between cerebrovascular disease and Alzheimer pathology.Curr Opin Psychiatry. 2016; 29: 168-173
- The clinical manifestations and pathophysiology of cerebral small vessel disease.Neurosci Bull. 2010; 26: 257-264
- Cerebral small vessel disease and Alzheimer's disease: a review.Front Neurol. 2020; : 11
- APOE and cerebral amyloid angiopathy in the elderly.Neuroreport. 2003; 14: 1535-1536
- Population studies of sporadic cerebral amyloid angiopathy and dementia: a systematic review.BMC Neurol. 2009; 9: 3
- APOE epsilon 4 influences the pathological phenotype of Alzheimer's disease by favouring cerebrovascular over parenchymal accumulation of A beta protein.Neuropathol Appl Neurobiol. 2003; 29: 231-238
- Apolipoprotein E-epsilon4 alleles in cerebral amyloid angiopathy and cerebrovascular pathology associated with Alzheimer's disease.Am J Pathol. 1996; 148: 2083-2095
- Insights into the pathogenesis and pathogenicity of cerebral amyloid angiopathy.Front Biosci (Landmark Ed). 2009; 14: 4778-4792
- Cerebral amyloid angiopathy in dementia and old age.J Neurol Neurosurg Psychiatry. 1986; 49: 1221-1226
- Alzheimer disease and cerebrovascular pathology: an update.J Neural Transm (Vienna). 2002; 109: 813-836
- Sporadic cerebral amyloid angiopathy: pathophysiology, neuroimaging features, and clinical implications.Semin Neurol. 2016; 36: 233-243
- The increasing impact of cerebral amyloid angiopathy: essential new insights for clinical practice.J Neurol Neurosurg Psychiatry. 2017; 88: 982-994
- Patients with Alzheimer disease with multiple microbleeds: relation with cerebrospinal fluid biomarkers and cognition.Stroke. 2009; 40: 3455-3460
- Cerebral amyloid angiopathy and cognitive outcomes in community-based older persons.Neurology. 2015; 85: 1930-1936
- Neuropsychological effects of cerebral amyloid angiopathy.Curr Neurol Neurosci Rep. 2016; 16: 1-6
- Bouras C. The relationship between cerebral amyloid angiopathy and cortical microinfarcts in brain ageing and Alzheimer's disease.Neuropathol Appl Neurobiol. 2013; 39: 498-509
- White matter hyperintensities and risks of cognitive impairment and dementia: a systematic review and meta-analysis of 36 prospective studies.Neurosci Biobehav Rev. 2021; 120: 16-27
- White matter injury in ischemic stroke.Prog Neurobiol. 2016; 141: 45-60
- Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration.Lancet Neurol. 2013; 12: 822-838
- Heterogeneity of small vessel disease: a systematic review of MRI and histopathology correlations.J Neurol Neurosurg Psychiatry. 2011; 82: 126-135
- Periventricular white matter hyperintensities and the risk of dementia: a CREDOS study.Int Psychogeriatr. 2015; 27: 2069-2077
- Independent effects of white matter hyperintensities on cognitive, neuropsychiatric, and functional decline: a longitudinal investigation using the National Alzheimer's Coordinating Center Uniform Data Set.Alzheimers Res Ther. 2019; 11: 64
- Associations of white matter hyperintensities with cognitive decline: a longitudinal study.J Alzheimers Dis. 2020; 73: 759-768
- White matter hyperintensities and cognition in mild cognitive impairment and Alzheimer's disease: a domain-specific meta-analysis.J Alzheimers Dis. 2018; 63: 515-527
- White matter hyperintensities as early and independent predictors of Alzheimer's disease risk.J Alzheimers Dis. 2014; 42: S393-S400
- White matter hyperintensities and cognition across different Alzheimer's biomarker profiles.J Am Geriatr Soc. 2021; 69: 1906-1915
- The correlation between white matter hyperintensity burden and regional brain volumetry in patients with Alzheimer's disease.Front Hum Neurosci. 2022; : 16
- Cerebral microbleeds: histopathological correlation of neuroimaging.Cerebrovasc Dis. 2011; 32: 528-534
- Beta-amyloid, blood vessels, and brain function.Stroke. 2009; 40: 2601-2606
- Brain microbleeds and Alzheimer's disease: innocent observation or key player?.Brain. 2011; 134: 335-344
- Cerebral microbleeds are associated with worse cognitive function: the Rotterdam Scan Study.Neurology. 2012; 78: 326-333
- Cerebral microbleeds, retinopathy, and dementia: the AGES-Reykjavik Study.Neurology. 2010; 75: 2221-2228
- Cerebral small vessel disease and the risk of Alzheimer's disease: a systematic review.Ageing Res Rev. 2018; 47: 41-48
- Serial susceptibility weighted MRI measures brain iron and microbleeds in dementia.J Alzheimers Dis. 2009; 17: 599-609
- Cerebral microbleeds: different prevalence, topography, and risk factors depending on dementia diagnosis—the Karolinska Imaging Dementia Study.AJNR Am J Neuroradiol. 2015; 36: 661-666
- Cerebral microbleeds: overview and implications in cognitive impairment.Alzheimers Res Ther. 2014; 6: 33
- Impaired cerebral autoregulation and vasomotor reactivity in sporadic Alzheimer's disease.Curr Alzheimer Res. 2014; 11: 11-17
- Forebrain-dominant deficit in cerebrovascular reactivity in Alzheimer's disease.Neurobiol Aging. 2012; 33: 75-82
- Age-related reductions in cerebrovascular reactivity using 4D flow MRI.Front Aging Neurosci. 2019; 11: 281
- Atherosclerosis, vascular amyloidosis and brain hypoperfusion in the pathogenesis of sporadic Alzheimer's disease.Neurol Res. 2004; 26: 525-539
- Relationships between arteriosclerosis, cerebral amyloid angiopathy and myelin loss from cerebral cortical white matter in Alzheimer's disease.Neuropathol Appl Neurobiol. 2004; 30: 46-56
- Transcranial doppler ultrasound blood flow velocity and pulsatility index as systemic indicators for Alzheimer's disease.Alzheimer's & Dementia: The J Alzheimer's Assoc. 2011; 7: 445-455
Rivera-Rivera LA, Cody KA, Eisenmenger L, et al. Assessment of vascular stiffness in the internal carotid artery proximal to the carotid canal in Alzheimer’s disease using pulse wave velocity from low rank reconstructed 4D flow MRI. J Cereb Blood Flow Metab 2020;41:298–311.
- Blood-brain barrier: ageing and microvascular disease–systematic review and meta-analysis.Neurobiol Aging. 2009; 30: 337-352
- Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia?.Stroke. 2003; 34: 806-812
- Subregional hippocampal atrophy predicts Alzheimer's dementia in the cognitively normal.Neurobiol Aging. 2010; 31: 1077-1088
- Neuroimaging correlates of pathologically defined subtypes of Alzheimer's disease: a case-control study.The Lancet Neurology. 2012; 11: 868-877
- Assessment of blood-brain barrier disruption using dynamic contrast-enhanced MRI. A systematic review.NeuroImage Clinical. 2014; 6: 262-274
- Measuring blood volume and vascular transfer constant from dynamic, T(2)*-weighted contrast-enhanced MRI.Magn Reson Med. 2004; 51: 961-968
- Arrival time correction for dynamic susceptibility contrast MR permeability imaging in stroke patients.PLoS One. 2012; 7: e52656
- Measurement of the blood-brain barrier permeability and leakage space using dynamic MR imaging. 1. Fundamental concepts.Magn Reson Med. 1991; 17: 357-367
- Mapping water exchange across the blood-brain barrier using 3D diffusion-prepared arterial spin labeled perfusion MRI.Magn Reson Med. 2019; 81: 3065-3079
- A two-stage approach for measuring vascular water exchange and arterial transit time by diffusion-weighted perfusion MRI.Magn Reson Med. 2012; 67: 1275-1284
- When perfusion meets diffusion: in vivo measurement of water permeability in human brain.J Cerebral Blood Flow and Metabolism: Off J Int Soc Cerebral Blood Flow and Metabolism. 2007; 27: 839-849
- Associations between midlife vascular risk factors and 25-year incident dementia in the Atherosclerosis Risk in Communities (ARIC) cohort.JAMA Neurol. 2017; 74: 1246-1254
- Blood pressure is associated with higher brain amyloid burden and lower glucose metabolism in healthy late middle-age persons.Neurobiol Aging. 2012; 33 (827.e11-827.e19)
- Interactive associations of vascular risk and β-Amyloid burden with cognitive decline in clinically normal elderly individuals: findings from the Harvard aging brain study.JAMA Neurol. 2018; 75: 1124-1131
- Age, vascular health, and Alzheimer disease biomarkers in an elderly sample.Ann Neurol. 2017; 82: 706-718
- Reproducibility of 24-h ambulatory blood pressure and measures of autonomic function: methodological and statistical issue.Blood Press Monit. 2017; 22: 244
- Reproducibility of blood pressure phenotypes identified by office and ambulatory blood pressure in treated hypertensive patients. Data from the PHYLLIS study.Hypertens Res. 2022; 45: 1599-1608
- MarkVCID cerebral small vessel consortium: II. Neuroimaging protocols.Alzheimers Dement. 2021; 17: 716-725
- MarkVCID cerebral small vessel consortium: I. Enrollment, clinical, fluid protocols.Alzheimers Dement. 2021; 17: 704-715
Services USDoHaH. National plan to address Alzheimer's disease: 2019 update. 2019.
- Preparing for preventive clinical trials: the Predict-HD study.Arch Neurol. 2006; 63: 883-890
- Prediction of manifest Huntington's disease with clinical and imaging measures: a prospective observational study.The Lancet Neurology. 2014; 13: 1193-1201
- Clinical and Biomarker changes in dominantly inherited Alzheimer's disease.New Eng J Med. 2012; 367: 795-804
- Presymptomatic studies in ALS: rationale, challenges, and approach.Neurology. 2012; 79: 1732-1739
- The impact of the availability of prevention studies on the desire to undergo predictive testing in persons at risk for autosomal dominant Alzheimer's disease.Contemporary Clinical Trials. 2013; 36: 256-262
- Presymptomatic ALS genetic counseling and testing: Experience and recommendations.Neurology. 2016; 86: 2295-2302
- The genetics of Parkinson disease.Ageing Res Rev. 2018; 42: 72-85
- Cerebrospinal fluid phospho-tau T217 outperforms T181 as a biomarker for the differential diagnosis of Alzheimer's disease and PET amyloid-positive patient identification.Alzheimer's Res & Therapy. 2020; 12: 26
- Revised Self-Monitoring Scale: A potential endpoint for frontotemporal dementia clinical trials.Neurology. 2020; 94: e2384-e2e95
- Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic prion disease.BMC Med. 2020; 18: 140
- Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.Nature. 1996; 383: 707-710
- Notch3 mutations in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a mendelian condition causing stroke and vascular dementia.Ann N Y Acad Sci. 1997; 826: 213-217
- Cerebral hemodynamics and white matter hyperintensities in CADASIL.J Cereb Blood Flow Metab. 2003; 23: 599-604
- Diffusion magnetic resonance histograms as a surrogate marker and predictor of disease progression in CADASIL: a two-year follow-up study.Stroke. 2005; 36: 2559-2565
- White matter damage on diffusion tensor imaging correlates with age-related cognitive decline.Neurology. 2006; 66: 217-222
- The Wisconsin Registry for Alzheimer's Prevention: a review of findings and current directions.Alzheimers Dement (Amst). 2018; 10: 130-142
- An active and socially integrated lifestyle in late life might protect against dementia.Lancet Neurol. 2004; 3: 343-353
- An active lifestyle postpones dementia onset by more than one year in very old adults.J Alzheimers Dis. 2012; 31: 835-842
- MIND diet slows cognitive decline with aging.Alzheimers Dement. 2015; 11: 1015-1022
- Relationships of dietary patterns, foods, and micro- and macronutrients with alzheimer's disease and late-life cognitive disorders: a systematic review.J Alzheimers Dis. 2017; 59: 815-849
- Aggarwal NT. MIND diet associated with reduced incidence of Alzheimer's disease.Alzheimers Dement. 2015; 11: 1007-1014
- Self-reported health behaviors and longitudinal cognitive performance in late middle age: Results from the Wisconsin Registry for Alzheimer's Prevention.PLoS One. 2020; 15e0221985
- Physical activity, cognitive decline, and risk of dementia: 28 year follow-up of Whitehall II cohort study.BMJ. 2017; 357: j2709
- The epidemiology of Alzheimer's disease modifiable risk factors and prevention.J Prev Alzheimers Dis. 2021; 8: 313-321
- Diabetes mellitus and risks of cognitive impairment and dementia: a systematic review and meta-analysis of 144 prospective studies.Ageing Res Rev. 2019; 55100944
- Blood pressure from mid- to late life and risk of incident dementia.Neurology. 2017; 89: 2447-2454
Article info
Publication history
Published online: December 15, 2022
Accepted:
December 12,
2022
Received in revised form:
December 5,
2022
Received:
September 26,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Published by Elsevier Inc.
