Title: Cerebral Small Vessel Disease in Sporadic and Familial Alzheimer Disease
Abstract: Alzheimer disease (AD) is the most common cause of dementia. Biological definitions of AD are limited to the cerebral burden of amyloid β plaques, neurofibrillary pathology, and neurodegeneration. However, current evidence suggests that various features of small vessel disease (SVD) are part of and covertly modify both sporadic and familial AD. Neuroimaging studies suggest that white matter hyperintensities explained by vascular mechanisms occurs frequently in the AD spectrum. Recent advances have further emphasized that frontal periventricular and posterior white matter hyperintensities are associated with cerebral amyloid angiopathy in familial AD. Although whether SVD markers precede the classically recognized biomarkers of disease is debatable, post-mortem studies show that SVD pathology incorporating small cortical and subcortical infarcts, microinfarcts, microbleeds, perivascular spacing, and white matter attenuation is commonly found in sporadic as well as in mutation carriers with confirmed familial AD. Age-related cerebral vessel pathologies such as arteriolosclerosis and cerebral amyloid angiopathy modify progression or worsen risk by shifting the threshold for cognitive impairment and AD dementia. The incorporation of SVD as a biomarker is warranted in the biological definition of AD. Therapeutic interventions directly reducing the burden of brain amyloid β have had no major impact on the disease or delaying cognitive deterioration, but lowering the risk of vascular disease seems the only rational approach to tackle both early- and late-onset AD dementia. Alzheimer disease (AD) is the most common cause of dementia. Biological definitions of AD are limited to the cerebral burden of amyloid β plaques, neurofibrillary pathology, and neurodegeneration. However, current evidence suggests that various features of small vessel disease (SVD) are part of and covertly modify both sporadic and familial AD. Neuroimaging studies suggest that white matter hyperintensities explained by vascular mechanisms occurs frequently in the AD spectrum. Recent advances have further emphasized that frontal periventricular and posterior white matter hyperintensities are associated with cerebral amyloid angiopathy in familial AD. Although whether SVD markers precede the classically recognized biomarkers of disease is debatable, post-mortem studies show that SVD pathology incorporating small cortical and subcortical infarcts, microinfarcts, microbleeds, perivascular spacing, and white matter attenuation is commonly found in sporadic as well as in mutation carriers with confirmed familial AD. Age-related cerebral vessel pathologies such as arteriolosclerosis and cerebral amyloid angiopathy modify progression or worsen risk by shifting the threshold for cognitive impairment and AD dementia. The incorporation of SVD as a biomarker is warranted in the biological definition of AD. Therapeutic interventions directly reducing the burden of brain amyloid β have had no major impact on the disease or delaying cognitive deterioration, but lowering the risk of vascular disease seems the only rational approach to tackle both early- and late-onset AD dementia. The most common cause of age-related dementia is the multifactorial Alzheimer disease (AD). Although <5% of biologically defined AD is thought to be familial in nature, even this proportion exhibits high phenotypic variability that can be modified by lifestyle or environmental factors. Late-onset AD is pathologically confirmed by the presence of extracellular amyloid β (Aβ) plaques, intracellular hyperphosphorylated tau, and neuron (or synaptic) loss.1Jack Jr., C.R. Bennett D.A. Blennow K. Carrillo M.C. Dunn B. Haeberlein S.B. Holtzman D.M. Jagust W. Jessen F. Karlawish J. Liu E. Molinuevo J.L. Montine T. Phelps C. Rankin K.P. Rowe C.C. Scheltens P. Siemers E. Snyder H.M. Sperling R. ContributorsNIA-AA Research Framework: toward a biological definition of Alzheimer's disease.Alzheimers Dement. 2018; 14: 535-562Abstract Full Text Full Text PDF PubMed Google Scholar Early-onset or familial AD bears similar biological features, although typically, the hallmark pathology accrues considerably before 65 years of age. Clinical AD patients predominantly present with an insidious progressive irreversible amnesia and global cognitive decline in the absence of overt vascular disease. However, numerous post-mortem studies show that vast majority of patients diagnosed with AD dementia invariably have cerebral vascular pathology above and beyond normally aging healthy individuals.2Neuropathology Group of the Medical Research Council Cognitive Function and Aging Study (MRC CFAS)Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales..Lancet. 2001; 357: 169-175Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 3Deramecourt V. Slade J.Y. Oakley A.E. Perry R.H. Ince P.G. Maurage C.A. Kalaria R.N. Staging and natural history of cerebrovascular pathology in dementia.Neurology. 2012; 78: 1043-1050Crossref PubMed Scopus (155) Google Scholar, 4Toledo J.B. Arnold S.E. Raible K. Brettschneider J. Xie S.X. Grossman M. Monsell S.E. Kukull W.A. Trojanowski J.Q. Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer's Coordinating Centre.Brain. 2013; 136: 2697-2706Crossref PubMed Scopus (382) Google Scholar Many of the brain vascular changes are attributed to covert or silent cerebral small vessel disease (SVD). SVD features involving intracranial vessels <1 mm in diameter may be acquired subsequent to the initial clinical diagnosis of AD but most likely result from long-standing hypertensive or other vascular disease, or from age-related intracranial microvascular pathology.5Debette S. Schilling S. Duperron M.G. Larsson S.C. Markus H.S. Clinical significance of magnetic resonance imaging markers of vascular brain injury: a systematic review and meta-analysis.JAMA Neurol. 2019; 76: 81-94Crossref PubMed Scopus (115) Google Scholar Though cerebral SVD independently contributes to morbidity, disability, and mortality, several studies have confirmed that SVD also adds to or modifies progression to dementia such that the threshold for impairment is reached earlier.6Wang R. Laveskog A. Laukka E.J. Kalpouzos G. Backman L. Fratiglioni L. Qiu C. MRI load of cerebral microvascular lesions and neurodegeneration, cognitive decline, and dementia.Neurology. 2018; 91: e1487-e1497Crossref PubMed Scopus (16) Google Scholar,7DeCarli C. Villeneuve S. Maillard P. Harvey D. Singh B. Carmichael O. Fletcher E. Olichney J. Farias S. Jagust W. Reed B. Mungas D. Vascular burden score impacts cognition independent of amyloid PET and MRI measures of Alzheimer's disease and vascular brain injury.J Alzheimers Dis. 2019; 68: 187-196Crossref PubMed Scopus (8) Google Scholar For example, in the Nun study, SVD type of pathology in the form of lacunar infarcts in the basal ganglia, thalamus, or deep white matter (WM) was described to be associated with a higher prevalence of dementia.8Snowdon D.A. Greiner L.H. Mortimer J.A. Riley K.P. Greiner P.A. Markesbery W.R. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study.JAMA. 1997; 277: 813-817Crossref PubMed Google Scholar The presence of small vessel changes in clinically diagnosed and pathologically confirmed AD is not necessarily denied,9Sweeney M.D. Montagne A. Sagare A.P. Nation D.A. Schneider L.S. Chui H.C. et al.Vascular dysfunction-the disregarded partner of Alzheimer's disease.Alzheimers Dement. 2019; 15: 158-167Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar but deciphering whether vascular brain injury occurs prior to or concomitantly with neurodegenerative changes, has become a burning issue in AD research. This review discusses the current evidence of SVD in early- and late-onset AD, and evaluate its contribution in the spectrum of AD. It also appraises whether early-onset AD cases support the proposal that prior vascular dysfunction is part of the biomarker profile of AD. This is timely because it is strikingly clear that reducing brain Aβ overload via any treatment intervention has not had a substantial impact on improving cognition,10Veitch D.P. Weiner M.W. Aisen P.S. Beckett L.A. Cairns N.J. Green R.C. Harvey D. Jack Jr., C.R. Jagust W. Morris J.C. Petersen R.C. Saykin A.J. Shaw L.M. Toga A.W. Trojanowski J.Q. Alzheimer's Disease Neuroimaging InitiativeUnderstanding disease progression and improving Alzheimer's disease clinical trials: recent highlights from the Alzheimer's Disease Neuroimaging Initiative.Alzheimers Dement. 2019; 15: 106-152Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar but lowering the severity or risk of vascular disease seems the worthwhile option to reduce the incidence of AD dementia. Although conscious efforts are made to exclude the presence of overt vascular disease in the diagnosis of AD dementia, reasonable evidence suggests that sporadic AD is associated with pre-existing or late acquired vascular risk factors. These include hypertension, diabetes mellitus, hypercholesterolemia, obesity, metabolic syndrome, and atherosclerosis; all collectively promote morbidity and specifically increase the probability of clinical AD diagnosis. Current systematic reviews and recent meta-analyses have identified hypertension in midlife, high body mass index in late life, hyperhomocysteinemia, diabetes, head trauma, and orthostatic hypotension to be most strongly associated with dementia or AD.11Akinyemi R.O. Mukaetova-Ladinska E.B. Attems J. Ihara M. Kalaria R.N. Vascular risk factors and neurodegeneration in ageing related dementias: Alzheimer's disease and vascular dementia.Curr Alzheimer Res. 2013; 10: 642-653Crossref PubMed Scopus (105) Google Scholar, 12Stark S.L. Roe C.M. Grant E.A. Hollingsworth H. Benzinger T.L. Fagan A.M. Buckles V.D. Morris J.C. Preclinical Alzheimer disease and risk of falls.Neurology. 2013; 81: 437-443Crossref PubMed Scopus (44) Google Scholar, 13Yu J.T. Xu W. Tan C.C. Andrieu S. Suckling J. Evangelou E. Pan A. Zhang C. Jia J. Feng L. Kua E.H. Wang Y.J. Wang H.F. Tan M.S. Li J.Q. Hou X.H. Wan Y. Tan L. Mok V. Tan L. Dong Q. Touchon J. Gauthier S. Aisen P.S. Vellas B. 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Chongqing Ageing Study GroupVascular risk factors promote conversion from mild cognitive impairment to Alzheimer disease.Neurology. 2011; 76: 1485-1491Crossref PubMed Scopus (266) Google Scholar Blood pressure is one of the most widely evaluated risk factors for dementia and AD in particular. Hypertension is a risk for WM damage as well as clinically covert lesions such as arteriolosclerosis, microbleeds, microinfarcts, infarcts, endothelial damage, and vascular inflammation.13Yu J.T. Xu W. Tan C.C. Andrieu S. Suckling J. Evangelou E. Pan A. Zhang C. Jia J. Feng L. Kua E.H. Wang Y.J. Wang H.F. Tan M.S. Li J.Q. Hou X.H. Wan Y. Tan L. Mok V. Tan L. Dong Q. Touchon J. Gauthier S. Aisen P.S. Vellas B. Evidence-based prevention of Alzheimer's disease: systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials.J Neurol Neurosurg Psychiatry. 2020; 91: 1201-1209Crossref PubMed Scopus (52) Google Scholar,16Carnevale D. Perrotta M. Lembo G. 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Brain arteriolosclerosis.Acta Neuropathol. 2021; 141: 1-24Crossref PubMed Scopus (6) Google Scholar Although nondemented, normally aging individuals have histories of hypertension, large cohort studies suggest an association between systolic hypertension (>160 mm Hg) in midlife and late-onset AD by a risk of 18% to 25%20Lennon M.J. Makkar S.R. Crawford J.D. Sachdev P.S. Midlife hypertension and Alzheimer's disease: a systematic review and meta-analysis.J Alzheimers Dis. 2019; 71: 307-316Crossref PubMed Scopus (0) Google Scholar or decreased risk of AD in the short term, possibly due to reverse causation.21Gregson J. Qizilbash N. Iwagami M. Douglas I. Johnson M. Pearce N. Pocock S. Blood pressure and risk of dementia and its subtypes: a historical cohort study with long-term follow-up in 2.6 million people.Eur J Neurol. 2019; 26: 1479-1486Crossref PubMed Scopus (8) Google Scholar Blood pressure variability, albeit visit-to-visit or day-to-day, is also associated with progression of AD,22de Heus R.A.A. Olde Rikkert M.G.M. Tully P.J. Lawlor B.A. Claassen J.A.H.R. NILVAD Study GroupBlood pressure variability and progression of clinical Alzheimer disease.Hypertension. 2019; 74: 1172-1180Crossref PubMed Scopus (0) Google Scholar and optimal blood pressure management appears to be important for prevention of dementia.23Ma Y. Tully P.J. Hofman A. Tzourio C. Blood pressure variability and dementia: a state-of-the-art review.Am J Hypertens. 2020; 33: 1059-1066Crossref PubMed Scopus (1) Google Scholar The case for hypertension is further supported by a recent meta-analysis that explored the association of incident AD with the use of five antihypertensive medications.24Ding J. Davis-Plourde K.L. Sedaghat S. Tully P.J. Wang W. Phillips C. Pase M.P. Himali J.J. Gwen Windham B. Griswold M. Gottesman R. Mosley T.H. White L. Guethnason V. Debette S. Beiser A.S. Seshadri S. Ikram M.A. Meirelles O. Tzourio C. Launer L.J. Antihypertensive medications and risk for incident dementia and Alzheimer's disease: a meta-analysis of individual participant data from prospective cohort studies.Lancet Neurol. 2020; 19: 61-70Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar High systolic blood pressure (>140 mm Hg) with a median follow-up of 7 to 22 years in those using any antihypertensive agent had reduced risk for developing AD (HR, 0.8; 95% CI, 0.7 to 1.0) compared with those not on any antihypertensive agent. There were no significant differences between one drug class versus all others on risk of dementia. This indicates that certain protective measures against cardiovascular pathology appear beneficial in AD, although the use of antihypertensives in secondary prevention of what is described as pure AD seems to be unclear.25Lebouvier T. Chen Y. Duriez P. Pasquier F. Bordet R. Antihypertensive agents in Alzheimer's disease: beyond vascular protection.Expert Rev Neurother. 2020; 20: 175-187Crossref PubMed Scopus (6) Google Scholar Findings from other longitudinal studies such as Atherosclerosis Risk in Communities (ARIC)26Walker K.A. Sharrett A.R. Wu A. Schneider A.L.C. Albert M. Lutsey P.L. Bandeen-Roche K. Coresh J. Gross A.L. Windham B.G. Knopman D.S. Power M.C. Rawlings A.M. Mosley T.H. Gottesman R.F. Association of midlife to late-life blood pressure patterns with incident dementia.JAMA. 2019; 322: 535-545Crossref PubMed Scopus (87) Google Scholar and SPRINT MIND27Nasrallah I.M. Pajewski N.M. Auchus A.P. Chelune G. Cheung A.K. 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Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer's disease.Acta Neuropathol. 2016; 131: 659-685Crossref PubMed Scopus (179) Google Scholar Each vascular factor or collectively all, in different combinations, may unevenly alter the vasculature of the body or brain to cause distortions in normal structure and function, and potentially induce a chronic cerebral hypoperfusive state in old age.29Suri S. Topiwala A. Chappell M.A. Okell T.W. Zsoldos E. Singh-Manoux A. Kivimaki M. Mackay C.E. Ebmeier K.P. Association of midlife cardiovascular risk profiles with cerebral perfusion at older ages.JAMA Netw Open. 2019; 2: e195776Crossref PubMed Scopus (8) Google Scholar Whether hypertension per se substantially increases AD pathology is still not clear. 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Staging and natural history of cerebrovascular pathology in dementia.Neurology. 2012; 78: 1043-1050Crossref PubMed Scopus (155) Google Scholar However, in a recent analysis from several centers, nearly 20% of AD subjects exhibited large infarcts.39Kryscio R.J. Abner E.L. Nelson P.T. Bennett D. Schneider J. Yu L. Hemmy L.S. Lim K.O. Masaki K. Cairns N. Xiong C. Woltjer R. Dodge H.H. Tyas S. Fardo D.W. Lou W. Wan L. Schmitt F.A. The effect of vascular neuropathology on late-life cognition: results from the SMART Project.J Prev Alzheimers Dis. 2016; 3: 85-91PubMed Google Scholar Findings from the National Alzheimer's Coordinating Centers showed that whereas only 32% of the AD cases reported cerebrovascular disease, SVD in terms of both parenchymal and vessel pathologies included lacunes in 20%, multiple microinfarcts in 20%, arteriosclerotic leukoencephalopathy in 9%, hemorrhages in 7%, atherosclerosis in 40%, arteriolosclerosis in 35%, and CAA in 41% of AD cases. 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Johnson K. Sperling R.A. Reiman E.M. Lopera F. Quiroz Y.T. Biological and cognitive markers of presenilin1 E280A autosomal dominant Alzheimer's disease: a comprehensive review of the Colombian kindred.J Prev Alzheimers Dis. 2019; 6: 112-120PubMed Google Scholar severe SVD pathology not necessarily attributed to CAA was noted (D. Sepulveda-Falla, R.N. Kalaria, unpublished data).Table 1Radiological and Pathologic Features of Spectrum of Small Vessel Disease in AD DementiaClinical featuresSVD featureImaging markerKey pathologic featuresDegree of change in AD (compare aging or neurological controls)∗Changes found in AD type of dementia above and beyond normally aging healthy subjects. Arrow (↑) indicates increase. Scale of change means scores: +, mild (1); ++ moderate (2), severe +++ (3). Microhemor