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Cerebral Small Vessel Disease in Sporadic and Familial Alzheimer Disease

  • Rajesh N. Kalaria
    Correspondence
    Address correspondence to Rajesh N. Kalaria, F.R.C.Path., Translational and Clinical Research Institute, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL, United Kingdom.
    Affiliations
    Neurovascular Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom

    Department of Human Anatomy, College of Health Sciences, University of Nairobi, Nairobi, Kenya
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  • Diego Sepulveda-Falla
    Affiliations
    Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Open AccessPublished:July 27, 2021DOI:https://doi.org/10.1016/j.ajpath.2021.07.004
      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.
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      Spectrum of SVD Pathology in AD

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      • Marcus D.S.
      • Fagan A.M.
      • Goate A.
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      • Holtzman D.M.
      • Buckles V.
      • Ghetti B.
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      • Jack Jr., C.
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      • Mayeux R.
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      Dominantly Inherited Alzheimer Network
      White matter hyperintensities are a core feature of Alzheimer's disease: evidence from the Dominantly Inherited Alzheimer Network.
      In a South African subject with presenilin 1 (PSEN1) Ile143Met mutation, border zone infarcts, microinfarcts, arteriolosclerosis, perivascular spaces, and severe WM attenuation were also noted.
      • Heckmann J.M.
      • Low W.C.
      • de Villiers C.
      • Rutherfoord S.
      • Vorster A.
      • Rao H.
      • Morris C.M.
      • Ramesar R.S.
      • Kalaria R.N.
      Novel presenilin 1 mutation with profound neurofibrillary pathology in an indigenous Southern African family with early-onset Alzheimer's disease.
      Similarly, in the large Colombian PSEN1 Glu280Ala kindred,
      • Fuller J.T.
      • Cronin-Golomb A.
      • Gatchel J.R.
      • Norton D.J.
      • Guzman-Velez E.
      • Jacobs H.I.L.
      • Hanseeuw B.
      • Pardilla-Delgado E.
      • Artola A.
      • Baena A.
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      • Kosik K.S.
      • Chen K.
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      • Johnson K.
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      • 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.
      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 Dementia
      Clinical 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). Microhemorrhages may be caused by leakage by two mechanisms: microaneurysms and rupture of walls due to deposition of fibrillar proteins or iron.28
      Stroke(s)/vascular originSilent infarctsWMHs on T2W, FLAIR, ↑ high signalUnclear++
      Transient Ischemic attacksWMHs on DWM; high signalUnclear+
      White matter attenuationWMHs (pvWMH, dWMH), WM atrophy in CAA; high signalDemyelination in deep WM; axon damage+++
      Lacunar infarctsHyperintense lesions on T2W/FLAIRLacunes (<1.5 cm) in BG, thalamus, WM++
      Cortical InfarctsHyperintense lesions on T2W/FLAIRCortical infarcts+
      MicroinfarctsTiny hyperintense lesions on T2W (3T, 7T)Microinfarcts (<0.5 cm) in GM and WM+++
      MicrobleedsT2
      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). Microhemorrhages may be caused by leakage by two mechanisms: microaneurysms and rupture of walls due to deposition of fibrillar proteins or iron.28
      W or GRE signal lobar and deep bleeds; hypointense lesions on T2W
      Hemosiderin deposits in cortex (CAA) and subcortical structures (hypertensive)++
      Intracerebral hemorrhagesHyperintense on CT; hypointense lesions on T2WICH, microaneurysms+
      Cerebral siderosisHypointense signal on GRESAH+
      Vascular pathologiesPerivascular spaces (enlarged Virchow-Robin spaces)Hyperintense rounded lesions on T2W/FLAIRPVS in WM; GM of BG++
      Intracranial atherosclerosisUnclearOccasional microatheromas in branches of MCA, ACA+
      ArteriolosclerosisUnclearModerate-severe arteriolosclerosis+++
      CAAPosterior WMHs, lobar microbleedsModerate-severe CAA in cortex; predominance in occipital lobe+++
      Vascular FunctionCBFResting CBFParietal, temporal lobes, BG+++
      BBB functionPermeability on MRI (contrast agents, Gd)EC damage, ↓ capillary density+++
      PVWPhase contrast MRI; pulse sequence with retrospective peripheral pulse gating sequencesArteriosclerotic vessels; collagen fibers+++
      Autonomic function (hypoperfusion)Tilt table, carotid sinus supersensitivity (OH, CSH)WMLs, arteriolosclerosis, microinfarcts in BG++
      Neuroimaging and pathologic changes involving SVD in AD.
      ACA, anterior cerebral artery; AD, Alzheimer disease; BG, basal ganglia; CAA, cerebral amyloid angiopathy; CBF, cerebral blood flow; CSH, carotid sinus hypersensitivity; DWM, deep white matter; dWMH, deep white matter hyperintensities; EC, endothelial cell; FLAIR, fluid attenuated inversion recovery; Gd, gadolinium; GM, grey matter; GRE, gradient echo; ICH, intracerebral hemorrhage; MCA, middle cerebral artery; MRI, magnetic resonance imaging; OH, orthostatic hypotension; PVS, perivascular space; pvWMH, periventricular white matter hyperintensities; PVW, pulse wave velocity; SAH, subarachnoid hemorrhage; SVD, small vessel disease; WM, white matter; WMH, white matter hyperintensities; WML, white matter lesion.
      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). Microhemorrhages may be caused by leakage by two mechanisms: microaneurysms and rupture of walls due to deposition of fibrillar proteins or iron.
      • Kalaria R.N.
      Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer's disease.
      Figure thumbnail gr1
      Figure 1A: Schematic of a coronal brain section showing different types of SVD pathologies found in sporadic and familial AD. Numbers in boxes (1 to 7) correspond to the location and type of lesions in B. Location of perivascular spaces is generally in the WM and subcortical structures including the basal ganglia and thalamus (see image 8, axial MR scan, and corresponding histopathological image 8 on right). B: Images 1 to 8 (left) show MR scans in the axial plane with different lesions recognized and quantified in AD patients during life. Images 1 to 8 (right) show microscopic images of equivalent pathologies found in late-onset AD cases. Each of the pathologies has been demonstrated and often quantified in different cohorts consistently indicating greater representation of these pathologies in sporadic as well as familial AD than in aging controls or less common neurodegenerative dementias.
      • Deramecourt 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.
      ,
      • Toledo 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.
      These include perivascular and deep WM lesions or attenuation (image 1, right and left), lacunar infarcts (<1.5 cm) (image 2, right and left), cortical or WM infarcts (1 to 2 cm) (image 3, right and left) in a PSEN1 Glu280Ala, microinfarcts (<0.5 cm) (image 4, right and left), lobar or deep microbleeds or hemosiderin (image 5, right and left), CAA or CAA-related ICH (image 6, right and left), superficial siderosis (image 7, right and left), and perivascular spaces (image 8, right and left). Increased perivascular spacing occurs because of reduction in arterial vascular tone and lack of perivascular solute drainage.
      • Carare R.O.
      • Aldea R.
      • Agarwal N.
      • Bacskai B.J.
      • Bechman I.
      • Boche D.
      • et al.
      Clearance of interstitial fluid (ISF) and CSF (CLIC) group-part of Vascular Professional Interest Area (PIA): cerebrovascular disease and the failure of elimination of Amyloid-beta from the brain and retina with age and Alzheimer's disease-opportunities for therapy.
      The WM changes ensue due to a chronic hypoxic state and decline in oligodendrocytes.
      • Fernando M.S.
      • Simpson J.E.
      • Matthews F.
      • Brayne C.
      • Lewis C.E.
      • Barber R.
      • Kalaria R.N.
      • Forster G.
      • Esteves F.
      • Wharton S.B.
      • Shaw P.J.
      • O'Brien J.T.
      • Ince P.G.
      White matter lesions in an unselected cohort of the elderly: molecular pathology suggests origin from chronic hypoperfusion injury.
      ,
      • Ihara M.
      • Polvikoski T.M.
      • Hall R.
      • Slade J.Y.
      • Perry R.H.
      • Oakley A.E.
      • Englund E.
      • O'Brien J.T.
      • Ince P.G.
      • Kalaria R.N.
      Quantification of myelin loss in frontal lobe white matter in vascular dementia, Alzheimer's disease, and dementia with Lewy bodies.
      Arrows in panels show the location of key lesion(s). C: Pie chart shows average proportions of SVD pathologies in community-based observational and longitudinal cohort studies. % SVD lesions involve at least one lacunar infarct, a microinfarct, moderate-to-severe arteriolosclerosis, or CAA. Arteriolosclerosis is sometimes described as arteriosclerosis or total SVD. Perivascular spaces or WM attenuation or WM lesions were not consistently recorded. Microinfarct, unless specified, was considered that seen with the light microscope or to be <1 mm in diameter.
      • Ince P.G.
      • Minett T.
      • Forster G.
      • Brayne C.
      • Wharton S.B.
      Medical Research Council Cognitive Function and Ageing Neuropathology Study
      Microinfarcts in an older population-representative brain donor cohort (MRC CFAS): prevalence, relation to dementia and mobility, and implications for the evaluation of cerebral small vessel disease.
      MR fluid attenuated inversion recovery image (image 3, left) from a 57-year–old male subject was kindly provided by and used with permission from Dr. Yakeel T. Quiroz (Departments of Psychiatry and Neurology, Harvard Medical School, Boston, MA). Scale bars = 50 μm (B). AD, Alzheimer disease; CAA, cerebral amyloid angiopathy; ICH, intracerebral hemorrhage; MR, magnetic resonance; SVD, small vessel disease; WM, white matter.
      Besides the inherent inconsistencies in reporting of SVD lesions across different centers, there is also an apparent mismatch or perhaps under-reporting of generally low prevalence of cardiovascular disease or relevant risk factors compared with degrees of SVD pathology in AD (and other neurodegenerative disorders such as Lewy body disease).
      • Toledo 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.
      In a recent study,
      • Javanshiri K.
      • Haglund M.
      • Englund E.
      Cardiovascular disease, diabetes mellitus, and hypertension in Lewy body disease: a comparison with other dementia disorders.
      clinical hypertensive disease or diabetes mellitus was recorded to be 10% lower, yet pathologic features of systemic vascular disease including moderate-to-severe coronary stenosis and variable infarction were up in 50% of the cases at post-mortem examination. Subclinical disease including cardiac dysfunction increases the risk of dementia.
      • Knopman D.S.
      • Gottesman R.F.
      • Sharrett A.R.
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      • DavisThomas S.
      • Windham B.G.
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      • Albert M.S.
      • Mosley Jr., T.H.
      Midlife vascular risk factors and midlife cognitive status in relation to prevalence of mild cognitive impairment and dementia in later life: the Atherosclerosis Risk in Communities Study.
      ,
      • de Bruijn R.F.A.G.
      • Portegies M.L.P.
      • Leening M.J.G.
      • Bos M.J.
      • Hofman A.
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      • Vernooij M.W.
      • Franco O.H.
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      • Ikram M.A.
      Subclinical cardiac dysfunction increases the risk of stroke and dementia: the Rotterdam Study.
      Individuals diagnosed with AD in the community at large also tend to have greater vascular pathology compared with those from memory clinics.
      Neuropathology 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..
      ,
      • Schneider J.A.
      • Aggarwal N.T.
      • Barnes L.
      • Boyle P.
      • Bennett D.A.
      The neuropathology of older persons with and without dementia from community versus clinic cohorts.
      Normally aging community-dwelling older persons have some brain changes, and those with dementia often have multiple brain pathologies. However, cerebrovascular disease in AD patients increases the risk of developing clinical dementia and is additive,
      • Arvanitakis Z.
      • Capuano A.W.
      • Leurgans S.E.
      • Bennett D.A.
      • Schneider J.A.
      Relation of cerebral vessel disease to Alzheimer's disease dementia and cognitive function in elderly people: a cross-sectional study.
      taking lower burdens of AD pathology to tip over the threshold. In the HAAS, the five most important pathologies include microinfarcts, which are clinically silent but are correlated with dementia.
      • Gelber R.P.
      • Launer L.J.
      • White L.R.
      The Honolulu-Asia Aging Study: epidemiologic and neuropathologic research on cognitive impairment.
      Recent studies have highlighted cerebral arteriolosclerosis to be common in AD and other dementias.
      • Blevins B.L.
      • Vinters H.V.
      • Love S.
      • Wilcock D.M.
      • Grinberg L.T.
      • Schneider J.A.
      • Kalaria R.N.
      • Katsumata Y.
      • Gold B.T.
      • Wang D.J.J.
      • Ma S.J.
      • Shade L.M.P.
      • Fardo D.W.
      • Hartz A.M.S.
      • Jicha G.A.
      • Nelson K.B.
      • Magaki S.D.
      • Schmitt F.A.
      • Teylan M.A.
      • Ighodaro E.T.
      • Phe P.
      • Abner E.L.
      • Cykowski M.D.
      • Van Eldik L.J.
      • Nelson P.T.
      Brain arteriolosclerosis.
      The arteriolar wall modifications
      • Deramecourt 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.
      comprise fibrinoid necrosis (and/or lipohyalinosis), microatheromas, and segmental arterial disorganization (Figure 1). Focal arteriolosclerotic changes characterized by degeneration of vascular myocytes (acellular) with concentric accumulation of extracellular matrix components, such as collagen and fibroblasts, are often evident in small vessels in the deep WM and basal ganglia.
      • Hase Y.
      • Polvikoski T.M.
      • Firbank M.J.
      • Craggs L.J.L.
      • Hawthorne E.
      • Platten C.
      • Stevenson W.
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      • Allan L.M.
      • Horsburgh K.
      • Kalaria R.N.
      Small vessel disease pathological changes in neurodegenerative and vascular dementias concomitant with autonomic dysfunction.
      Both cerebral arteriolosclerosis and atherosclerosis are independently associated with dementia and contribute to low scores in most cognitive domains, suggesting that covert vessel pathology is an under-recognized risk for AD dementia.
      • Ighodaro E.T.
      • Abner E.L.
      • Fardo D.W.
      • Lin A.-L.
      • Katsumata Y.
      • Schmitt F.A.
      • Kryscio R.J.
      • Jicha G.A.
      • Neltner J.H.
      • Monsell S.E.
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      • Appiah F.
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      • Nelson P.T.
      Alzheimer's Disease Neuroimaging Initiative (ADNI)
      Risk factors and global cognitive status related to brain arteriolosclerosis in elderly individuals.
      Interestingly, the presence of apolipoprotein E (APOE; ApoE) ε4 allele or vascular risk factors did not change the association between either of these vascular pathologies and dementia outcome.
      • Arvanitakis Z.
      • Capuano A.W.
      • Leurgans S.E.
      • Bennett D.A.
      • Schneider J.A.
      Relation of cerebral vessel disease to Alzheimer's disease dementia and cognitive function in elderly people: a cross-sectional study.
      There is also likely to be a complex, yet unappreciated, physiological interaction between risk factors associated with metabolic syndrome such as hypertension and inflammation to culminate in the arteriolar pathology.
      • Blevins B.L.
      • Vinters H.V.
      • Love S.
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      • Fardo D.W.
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      • Nelson P.T.
      Brain arteriolosclerosis.
      Arteriolar changes in familial AD do not appear to be vastly different from familial SVD such as those in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
      • Craggs L.J.
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      • Kalaria R.N.
      Quantitative vascular pathology and phenotyping familial and sporadic cerebral small vessel diseases.
      In the PSEN1 Pro117Leu mutation carriers, in addition to attenuation and perivascular spaces in the WM, there is an accelerated process of transformation in arteriolar myocytes characterized by loss of the tunica media, marked fibrous thickening of arteries and arterioles, and double-barreled arterioles that are comparable to, but distinct in some ways, from those in CADASIL. Cerebral capillaries with Aβ deposits also reveal enhanced expression of fibrillar collagen 3 and 4. Ultrastructural studies indicate the presence of both Aβ and collagen fibers within thickened basement membrane of capillaries. Degenerated-appearing pericytes are also observed with clusters of collagen fibers between lamellae of basement membranes.
      • Szpak G.M.
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      Small cerebral vessel disease in familial amyloid and non-amyloid angiopathies: FAD-PS-1 (P117L) mutation and CADASIL. Immunohistochemical and ultrastructural studies.
      In general, these observations are consistent with other pathologic studies of familial AD.
      • Mann D.M.A.
      • Davidson Y.S.
      • Robinson A.C.
      • Allen N.
      • Hashimoto T.
      • Richardson A.
      • Jones M.
      • Snowden J.S.
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      • Strydom A.
      Patterns and severity of vascular amyloid in Alzheimer's disease associated with duplications and missense mutations in APP gene, Down syndrome and sporadic Alzheimer's disease.
      ,
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      • Low W.C.
      • de Villiers C.
      • Rutherfoord S.
      • Vorster A.
      • Rao H.
      • Morris C.M.
      • Ramesar R.S.
      • Kalaria R.N.
      Novel presenilin 1 mutation with profound neurofibrillary pathology in an indigenous Southern African family with early-onset Alzheimer's disease.
      ,
      • Sabogal-Guáqueta A.M.
      • Arias-Londoño J.D.
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      Common disbalance in the brain parenchyma of dementias: phospholipid profile analysis between CADASIL and sporadic Alzheimer's disease.
      Patterns of SVD are remarkably similar in neurodegenerative diseases, and the WM is particularly vulnerable irrespective of primary ischemic injury or a proteinopathy.
      • Deramecourt 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.
      ,
      • Hase Y.
      • Ding R.
      • Harrison G.
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      • King A.
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      • Platten C.
      • Stevenson W.
      • Craggs L.J.L.
      • Kalaria R.N.
      White matter capillaries in vascular and neurodegenerative dementias.
      The natural history and staging of SVD suggest that arteriolosclerosis and CAA are the earliest changes. Modifications in perivascular spaces and myelin loss are the next most common lesions. Lacunar or regional infarcts, microinfarcts, and microbleeds occur because of an independent process or in the final phases of SVD (Figure 1). These may result from occlusion by microemobili or microthombi originating form artery-to-artery thromboembolism and emboli from the heart.
      • Del Bene A.
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      • Wardlaw J.M.
      Variation in risk factors for recent small subcortical infarcts with infarct size, shape, and location.
      Other causes include microaneurysms and repeated parenchymal injury resulting from the disruption of flow due to arteriolar stiffening and tortuosity. The regional progression of vessel changes suggests that CAA proceeds from neocortical to subcortical structures. Although pre-existing hypertensive disease distorts and damages the microvasculature,
      • Blevins B.L.
      • Vinters H.V.
      • Love S.
      • Wilcock D.M.
      • Grinberg L.T.
      • Schneider J.A.
      • Kalaria R.N.
      • Katsumata Y.
      • Gold B.T.
      • Wang D.J.J.
      • Ma S.J.
      • Shade L.M.P.
      • Fardo D.W.
      • Hartz A.M.S.
      • Jicha G.A.
      • Nelson K.B.
      • Magaki S.D.
      • Schmitt F.A.
      • Teylan M.A.
      • Ighodaro E.T.
      • Phe P.
      • Abner E.L.
      • Cykowski M.D.
      • Van Eldik L.J.
      • Nelson P.T.
      Brain arteriolosclerosis.
      cerebral vessels laden with Aβ aggregates cause arteriosclerotic changes and damage the endothelium. Specific segmental patterns of capillary and arteriolar dysfunction appear to contribute to CAA and AD pathology.
      • Kalaria R.N.
      • Premkumar D.R.
      • Pax A.B.
      • Cohen D.L.
      • Lieberburg I.
      Production and increased detection of amyloid beta protein and amyloidogenic fragments in brain microvessels, meningeal vessels and choroid plexus in Alzheimer's disease.
      ,
      • Bourassa P.
      • Tremblay C.
      • Schneider J.A.
      • Bennett D.A.
      • Calon F.
      Beta-amyloid pathology in human brain microvessel extracts from the parietal cortex: relation with cerebral amyloid angiopathy and Alzheimer's disease.
      Although initiating factors causing CAA microangiopathy may be different, end-stage pathology appears invariably similar, involving replacement of myocytes with collagenous or other nontensile fibrillar material in both sporadic and familial cases. Intracranial arterial dolichoectasia also appears another cause of SVD, although this has not been widely described in AD. Microaneurysms arise in the context of hypertension, at weakened sites in vessel walls. The walls of aneurysms are composed of hyaline connective tissue, damaged myocytes, and elastica interna that may rupture to produce globular hemorrhages. They are transformed into fibrocollagenous balls, evident as complex tortuosities, when they heal due to thrombosis and fibrosis. They are most common at the interface between the grey matter and WM in most dementias.
      Atherosclerosis coexists with sporadic SVD involving large extracranial vessels and cardioembolic disease. Some cohort studies have reported that atheromas within basal brain vessels are common in AD.
      • Toledo J.B.
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      • Monsell S.E.
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      Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer's Coordinating Centre.
      ,
      • Arvanitakis Z.
      • Capuano A.W.
      • Leurgans S.E.
      • Bennett D.A.
      • Schneider J.A.
      Relation of cerebral vessel disease to Alzheimer's disease dementia and cognitive function in elderly people: a cross-sectional study.
      ,
      • Roher A.E.
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      Intracranial atherosclerosis as a contributing factor to Alzheimer's disease dementia.
      Small vessel atherosclerosis or microatheromas are occasionally also found within proximal segments of penetrating arteries at junctions of branching and parent arteries, and in parent vessels overlying the branch origin. The pathogenesis of atherosclerosis in small cerebral vessels does not differ substantially from that in extracranial vessels but is characterized by macrophages and nearly complete stenosis.
      • Kalaria R.N.
      Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer's disease.
      It is not surprising that subsets of proteins and modules associated with cerebral atherosclerosis were also found in AD brains.
      • Wingo A.P.
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      Shared proteomic effects of cerebral atherosclerosis and Alzheimer's disease on the human brain.

      Radiologically-Defined SVD in Late-Onset AD

      WMH on T2-weighted magnetic resonance imaging (MRI) have been invariably considered as radiological surrogate markers for SVD (Figure 1). The frequency of WMH or WM lesions increases to 94% by 80 years of age. The lesions are more common and extensive in patients with cardiovascular risk factors, and increase risk of stroke, dementia, and death. Both periventricular and deep WMH of vascular origin are common in late-onset AD,
      • Prins N.D.
      • Scheltens P.
      White matter hyperintensities, cognitive impairment and dementia: an update.
      and WMH and Aβ accumulation worsen cognitive outcomes.
      • Scott J.A.
      • Braskie M.N.
      • Tosun D.
      • Thompson P.M.
      • Weiner M.
      • DeCarli C.
      • Carmichael O.T.
      Alzheimer's Disease Neuroimaging Initiative
      Cerebral amyloid and hypertension are independently associated with white matter lesions in elderly.
      ,
      • Roseborough A.
      • Ramirez J.
      • Black S.E.
      • Edwards J.D.
      Associations between amyloid beta and white matter hyperintensities: a systematic review.
      A recent systematic analysis indicated that extensive WMH burden was associated with higher risk of AD (HR, 1.5), suggesting that MRI markers of vascular brain injury have major clinical significance and implicate prevention strategies in individuals with covert SVD.
      • Debette 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.
      Some frontal periventricular and posterior WMH or WM lesions are present in a large majority of familial cases of AD.
      • Walsh P.
      • Sudre C.H.
      • Fiford C.M.
      • Ryan N.S.
      • Lashley T.
      • Frost C.
      • Barnes J.
      • Investigators
      The age-dependent associations of white matter hyperintensities and neurofilament light in early- and late-stage Alzheimer's disease.
      In keeping with the pathology,
      • Hase Y.
      • Polvikoski T.M.
      • Firbank M.J.
      • Craggs L.J.L.
      • Hawthorne E.
      • Platten C.
      • Stevenson W.
      • Deramecourt V.
      • Ballard C.
      • Kenny R.A.
      • Perry R.H.
      • Ince P.
      • Carare R.O.
      • Allan L.M.
      • Horsburgh K.
      • Kalaria R.N.
      Small vessel disease pathological changes in neurodegenerative and vascular dementias concomitant with autonomic dysfunction.
      AD subjects also have less subcortical grey matter and WM with greater volumes of whole-brain, periventricular, and deep WM subcortical hyperintensities as well as lacunar lesions.
      • Ramirez J.
      • McNeely A.A.
      • Scott C.J.
      • Stuss D.T.
      • Black S.E.
      Subcortical hyperintensity volumetrics in Alzheimer's disease and normal elderly in the Sunnybrook Dementia Study: correlations with atrophy, executive function, mental processing speed, and verbal memory.
      Diffusion tensor imaging has been used to assess WM microstructural integrity and assess the progression of neurodegeneration in initial stages of disease.
      • Agosta F.
      • Pievani M.
      • Sala S.
      • Geroldi C.
      • Galluzzi S.
      • Frisoni G.B.
      • Filippi M.
      White matter damage in Alzheimer disease and its relationship to gray matter atrophy.
      ,
      • Lo Buono V.
      • Palmeri R.
      • Corallo F.
      • Allone C.
      • Pria D.
      • Bramanti P.
      • Marino S.
      Diffusion tensor imaging of white matter degeneration in early stage of Alzheimer's disease: a review.
      Whether spatiotemporal patterns of these WM changes precede dementia symptoms in AD is uncertain. However, WM microstructural changes and increased water diffusivity in the WM in AD appear akin to SVD. Increased free water in normal-appearing WM in AD even without overt cerebrovascular disease suggests that mild vascular damage may occur due to microvascular degeneration and neuroinflammation-related BBB permeability.
      • Ji F.
      • Pasternak O.
      • Liu S.
      • Loke Y.M.
      • Choo B.L.
      • Hilal S.
      • Xu X.
      • Ikram M.K.
      • Venketasubramanian N.
      • Chen C.L.
      • Zhou J.
      Distinct white matter microstructural abnormalities and extracellular water increases relate to cognitive impairment in Alzheimer's disease with and without cerebrovascular disease.
      In addition to WMH, a repertoire of SVD features can be detected by MRI in AD that are routinely demonstrated under the microscope (Figure 1). This includes lacunar infarcts, perivascular spacing, microbleeds, and microinfarcts. Most lacunar infarcts are clinically silent, as are microinfarcts, but both are found in greater numbers in AD compared with healthy aging subjects. These lesions may gradually disrupt cognitive network, modify global cognitive performance, and cause focal atrophy. Independent of the proteinopathy in AD, ongoing studies with more sensitive 7-T MR scanners and higher resolution modalities using 3-T suggest that microinfarcts and microbleeds
      • Conijn M.M.A.
      • Hoogduin J.M.
      • van der Graaf Y.
      • Hendrikse J.
      • Luijten P.R.
      • Geerlings M.I.
      Microbleeds, lacunar infarcts, white matter lesions and cerebrovascular reactivity – a 7 T study.
      arise from cardiac microemboli, supporting the role of cardiovascular abnormalities in AD. Microbleeds as radiological evidence of SVD have also been detected in familial AD, specifically in patients carrying PSEN1 missense mutations Ala260Gly, Pro284Ser, and Pro355Ser (AlzForum, http://www.alzforum.org/mutations, last accessed January 15, 2021).
      Above all, the evidence for the presence of SVD in both sporadic and familial AD is compelling, although the interactions between vascular and neurodegenerative processes may not be understood. In support of the radiological findings and presence of other biomarkers of SVD, collective evidence from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) studies suggests that vascular alterations such as cerebrovascular resistance and hypoperfusion precede Aβ deposition and are predictive of disease progression.
      • Iturria-Medina Y.
      • Sotero R.C.
      • Toussaint P.J.
      • Mateos-Perez J.M.
      • Evans A.C.
      Alzheimer's Disease Neuroimaging Initiative
      Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis.
      • Yew B.
      • Nation D.A.
      Alzheimer's Disease Neuroimaging Initiative
      Cerebrovascular resistance: effects on cognitive decline, cortical atrophy, and progression to dementia.
      • Korte N.
      • Nortley R.
      • Attwell D.
      Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease.
      Analysis of >7700 brain images and 1000 plasma and cerebrospinal fluid (CSF) biomarkers suggests that intrabrain vascular dysregulation is an early pathologic event during disease development. High abnormal levels of specific proteins associated with the integrity of the vascular system have been noted. This strongly implicates the inclusion of covert SVD features in the biomarker model of AD depicting disease progression. Congruent with this, brain extracellular vesicles were identified with molecular mediators of hypoxia responses and neuroprotection in preclinical AD and mixed dementias, supporting involvement of a vascular component in the etiology of AD.
      • Gallart-Palau X.
      • Serra A.
      • Hase Y.
      • Tan C.F.
      • Chen C.P.
      • Kalaria R.N.
      • Sze S.K.
      Brain-derived and circulating vesicle profiles indicate neurovascular unit dysfunction in early Alzheimer's disease.
      Elderly free of cardiovascular disease including atrial fibrillation have a lower cardiac index or output, which corresponds with lower cerebral blood flow (CBF) in the temporal lobes.
      • Jefferson A.L.
      • Liu D.
      • Gupta D.K.
      • Pechman K.R.
      • Watchmaker J.M.
      • Gordon E.A.
      • Rane S.
      • Bell S.P.
      • Mendes L.A.
      • Davis L.T.
      • Gifford K.A.
      • Hohman T.J.
      • Wang T.J.
      • Donahue M.J.
      Lower cardiac index levels relate to lower cerebral blood flow in older adults.
      In addition, cardiovascular disease including myocardial infarction in midlife is more associated with lower grey matter perfusion in older age, but not very late in life.
      • Suri 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.
      Using advanced dynamic contrast-enhanced MRI sequences with high spatial and temporal resolutions, BBB breakdown in the hippocampus was suggested to occur in early stages of AD prior to laying down of disease pathology. This breach appears worse in individuals with mild cognitive impairment. Both clinical imaging and CSF biomarker studies indicate BBB abnormalities
      • Nation D.A.
      • Sweeney M.D.
      • Montagne A.
      • Sagare A.P.
      • D'Orazio L.M.
      • Pachicano M.
      • Sepehrband F.
      • Nelson A.R.
      • Buennagel D.P.
      • Harrington M.G.
      • Benzinger T.L.S.
      • Fagan A.M.
      • Ringman J.M.
      • Schneider L.S.
      • Morris J.C.
      • Chui H.C.
      • Law M.
      • Toga A.W.
      • Zlokovic B.V.
      Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction.
      with reduced CBF occur 10 to 20 years prior to onset of clinical symptoms of AD.
      • Benzinger T.L.
      • Blazey T.
      • Jack Jr., C.R.
      • Koeppe R.A.
      • Su Y.
      • Xiong C.
      • et al.
      Regional variability of imaging biomarkers in autosomal dominant Alzheimer's disease.
      More recent studies have shown that CSF changes in markers of pericyte injury and BBB damage predict cognitive decline in patients with mild cognitive impairment independently of accumulation of Aβ or hyperphosphorylated tau.
      • Nation D.A.
      • Sweeney M.D.
      • Montagne A.
      • Sagare A.P.
      • D'Orazio L.M.
      • Pachicano M.
      • Sepehrband F.
      • Nelson A.R.
      • Buennagel D.P.
      • Harrington M.G.
      • Benzinger T.L.S.
      • Fagan A.M.
      • Ringman J.M.
      • Schneider L.S.
      • Morris J.C.
      • Chui H.C.
      • Law M.
      • Toga A.W.
      • Zlokovic B.V.
      Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction.
      ,
      • Montagne A.
      • Nation D.A.
      • Sagare A.P.
      • Barisano G.
      • Sweeney M.D.
      • Chakhoyan A.
      • Pachicano M.
      • Joe E.
      • Nelson A.R.
      • D'Orazio L.M.
      • Buennagel D.P.
      • Harrington M.G.
      • Benzinger T.L.S.
      • Fagan A.M.
      • Ringman J.M.
      • Schneider L.S.
      • Morris J.C.
      • Reiman E.M.
      • Caselli R.J.
      • Chui H.C.
      • Tcw J.
      • Chen Y.
      • Pa J.
      • Conti P.S.
      • Law M.
      • Toga A.W.
      • Zlokovic B.V.
      APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline.
      Thus, focal vascular dysfunction appears in early phases of AD perhaps concomitant with initial Aβ accrual. Observations from sporadic disease are consistent with earlier findings in the Colombian PSEN1 Glu280Ala mutation carriers; regional cerebral perfusion abnormalities detected on single-photon emission tomography occur before development of clinical symptoms.
      • Fuller J.T.
      • Cronin-Golomb A.
      • Gatchel J.R.
      • Norton D.J.
      • Guzman-Velez E.
      • Jacobs H.I.L.
      • Hanseeuw B.
      • Pardilla-Delgado E.
      • Artola A.
      • Baena A.
      • Bocanegra Y.
      • Kosik K.S.
      • Chen K.
      • Tariot P.N.
      • 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.
      AD patients also demonstrate decreased perfusion in the posterior parietal and superior frontal cortex.
      • Johnson K.A.
      • Lopera F.
      • Jones K.
      • Becker A.
      • Sperling R.
      • Hilson J.
      • Londono J.
      • Siegert I.
      • Arcos M.
      • Moreno S.
      • Madrigal L.
      • Ossa J.
      • Pineda N.
      • Ardila A.
      • Roselli M.
      • Albert M.S.
      • Kosik K.S.
      • Rios A.
      Presenilin-1-associated abnormalities in regional cerebral perfusion.
      In another study on familial AD, early CBF changes particularly in the lenticulostriate arterial territories were identified in asymptomatic and mildly symptomatic subjects.
      • McDade E.
      • Kim A.
      • James J.
      • Sheu L.K.
      • Kuan D.C.
      • Minhas D.
      • Gianaros P.J.
      • Ikonomovic S.
      • Lopez O.
      • Snitz B.
      • Price J.
      • Becker J.
      • Mathis C.
      • Klunk W.
      Cerebral perfusion alterations and cerebral amyloid in autosomal dominant Alzheimer disease.
      The endothelium of cerebral vessels and capillaries represents a vulnerable interface, which may be chronically activated in SVD.
      • Sweeney 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.
      ,
      • Kalaria R.N.
      Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer's disease.
      ,
      • Carare R.O.
      • Aldea R.
      • Agarwal N.
      • Bacskai B.J.
      • Bechman I.
      • Boche D.
      • et al.
      Clearance of interstitial fluid (ISF) and CSF (CLIC) group-part of Vascular Professional Interest Area (PIA): cerebrovascular disease and the failure of elimination of Amyloid-beta from the brain and retina with age and Alzheimer's disease-opportunities for therapy.
      It has been proposed that in SVD, capillary flow patterns are disrupted to retard oxygen extraction and cause SVD-like pathology and lead to neurodegeneration.
      • Ostergaard L.
      • Engedal T.S.
      • Moreton F.
      • Hansen M.B.
      • Wardlaw J.M.
      • Dalkara T.
      • Markus H.S.
      • Muir K.W.
      Cerebral small vessel disease: capillary pathways to stroke and cognitive decline.
      However, not only hemodynamic events, but also arteriolar wall disintegration resulting from arterial stiffening, may weaken the BBB and cause chronic leakage of fluid and macromolecules (Table 2 and Figure 2). In time, this may induce an inflammatory response with increased traffic in neutrophils and lymphocytes or perivascular macrophages. In older cases, age-related decline in BBB restoration mechanisms via astrocytic response may also promote microhemorrhages in the form of perivascular hemosiderin (Figure 2). Even though so far, there is no conclusive evidence of BBB damage in familial AD independent of CAA, early or non-amyloidogenic BBB breakdown has been identified in several AD murine models involving amyloid precursor protein (APP), PSEN1, tau, and -APOE mutations. These findings include loss of endothelial tight junctions, basement membrane degeneration. and pericytes loss. Of particular relevance is the mice lacking PSEN1 presenting with abnormal vessel development.
      • Nakajima M.
      • Yuasa S.
      • Ueno M.
      • Takakura N.
      • Koseki H.
      • Shirasawa T.
      Abnormal blood vessel development in mice lacking presenilin-1.
      This effect can be attributed to the role of γ-secretase in the cleavage and activation of Notch3, a key player in angiogenesis.
      Table 2Molecular Pathology of the Microcirculation and BBB in Late-Onset AD
      Cellular featureMorphological changesBiochemical markers
      Cerebral endothelium loss of glucose transporter, Na+/K+ ATPaseLoss of cytoplasm and endoplasmic reticulum. Increased pinocytosis.↓ GLUT1, Na+/K+ ATPase, CD31, CD34
      Changes in cytoplasm (oxidative and endoplasmic reticulum stresses)↑ Glucose-6-phosphatase; proteases (endothelin converting enzyme-1)
      Endothelial membranes/microvascular endfeet↓ Alkaline phosphatase, γ-GGT, cholinesterases
      Decreased mitochondria↓ Carnitine acetyltransferase
      Loss of tight junctions
      Vascular basement membraneThickening of the ECM, collagen fibers↑ COL, perlecans, fibrinogen, matrix metalloproteinases
      Perivascular cellsIncreased astrocytic feet↑ GFAP reactivity
      Pericytes: cell numbers and coverage↑ CSF sPDGFRβ1; ↑ cortex PDGFRβ1cortex; ↓WM PDGFRβ1; ↑ perivascular macrophage markers, CD68, TREM2
      Arteries/arteriolesLoss of vascular smooth muscle cells; increased microthrombi↓ α-Smooth muscle actin; accumulation of Aβ
      Cerebral microvesselsChanges in endothelium and perivascular macrophages↑ Inflammatory mediators ICAM1 and cytokines
      Summary of observations derived from several previous studies.
      • Sweeney 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.
      ,
      • Kalaria R.N.
      Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer's disease.
      ,
      • Carare R.O.
      • Aldea R.
      • Agarwal N.
      • Bacskai B.J.
      • Bechman I.
      • Boche D.
      • et al.
      Clearance of interstitial fluid (ISF) and CSF (CLIC) group-part of Vascular Professional Interest Area (PIA): cerebrovascular disease and the failure of elimination of Amyloid-beta from the brain and retina with age and Alzheimer's disease-opportunities for therapy.
      Arrows indicate decreases (↓) or increases (↑).
      Aβ, amyloid β protein; AD, Alzheimer disease; AlkP, alkaline phosphatase; BBB, blood-brain barrier; CD, clusters of differentiation markers; CD31, CD34 cluster of differentiation markers 31 and 34 for endothelium; CD68, cluster of differentiation marker 68 for microglia; COL, collagens; CSF, cerebrospinal fluid; EC, endothelial cell; ECM, extracellular matrix; eNOS, endothelial nitric oxide synthase; GFAP, glial fibrillary acid protein; GGT, γ-glutamyl transpeptidase; GLUT1, glucose transporter 1; HIF-1α, hypoxia inducible factor 1α; NV, neurovascular; PDGFRβ, platelet-derived growth factor receptor β; PVS, perivascular space; SMC, smooth muscle cell; TREM2, triggering receptor expressed on myeloid cells 2; VEGF, vascular endothelial growth factor; WM, white matter.
      Figure thumbnail gr2
      Figure 2Cerebrovascular pathology in subcortical WM in AD. A–C: Severe arteriolar hyalinization (A), calcification in basal ganglia (B), and moderately hyalinized vessel in rarefied WM (C). D–F: Periarteriolar microhemorrhage (arrows) in temporal WM in a subject with CAA. Serial sections stained with hematoxylin and eosin (D), Perl's stain for iron (E), and GLUT1 antibody (brown) (F). G–I: Double immunohistochemistry (brown = GLUT1, black = COL4) shows leakage sites of GLUT1-positive erythrocytes perivascular to arterioles in the WM of an AD case. G: Arrows indicate perivascular infiltrates, shown at higher magnification in H and I. J–L: Double immunohistochemistry (brown = GLUT1, black = COL4) shows sites of infiltration of GLUT1-positive erythrocytes around capillaries and arterioles (arrows), some showing increased perivascular spaces (arrowheads). Comparison of images in panels D–F and G–I demonstrates differences in chronic and acute leakage from blood. M–O: ICAM1 IR in the WM of aging control (M), AD (N), and VaD (O) subjects. Increased IR in vessel walls and diffuse deposits is shown (arrows). Fibrinogen showed similar IR. P–R: APP IR in the WM of aging control (P), AD (Q), and VaD (R) subjects. Diffuse APP IR shows sites of damage (arrows). B, F, and I: Note the frequent perivascular spaces found in the WM in AD (arrowheads). Scale bars = 50 μm. AD, Alzheimer disease; APP, amyloid precursor protein; CAA, cerebral amyloid angiopathy; COL, collagen 4; GLUT1, glucose transporter 1; ICAM1, intracellular adhesion molecule 1; IR, immunoreactivity; SVD, small vessel disease; VaD, vascular dementia; WM, white matter.

      WM Pathology and SVD in AD

      Cerebral WM rarefaction or attenuation is a frequent structural change in AD (Figure 2). Periventricular WM lesions are similar to those in Binswanger's disease in up to 60% of AD.
      • Englund E.
      Neuropathology of white matter changes in Alzheimer's disease and vascular dementia.
      Post-mortem studies showed that patterns of loss of myelin in AD are similar to those in vascular dementia.
      • Ihara M.
      • Polvikoski T.M.
      • Hall R.
      • Slade J.Y.
      • Perry R.H.
      • Oakley A.E.
      • Englund E.
      • O'Brien J.T.
      • Ince P.G.
      • Kalaria R.N.
      Quantification of myelin loss in frontal lobe white matter in vascular dementia, Alzheimer's disease, and dementia with Lewy bodies.
      Axonal degeneration and gliosis in the deep WM are also described to be common in AD. Similarly, other components of the gliovascular unit including capillaries undergo degeneration and dilation in the WM in AD.
      • Hase Y.
      • Ding R.
      • Harrison G.
      • Hawthorne E.
      • King A.
      • Gettings S.
      • Platten C.
      • Stevenson W.
      • Craggs L.J.L.
      • Kalaria R.N.
      White matter capillaries in vascular and neurodegenerative dementias.
      ,
      • Hase Y.
      • Horsburgh K.
      • Ihara M.
      • Kalaria R.N.
      White matter degeneration in vascular and other ageing-related dementias.
      Pathologic correlates of WMH when SVD is obvious suggest demyelination, axonal abnormalities, clasmatodendrosis, microglial activation, hemosiderin deposits, arteriolosclerosis, pericyte cell loss, and BBB dysfunction secondary to degrees of vascular brain injury.
      • Ding R.
      • Hase Y.
      • Ameen-Ali K.E.
      • Ndung'u M.
      • Stevenson W.
      • Barsby J.
      • Gourlay R.
      • Akinyemi T.
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      • Uemura M.T.
      • Polvikoski T.
      • Mukaetova-Ladinska E.
      • Ihara M.
      • Kalaria R.N.
      Loss of capillary pericytes and the blood-brain barrier in white matter in poststroke and vascular dementias and Alzheimer's disease.
      In support of these morphological findings, Wong et al
      • Wong S.M.
      • Jansen J.F.A.
      • Zhang C.E.
      • Hoff E.I.
      • Staals J.
      • van Oostenbrugge R.J.
      • Backes W.H.
      Blood-brain barrier impairment and hypoperfusion are linked in cerebral small vessel disease.
      provided in vivo evidence to suggest the integrity of the BBB is compromised in relation to cerebral hypoperfusion in the WM. They reported that lower CBF was correlated with higher leakage measures in the perilesional zones, which became stronger in the proximity of WMH. However, such WM alterations cannot be fully accounted for by degenerative processes secondary to grey matter damage,
      • Agosta F.
      • Pievani M.
      • Sala S.
      • Geroldi C.
      • Galluzzi S.
      • Frisoni G.B.
      • Filippi M.
      White matter damage in Alzheimer disease and its relationship to gray matter atrophy.
      ,
      • Englund E.
      Neuropathology of white matter changes in Alzheimer's disease and vascular dementia.
      but may stem from vascular amyloid deposition, microvascular damage, and lack of solute drainage.
      • Weller R.O.
      • Hawkes C.A.
      • Kalaria R.N.
      • Werring D.J.
      • Carare R.O.
      White matter changes in dementia: role of impaired drainage of interstitial fluid.
      Diffusion tensor imaging studies in mutation carriers in familial AD indicate changes in the cerebral WM occur years before symptom onset.
      • Araque Caballero M.Á.
      • Suárez-Calvet M.
      • Duering M.
      • Franzmeier N.
      • Benzinger T.
      • Fagan A.M.
      • Bateman R.J.
      • Jack C.R.
      • Levin J.
      • Dichgans M.
      • Jucker M.
      • Karch C.
      • Masters C.L.
      • Morris J.C.
      • Weiner M.
      • Rossor M.
      • Fox N.C.
      • Lee J.-H.
      • Salloway S.
      • Danek A.
      • Goate A.
      • Yakushev I.
      • Hassenstab J.
      • Schofield P.R.
      • Haass C.
      • Ewers M.
      White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer's disease.
      The mean diffusivity within the posterior parietal and medial frontal WM in mutation carriers was found to be stronger than in noncarriers. Higher mean diffusivity in fiber tracts was associated with lower grey matter volume in projection zones. These results suggest that regionally selective WM damage occurs considerably before the onset of disease that is associated with primary AD pathology and microglia activation rather than any overt vascular disease. WM changes in neurodegenerative diseases could reflect pathologic processes other than those involved in SVD, that is, that nonvascular damage could increase fluid motion in discrete areas of the WM to result in hyperintense signals.
      • Erten-Lyons D.
      • Woltjer R.
      • Kaye J.
      • Mattek N.
      • Dodge H.H.
      • Green S.
      • Tran H.
      • Howieson D.B.
      • Wild K.
      • Silbert L.C.
      Neuropathologic basis of white matter hyperintensity accumulation with advanced age.
      However, early changes in WM cannot all be explained by neurodegenerative pathology because there would not be sufficient burdens of neurodegenerative pathology at early stages.
      • Jack Jr., C.R.
      • Bennett D.A.
      • Blennow K.
      • Carrillo M.C.
      • Dunn B.
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      • Sperling R.
      Contributors
      NIA-AA Research Framework: toward a biological definition of Alzheimer's disease.
      Is it possible then, that the presence of low perfusion or disturbed arterial pulsation within the deeper layers of the WM disrupts flow in the long perforating arteries to cause a chronic hypoxic state and damage the deep WM?
      Similar to indications of BBB damage, there is still no human pathologic evidence of WM damage independent of Aβ pathology (Table 1 and Figure 2). However, alterations in myelin morphology and oligodendrocyte differentiation have been observed early in APP/PSEN1 mice.
      • Wu Y.
      • Ma Y.
      • Liu Z.
      • Geng Q.
      • Chen Z.
      • Zhang Y.
      Alterations of myelin morphology and oligodendrocyte development in early stage of Alzheimer's disease mouse model.
      Astrocytic clasmatodendrosis has shown to be a pathologic correlate of WM damage.
      • Hase Y.
      • Horsburgh K.
      • Ihara M.
      • Kalaria R.N.
      White matter degeneration in vascular and other ageing-related dementias.
      Accordingly, the authors have observed this feature in the WM of PSEN1 Glu280Ala cases (D. Sepulveda-Falla, R.N. Kalaria, unpublished data).

      Consequences of Chronic Vascular Disease

      Besides age, hypertension and diabetes mellitus are among the strong risk factors for SVD. Whereas it is not fully understood how diabetes might lead to SVD,
      • Bello-Chavolla O.Y.
      • Antonio-Villa N.E.
      • Vargas-Vázquez A.
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      Pathophysiological mechanisms linking type 2 diabetes and dementia: review of evidence from clinical, translational and epidemiological research.
      the deleterious effects of increased blood pressure are mediated by structural changes in smaller arteries leading to arteriolosclerosis with two main consequences. First, the progressive segmental loss of myocytes with replacement by collagen fibers reduces vessel wall tone or elasticity in response to variations in blood pressure and loss of autoregulation through disruption of the perivascular nerve plexii. Second, the persistent high pulse pressure leads to focal disruption of capillaries, particularly in the deeper structures. This causes edema and BBB breach with chronic leakage of fluid and macromolecules (Figure 2) as well as incidental infarction, particularly in subcortical structures.
      Aging-associated central arterial stiffness may increase SVD features with consequences on progression in the AD continuum. For example, aortic stiffening conveyed by higher pulse wave velocity, and therefore higher pulsatility, was associated with lower CBF particularly in the temporal lobes although cerebrovascular reactivity was preserved in APOE ε4 allele carriers with mild cognitive impairment.
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      Higher aortic stiffness is related to lower cerebral blood flow and preserved cerebrovascular reactivity in older adults.
      Consistent with this, higher systolic blood pressure and pulse pressure,
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      Alzheimer's Disease Neuroimaging Initiative
      Cardiovascular risk factors, cortisol, and amyloid-beta deposition in Alzheimer's Disease Neuroimaging Initiative.
      attributable to arterial stiffness, were related to greater cerebral retention of Pittsburgh Compound-B (PiB) in presymptomatic and AD patients. Arterial stiffness, or the surrogate marker pulse wave velocity, and mean arterial pressure were also highest in individuals with both high PiB retention and WMH (double hit), promoting the development of AD.
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      Although resting CBF may not be affected, higher pulsatility index likely promotes larger WMH volumes and increases perivascular spaces in subcortical structures.
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      Small vessel disease is associated with altered cerebrovascular pulsatility but not resting cerebral blood flow.
      It is conceivable that early in the presymptomatic stage prior to the manifestation of disease phenotype, vascular reactivity is compromised due to covert changes in vessel walls whether they are CAA or AD mutation carriers.
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      Rodent models of Aβ amyloidosis including those exhibiting CAA have demonstrated impairment in different features of cerebrovascular function including CBF, functional hyperemia, and cerebral autoregulation.
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      Although higher cerebrovascular resistance and altered transfer of CBF to cortical oxygenation in AD suggests that the microcirculation and properties of the microvasculature are changed,
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      all functional measures are not consistently replicated in AD. For example, it is controversial whether autoregulation in AD is altered per se to reflect in SVD-related cerebral perfusion. In an earlier study, Zazulia et al
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      demonstrated that the efficacy of cerebral autoregulation, assessed during stepwise changes in arterial pressure, was reduced in individuals with amnestic mild cognitive impairment, which is a prodromal stage of AD. Various limitations including cohort sizes, coexisting factors, imaging techniques, variability in disease progression and study power can be attributed to inconsistent findings.

      SVD and CAA in Sporadic and Familial AD

      For more than 100 years, cerebral congophilic angiopathy, or now widely described as CAA, has been identified as a pathologic hallmark of brain disease.
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      CAA was originally identified to be associated with wall thickening of small and medium-sized vessels together with the occurrence of cerebral microbleeds. Vessel wall thickening characteristically showed accumulation of eosinophilic material, Congo Red positive, identifying it as amyloid. The most common type of CAA is Aβ angiopathy, which is reported to be as high as 90% in AD.
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      • Leverenz J.B.
      • Steinbart E.
      • Stahl J.
      • Klunk W.
      • Yu C.E.
      • Bird T.D.
      Alzheimer's disease phenotypes and genotypes associated with mutations in presenilin 2.
      • Wells J.L.
      • Pasternak S.H.
      Case report of a 63-year-old patient with Alzheimer disease and a novel presenilin 2 mutation.
      The first case in Argentina with marked vascular pathology including CAA carried the APP Ala171Thr mutation.
      • Suarez M.C.F.
      • Brusco I.
      • Damasso C.
      • Olivar N.
      • Morelli L.
      • Russo G.
      Heterozygous APP A713T mutation carrier with inflammatoy amyloid angiopathy and family history of Alzheimer's disease: first case in Argentina.
      Specifically, at least 16 mutations in the APP and PSEN1 genes are outright known for CAA in the clinical phenotype (Table 3). However, of 68 mutations identified in APP, 15 of them present with CAA. APP mutations are localized between amino acids 670 to 694 and 713 to 717. The first cluster corresponds to α- and β-secretase cleavage sites and the second cluster to γ-secretase cleavage sites, indicating a direct role of abnormal Aβ peptide(s) generation and their accumulation in cerebral vessels. Several murine AD models developed from these APP mutations have indicated CAA as well and have favored research in AD vascular pathology. So far, more than 320 PSEN1 mutations have been identified. Accordingly, 37 PSEN1 missense mutations are associated with the presence of mild-to-severe CAA (Table 3). These mutations are evenly distributed alongside the PSEN1 gene sequence. However, PSEN1 mutations below codon 200 have been characterized as having milder CAA pathology, whereas PSEN1 mutations above codon 200 characteristically show severe CAA. Finally, while 64 mutations for PSEN2 have been identified, at least 4 mutations have been associated with the presence of CAA (Table 3). It has been suggested that the composition of Aβ aggregates differs between parenchymal deposits and those found in CAA-affected vessels. Parenchymal deposits are typically composed of longer Aβ peptides, often with additional posttranslational modifications. CAA deposits, on the other hand, show shorter forms of Aβ peptides.
      • Gkanatsiou E.
      • Portelius E.
      • Toomey C.E.
      • Blennow K.
      • Zetterberg H.
      • Lashley T.
      • Brinkmalm G.
      A distinct brain beta amyloid signature in cerebral amyloid angiopathy compared to Alzheimer's disease.
      Mutations in APP, PSEN1, and PSEN2 genes modify size and biochemical profiles of Aβ peptides generated from APP. The authors have shown that familial AD cases also show a distinctive Aβ peptide signature in CAA deposits when compared with those from sporadic AD cases.
      • Dinkel F.
      • Trujillo-Rodriguez D.
      • Villegas A.
      • Streffer J.
      • Mercken M.
      • Lopera F.
      • Glatzel M.
      • Sepulveda-Falla D.
      Decreased deposition of beta-amyloid 1-38 and increased deposition of beta-amyloid 1-42 in brain tissue of Presenilin-1 E280A familial Alzheimer's disease patients.
      Table 3Familial AD Causative Mutations for CAA
      GeneMutation
      Genotypes of different mutations per original references derived from the Alzforum Database (http://www.alzforum.org/mutations, last accessed January 15, 2021).
      CAA
      Presence of variable degrees of CAA predominantly in cortical regions.
      Notes
      Presence or absence of CAA in various transgenic mouse models and features noted in case reports.
      References
      References include citations of four abstracts.
      APPLysMet670/671AsnLeuYesMouse model, CAA at 12–19 months
      • Reinert J.
      • Richard B.C.
      • Klafki H.W.
      • Friedrich B.
      • Bayer T.A.
      • Wiltfang J.
      • Kovacs G.G.
      • Ingelsson M.
      • Lannfelt L.
      • Paetau A.
      • Bergquist J.
      • Wirths O.
      Deposition of C-terminally truncated Abeta species Abeta37 and Abeta39 in Alzheimer's disease and transgenic mouse models.
      Ala673ValYes
      • Giaccone G.
      • Morbin M.
      • Moda F.
      • Botta M.
      • Mazzoleni G.
      • Uggetti A.
      • Catania M.
      • Moro M.L.
      • Redaelli V.
      • Spagnoli A.
      • Rossi R.S.
      • Salmona M.
      • Di Fede G.
      • Tagliavini F.
      Neuropathology of the recessive A673V APP mutation: Alzheimer disease with distinctive features.
      Asp678HisYesAlso present with cerebral microvasculopathy (23931937)
      • Huang C.Y.
      • Hsiao I.T.
      • Lin K.J.
      • Huang K.L.
      • Fung H.C.
      • Liu C.H.
      • Chang T.Y.
      • Weng Y.C.
      • Hsu W.C.
      • Yen T.C.
      • Huang C.C.
      Amyloid PET pattern with dementia and amyloid angiopathy in Taiwan familial AD with D678H APP mutation.
      Ala692GlyYes
      • Cras P.
      • van Harskamp F.
      • Hendriks L.
      • Ceuterick C.
      • van Duijn C.M.
      • Stefanko S.Z.
      • Hofman A.
      • Kros J.M.
      • Van Broeckhoven C.
      • Martin J.J.
      Presenile Alzheimer dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692Ala-->Gly mutation.
      Glu693GlyYesMouse model shows no CAA
      • Reinert J.
      • Richard B.C.
      • Klafki H.W.
      • Friedrich B.
      • Bayer T.A.
      • Wiltfang J.
      • Kovacs G.G.
      • Ingelsson M.
      • Lannfelt L.
      • Paetau A.
      • Bergquist J.
      • Wirths O.
      Deposition of C-terminally truncated Abeta species Abeta37 and Abeta39 in Alzheimer's disease and transgenic mouse models.
      Glu693LysYes
      • Tagliavini F.
      • Rossi G.
      • Padovani A.
      • Magoni M.
      • Andora G.
      • Sgarzi M.
      • Bizzi A.
      • Savoiardo M.
      • Carella F.
      • Morbin M.
      • Giaccone G.
      • Bugiani O.
      A new βPP mutation related to hereditary cerebral haemorrhage.
      Glu693GlnYesMouse model, CAA at 12–22 months
      • Timmers W.F.
      • Tagliavini F.
      • Haan J.
      • Frangione B.
      Parenchymal preamyloid and amyloid deposits in the brains of patients with hereditary cerebral hemorrhage with amyloidosis–Dutch type.
      Asp694AsnYesMouse model: APPSwDI (Swedish Lys760Asn/Met671Leu, Dutch Glu693Gln and Iowa Asp694Asn), considered to be the optimal CAA model
      • Mok T.
      • Chalissery A.J.
      • Byrne S.
      • Costelloe L.
      • Galvin L.
      • Vinters H.V.
      • Farrell M.A.
      • Brett F.M.
      • Moroney J.T.
      Familial cerebral amyloid angiopathy due to the Iowa mutation in an Irish family.
      Ala713ThrYesWM changes, cerebral microangiopathy and CAA
      First case in Argentina with APP Ala171Thr mutation showing marked vascular pathology.154
      • Armstrong J.
      • Boada M.
      • Rey M.J.
      • Vidal N.
      • Ferrer I.
      Familial Alzheimer disease associated with A713T mutation in APP.
      ,
      • Suarez M.C.F.
      • Brusco I.
      • Damasso C.
      • Olivar N.
      • Morelli L.
      • Russo G.
      Heterozygous APP A713T mutation carrier with inflammatoy amyloid angiopathy and family history of Alzheimer's disease: first case in Argentina.
      Thr714IleYesTransgenic APP695 mouse harboring Lys670Asn, Met671Leu, and Thr714Ile, develops CAA
      • Kumar-Singh S.
      • De Jonghe C.
      • Cruts M.
      • Kleinert R.
      • Wang R.
      • Mercken M.
      • De Strooper B.
      • Vanderstichele H.
      • Lofgren A.
      • Vanderhoeven I.
      • Backhovens H.
      • Vanmechelen E.
      • Kroisel P.M.
      • Van Broeckhoven C.
      Nonfibrillar diffuse amyloid deposition due to a gamma(42)-secretase site mutation points to an essential role for N-truncated A beta(42) in Alzheimer's disease.
      Ile716PheYes
      • Reinert J.
      • Richard B.C.
      • Klafki H.W.
      • Friedrich B.
      • Bayer T.A.
      • Wiltfang J.
      • Kovacs G.G.
      • Ingelsson M.
      • Lannfelt L.
      • Paetau A.
      • Bergquist J.
      • Wirths O.
      Deposition of C-terminally truncated Abeta species Abeta37 and Abeta39 in Alzheimer's disease and transgenic mouse models.
      Val717PheYesMouse model shows no CAA
      • Ghetti B.
      • Murrell J.
      • Benson M.D.
      • Farlow M.R.
      Spectrum of amyloid beta-protein immunoreactivity in hereditary Alzheimer disease with a guanine to thymine missense change at position 1924 of the APP gene.
      Val717GlyYes
      • Mann D.M.
      • Jones D.
      • Snowden J.S.
      • Neary D.
      • Hardy J.
      Pathological changes in the brain of a patient with familial Alzheimer's disease having a missense mutation at codon 717 in the amyloid precursor protein gene.
      Val717IleYesMouse model, CAA at 15 months
      • Lantos P.L.
      • Luthert P.J.
      • Hanger D.
      • Anderton B.H.
      • Mullan M.
      • Rossor M.
      Familial Alzheimer's disease with the amyloid precursor protein position 717 mutation and sporadic Alzheimer's disease have the same cytoskeletal pathology.
      Val717LeuYes
      • Ghetti B.
      • Hake A.M.
      • Murrell J.R.
      • Epperson F.
      • Farlow M.R.
      • Vidal R.
      • Spina S.
      Familial Alzheimer's disease associated with the V717l amyloid precursor protein gene mutation: neuropathological characterization.
      PSEN1Ile83_MetM84delYes(DelIleMet, ΔIle83/Met84, ΔIle83/ΔMet84)
      • Steiner H.
      • Revesz T.
      • Neumann M.
      • Romig H.
      • Grim M.G.
      • Pesold B.
      • Kretzschmar H.A.
      • Hardy J.
      • Holton J.L.
      • Baumeister R.
      • Houlden H.
      • Haass C.
      A pathogenic presenilin-1 deletion causes abberrant Abeta 42 production in the absence of congophilic amyloid plaques.
      Met84ThrYes
      • Lanoiselée H.-M.
      • Nicolas G.
      • Wallon D.
      • Rovelet-Lecrux A.
      • Lacour M.
      • Rousseau S.
      • et al.
      collaborators of the CNR-MAJ project
      APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: a genetic screening study of familial and sporadic cases.
      Val89Leu (G>T)Yes
      • Queralt R.
      • Ezquerra M.
      • Lleo A.
      • Castellvi M.
      • Gelpi J.
      • Ferrer I.
      • Acarin N.
      • Pasarin L.
      • Blesa R.
      • Oliva R.
      A novel mutation (V89L) in the presenilin 1 gene in a family with early onset Alzheimer's disease and marked behavioural disturbances.
      Leu113_Ile114insThrYes(Intron4, p.113+1delGly, splice5, InsThrAlaCys)
      • Singleton A.B.
      • Hall R.
      • Ballard C.G.
      • Perry R.H.
      • Xuereb J.H.
      • Rubinsztein D.C.
      • Tysoe C.
      • Matthews P.
      • Cordell B.
      • Kumar-Singh S.
      • De Jonghe C.
      • Cruts M.
      • van Broeckhoven C.
      • Morris C.M.
      Pathology of early-onset Alzheimer's disease cases bearing the Thr113-114ins presenilin-1 mutation.
      Leu113GlnsYes
      • Finckh U.
      • Kuschel C.
      • Anagnostouli M.
      • Patsouris E.
      • Pantes G.V.
      • Gatzonis S.
      • Kapaki E.
      • Davaki P.
      • Lamszus K.
      • Stavrou D.
      • Gal A.
      Novel mutations and repeated findings of mutations in familial Alzheimer disease.
      Thr116AsnYes
      • Sutovsky S.
      • Smolek T.
      • Turcani P.
      • Petrovic R.
      • Brandoburova P.
      • Jadhav S.
      • Novak P.
      • Attems J.
      • Zilka N.
      Neuropathology and biochemistry of early onset familial Alzheimer's disease caused by presenilin-1 missense mutation Thr116Asn.
      Pro117LeuYes
      • Szpak G.M.
      • Lewandowska E.
      • Wierzba-Bobrowicz T.
      • Bertrand E.
      • Pasennik E.
      • Mendel T.
      • Stepień T.
      • Leszczyńska A.
      • Rafalowska J.
      Small cerebral vessel disease in familial amyloid and non-amyloid angiopathies: FAD-PS-1 (P117L) mutation and CADASIL. Immunohistochemical and ultrastructural studies.
      Glu120GlyYes
      • Lladó A.
      • Sánchez-Valle R.
      • Rey M.J.
      • Mercadal P.
      • Almenar C.
      • López-Villegas D.
      • Fortea J.
      • Molinuevo J.L.
      [New mutation in the PSEN1 (E120G) gene associated with early onset Alzheimer's disease]. Spanish.
      Asn135TyrYes
      • Natelson Love M.
      • Clark D.G.
      • Cochran J.N.
      • Den Beste K.A.
      • Geldmacher D.S.
      • Benzinger T.L.
      • Gordon B.A.
      • Morris J.C.
      • Bateman R.J.
      • Roberson E.D.
      Clinical, imaging, pathological, and biochemical characterization of a novel presenilin 1 mutation (N135Y) causing Alzheimer's disease.
      Met139ValYes
      • Arber C.
      • Lovejoy C.
      • Harris L.
      • Willumsen N.
      • Alatza A.
      • Casey J.M.
      • Lines G.
      • Kerins C.
      • Mueller A.K.
      • Zetterberg H.
      • Hardy J.
      • Ryan N.S.
      • Fox N.C.
      • Lashley T.
      • Wray S.
      Familial Alzheimer's disease mutations in PSEN1 lead to premature human stem cell neurogenesis.
      Ile143MetYesCAA prominent in meningeal vessels
      • Heckmann J.M.
      • Low W.C.
      • de Villiers C.
      • Rutherfoord S.
      • Vorster A.
      • Rao H.
      • Morris C.M.
      • Ramesar R.S.
      • Kalaria R.N.
      Novel presenilin 1 mutation with profound neurofibrillary pathology in an indigenous Southern African family with early-onset Alzheimer's disease.
      Ile143ValYes
      • Gallo M.
      • Marcello N.
      • Curcio S.A.
      • Colao R.
      • Geracitano S.
      • Bernardi L.
      • Anfossi M.
      • Puccio G.
      • Frangipane F.
      • Clodomiro A.
      • Mirabelli M.
      • Vasso F.
      • Smirne N.
      • Muraca G.
      • Di Lorenzo R.
      • Maletta R.
      • Ghidoni E.
      • Bugiani O.
      • Tagliavini F.
      • Giaccone G.
      • Bruni A.C.
      A novel pathogenic PSEN1 mutation in a family with Alzheimer's disease: phenotypical and neuropathological features.
      Leu174MetYes
      • Bertoli Avella A.M.
      • Marcheco Teruel B.
      • Llibre Rodriguez J.J.
      • Gomez Viera N.
      • Borrajero Martinez I.
      • Severijnen E.A.
      • Joosse M.
      • van Duijn C.M.
      • Heredero Baute L.
      • Heutink P.
      A novel presenilin 1 mutation (L174 M) in a large Cuban family with early onset Alzheimer disease.
      Glu184AspYes
      • Yasuda M.
      • Maeda K.
      • Ikejiri Y.
      • Kawamata T.
      • Kuroda S.
      • Tanaka C.
      A novel missense mutation in the presenilin-1 gene in a familial Alzheimer's disease pedigree with abundant amyloid angiopathy.
      Ile202PheYes
      • Ryan N.S.
      • Lashley T.
      • Revesz T.
      • Dantu K.
      • Fox N.C.
      • Morris H.R.
      Spontaneous ARIA (amyloid-related imaging abnormalities) and cerebral amyloid angiopathy related inflammation in presenilin 1-associated familial Alzheimer's disease.
      Gly217AspYes
      • Takao M.
      • Ghetti B.
      • Hayakawa I.
      • Ikeda E.
      • Fukuuchi Y.
      • Miravalle L.
      • Piccardo P.
      • Murrell J.R.
      • Glazier B.S.
      • Koto A.
      A novel mutation (G217D) in the Presenilin 1 gene (PSEN1) in a Japanese family: presenile dementia and parkinsonism are associated with cotton wool plaques in the cortex and striatum.
      Leu219ProYes
      • Smith M.J.
      • Gardner R.J.
      • Knight M.A.
      • Forrest S.M.
      • Beyreuther K.
      • Storey E.
      • McLean C.A.
      • Cotton R.G.
      • Cappal R.
      • Masters C.L.
      Early-onset Alzheimer's disease caused by a novel mutation at codon 219 of the presenilin-1 gene.
      Aal260Gly
      Magnetic resonance imaging positive for microbleeds suggests likely CAA (compare Figure 1B, images 5 and 6).
      ?
      • Piaceri I.
      • Chiari A.
      • Galli C.
      • Bagnoli S.
      • Ferrari C.
      • Saavedra S.T.
      • Molinari M.A.
      • Vinceti G.
      • Sorbi S.
      • Nacmias B.
      Incomplete penetrance in familial Alzheimer's disease with PSEN1 Ala260Gly mutation.
      Val261PheYes
      • Farlow M.R.
      • Murrell J.R.
      • Hulette C.M.
      • Ghetti B.
      Hereditary lateral sclerosis and Alzheimer disease associated with mutation at codon 261 of the presenilin 1 (PS1) gene.
      Gly266SerYes
      • Akatsu H.
      • Yamagata H.
      • Wake A.
      • Watanabe I.
      • Kimura N.
      • Kamada K.
      • Miyazaki T.
      • Tanabe H.
      • Miki T.
      • Yamamoto T.
      • Hori A.
      • Mimuro M.
      • Yoshida M.
      • Hashizume Y.
      The first autopsy case report of familial Alzheimer's disease (AD) associated with a mutation at G266S in the presenilin 1 (PSEN1) gene.
      Pro267AlaYes
      • Ringman J.M.
      • Monsell S.
      • Ng D.W.
      • Zhou Y.
      • Nguyen A.
      • Coppola G.
      • Van Berlo V.
      • Mendez M.F.
      • Tung S.
      • Weintraub S.
      • Mesulam M.-M.
      • Bigio E.H.
      • Gitelman D.R.
      • Fisher-Hubbard A.O.
      • Albin R.L.
      • Vinters H.V.
      Neuropathology of autosomal dominant Alzheimer disease in the National Alzheimer Coordinating Center database.
      Leu268ProYes
      • Sánchez-Valle R.
      • Lladó A.
      • Ezquerra M.
      • Rey M.J.
      • Rami L.
      • Molinuevo J.L.
      A novel mutation in the PSEN1 gene (L286P) associated with familial early-onset dementia of Alzheimer type and lobar haematomas.
      Arg269HisYes
      • Gómez-Isla T.
      • Wasco W.
      • Pettingell W.P.
      • Gurubhagavatula S.
      • Schmidt S.D.
      • Jondro P.D.
      • McNamara M.
      • Rodes L.A.
      • DiBlasi T.
      • Growdon W.B.
      • Seubert P.
      • Schenk D.
      • Growdon J.H.
      • Hyman B.T.
      • Tanzi R.E.
      A novel presenilin-1 mutation: increased beta-amyloid and neurofibrillary changes.
      Leu271ValYes
      • Kwok J.B.
      • Halliday G.M.
      • Brooks W.S.
      • Dolios G.
      • Laudon H.
      • Murayama O.
      • Hallupp M.
      • Badenhop R.F.
      • Vickers J.
      • Wang R.
      • Naslund J.
      • Takashima A.
      • Gandy S.E.
      • Schofield P.R.
      Presenilin-1 mutation L271V results in altered exon 8 splicing and Alzheimer's disease with non-cored plaques and no neuritic dystrophy.
      Val272AlaYes
      • Jimenez-Escrig A.
      • Rabano A.
      • Guerrero C.
      • Simon J.
      • Barquero M.S.
      • Güell I.
      • Ginestal R.C.
      • Montero T.
      • Orensanz L.
      New V272A presenilin 1 mutation with very early onset subcortical dementia and parkinsonism.
      Arg278IleYes
      • Arber C.
      • Lovejoy C.
      • Harris L.
      • Willumsen N.
      • Alatza A.
      • Casey J.M.
      • Lines G.
      • Kerins C.
      • Mueller A.K.
      • Zetterberg H.
      • Hardy J.
      • Ryan N.S.
      • Fox N.C.
      • Lashley T.
      • Wray S.
      Familial Alzheimer's disease mutations in PSEN1 lead to premature human stem cell neurogenesis.
      Glu280AlaYesPaisa mutation
      • Dinkel F.
      • Trujillo-Rodriguez D.
      • Villegas A.
      • Streffer J.
      • Mercken M.
      • Lopera F.
      • Glatzel M.
      • Sepulveda-Falla D.
      Decreased deposition of beta-amyloid 1-38 and increased deposition of beta-amyloid 1-42 in brain tissue of Presenilin-1 E280A familial Alzheimer's disease patients.
      GluE280GlyYes
      • O'Riordan S.
      • McMonagle P.
      • Janssen J.C.
      • Fox N.C.
      • Farrell M.
      • Collinge J.
      • Rossor M.N.
      • Hutchinson M.
      Presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI white-matter abnormalities.
      Leu282ValYes
      • Dermaut B.
      • Kumar-Singh S.
      • De Jonghe C.
      • Cruts M.
      • Lofgren A.
      • Lubke U.
      • Cras P.
      • Dom R.
      • De Deyn P.P.
      • Martin J.J.
      • Van Broeckhoven C.
      Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease due to a novel presenilin 1 mutation.
      Pro284LeuYes
      • Bagyinszky E.
      • Youn Y.C.
      • An S.S.
      • Kim S.
      Mutations, associated with early-onset Alzheimer's disease, discovered in Asian countries.
      Leu286ProYes
      • Sánchez-Valle R.
      • Lladó A.
      • Ezquerra M.
      • Rey M.J.
      • Rami L.
      • Molinuevo J.L.
      A novel mutation in the PSEN1 gene (L286P) associated with familial early-onset dementia of Alzheimer type and lobar haematomas.
      Ser290CysYesThr291_Ser319del (ΔAla9, Δ9)
      • Crook R.
      • Verkkoniemi A.
      • Perez-Tur J.
      • Mehta N.
      • Baker M.
      • Houlden H.
      • Farrer M.
      • Hutton M.
      • Lincoln S.
      • Hardy J.
      • Gwinn K.
      • Somer M.
      • Paetau A.
      • Kalimo H.
      • Ylikoski R.
      • Poyhonen M.
      • Kucera S.
      • Haltia M.
      A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1.
      Gly378GluYes
      • Finckh U.
      • Kuschel C.
      • Anagnostouli M.
      • Patsouris E.
      • Pantes G.V.
      • Gatzonis S.
      • Kapaki E.
      • Davaki P.
      • Lamszus K.
      • Stavrou D.
      • Gal A.
      Novel mutations and repeated findings of mutations in familial Alzheimer disease.
      Leu392ValYes
      • Bagyinszky E.
      • Youn Y.C.
      • An S.S.
      • Kim S.
      Mutations, associated with early-onset Alzheimer's disease, discovered in Asian countries.
      Asn405SerYes
      • Yasuda M.
      • Maeda S.
      • Kawamata T.
      • Tamaoka A.
      • Yamamoto Y.
      • Kuroda S.
      • Maeda K.
      • Tanaka C.
      Novel presenilin-1 mutation with widespread cortical amyloid deposition but limited cerebral amyloid angiopathy.
      Gly417SerYes
      • Miki T.
      • Yokota O.
      • Haraguchi T.
      • Ikeuchi T.
      • Zhu B.
      • Takenoshita S.
      • Terada S.
      • Yamada N.
      Young adult-onset, very slowly progressive cognitive decline with spastic paraparesis in Alzheimer's disease with cotton wool plaques due to a novel presenilin1 G417S mutation.
      Ala431ValYes
      • Bagyinszky E.
      • Youn Y.C.
      • An S.S.
      • Kim S.
      Mutations, associated with early-onset Alzheimer's disease, discovered in Asian countries.
      Thr440delYes
      • Ishikawa A.
      • Piao Y.S.
      • Miyashita A.
      • Kuwano R.
      • Onodera O.
      • Ohtake H.
      • Suzuki M.
      • Nishizawa M.
      • Takahashi H.
      A mutant PSEN1 causes dementia with Lewy bodies and variant Alzheimer's disease.
      PSEN2Aal85ValYes
      • Piscopo P.
      • Marcon G.
      • Piras M.R.
      • Crestini A.
      • Campeggi L.M.
      • Deiana E.
      • Cherchi R.
      • Tanda F.
      • Deplano A.
      • Vanacore N.
      • Tagliavini F.
      • Pocchiari M.
      • Giaccone G.
      • Confaloni A.
      A novel PSEN2 mutation associated with a peculiar phenotype.
      Lys115GlufsYes
      • Braggin J.E.
      • Bucks S.A.
      • Course M.M.
      • Smith C.L.
      • Sopher B.
      • Osnis L.
      • Shuey K.D.
      • Domoto-Reilly K.
      • Caso C.
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      Asn141IleYesVolga German mutation
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      Leu221ThrYes
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      Case report of a 63-year-old patient with Alzheimer disease and a novel presenilin 2 mutation.
      AD, Alzheimer disease; APP, amyloid precursor protein; CAA, cerebral amyloid angiopathy; PSEN1, presenilin 1; PSEN2, presenilin 2; WM, white matter.
      Genotypes of different mutations per original references derived from the Alzforum Database (http://www.alzforum.org/mutations, last accessed January 15, 2021).
      Presence of variable degrees of CAA predominantly in cortical regions.
      Presence or absence of CAA in various transgenic mouse models and features noted in case reports.
      § References include citations of four abstracts.
      Magnetic resonance imaging positive for microbleeds suggests likely CAA (compare Figure 1B, images 5 and 6).
      First case in Argentina with APP Ala171Thr mutation showing marked vascular pathology.
      • Suarez M.C.F.
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      • Russo G.
      Heterozygous APP A713T mutation carrier with inflammatoy amyloid angiopathy and family history of Alzheimer's disease: first case in Argentina.
      In sporadic AD, CAA is more common in individuals with infarction and hemorrhages, and is also recognized as an independent factor for severe cognitive impairment and dementia. SVD pathology in CAA is characterized by progressive segmental arteriolosclerosis involving the medial-adventitial layers of intracranial arteries. Of the two types of CAA, Type I is associated with capillaries implicating focal BBB damage. Pathologic studies have shown variable patterns of CAA between early-onset and late-onset AD; Type I CAA is more common and more severe in APP duplication and missense mutations and in Down's syndrome compared with those in sporadic early- and late-onset AD.
      • Mann D.M.A.
      • Davidson Y.S.
      • Robinson A.C.
      • Allen N.
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      • Richardson A.
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      Patterns and severity of vascular amyloid in Alzheimer's disease associated with duplications and missense mutations in APP gene, Down syndrome and sporadic Alzheimer's disease.
      That CAA plays a role in the pathogenesis of microvascular lesions is important,
      • Kovari E.
      • Herrmann F.R.
      • Hof P.R.
      • Bouras C.
      The relationship between cerebral amyloid angiopathy and cortical microinfarcts in brain ageing and Alzheimer's disease.
      ,
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      • Fujita Y.
      • Ito H.
      • Takahashi R.
      • Tomimoto H.
      Cortical microinfarcts in Alzheimer's disease and subcortical vascular dementia.
      but it is not the only factor, implying that even in familial AD, microvessels may undergo age-related changes prior to the appearance of CAA and independent of Aβ accumulation.
      • Weller R.O.
      • Hawkes C.A.
      • Kalaria R.N.
      • Werring D.J.
      • Carare R.O.
      White matter changes in dementia: role of impaired drainage of interstitial fluid.
      For example, cerebral hypoperfusion associated with WM damage accelerates CAA and promotes cortical microinfarcts.
      • Okamoto Y.
      • Yamamoto T.
      • Kalaria R.N.
      • Senzaki H.
      • Maki T.
      • Hase Y.
      • Kitamura A.
      • Washida K.
      • Yamada M.
      • Ito H.
      • Tomimoto H.
      • Takahashi R.
      • Ihara M.
      Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts.
      In early-onset autosomal-dominantly inherited AD patients, ischemic WM changes can be detected at least 2 decades before the development of dementia. The Dominantly Inherited Alzheimer Network (DIAN) study indicated that mutation carriers had greater total WMH volumes, which appeared to increase approximately 6 years prior to expected symptom onset.
      • Lee S.
      • Viqar F.
      • Zimmerman M.E.
      • Narkhede A.
      • Tosto G.
      • Benzinger T.L.
      • Marcus D.S.
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      • Holtzman D.M.
      • Buckles V.
      • Ghetti B.
      • McDade E.
      • Martins R.N.
      • Saykin A.J.
      • Masters C.L.
      • Ringman J.M.
      • Ryan N.S.
      • Forster S.
      • Laske C.
      • Schofield P.R.
      • Sperling R.A.
      • Salloway S.
      • Correia S.
      • Jack Jr., C.
      • Weiner M.
      • Bateman R.J.
      • Morris J.C.
      • Mayeux R.
      • Brickman A.M.
      Dominantly Inherited Alzheimer Network
      White matter hyperintensities are a core feature of Alzheimer's disease: evidence from the Dominantly Inherited Alzheimer Network.
      Given the propensity for a posterior distribution of WMH, CAA, which tends to be more prominent in the occipital lobe, was thought to be one of the mediating factors. These findings suggest that WMH are an essential feature of AD and should be incorporated into the biomarker model and a potential therapeutic target.
      • Lee S.
      • Viqar F.
      • Zimmerman M.E.
      • Narkhede A.
      • Tosto G.
      • Benzinger T.L.
      • Marcus D.S.
      • Fagan A.M.
      • Goate A.
      • Fox N.C.
      • Cairns N.J.
      • Holtzman D.M.
      • Buckles V.
      • Ghetti B.
      • McDade E.
      • Martins R.N.
      • Saykin A.J.
      • Masters C.L.
      • Ringman J.M.
      • Ryan N.S.
      • Forster S.
      • Laske C.
      • Schofield P.R.
      • Sperling R.A.
      • Salloway S.
      • Correia S.
      • Jack Jr., C.
      • Weiner M.
      • Bateman R.J.
      • Morris J.C.
      • Mayeux R.
      • Brickman A.M.
      Dominantly Inherited Alzheimer Network
      White matter hyperintensities are a core feature of Alzheimer's disease: evidence from the Dominantly Inherited Alzheimer Network.
      ,
      • Lee S.
      • Zimmerman M.E.
      • Narkhede A.
      • Nasrabady S.E.
      • Tosto G.
      • Meier I.B.
      • Benzinger T.L.S.
      • Marcus D.S.
      • Fagan A.M.
      • Fox N.C.
      • Cairns N.J.
      • Holtzman D.M.
      • Buckles V.
      • Ghetti B.
      • McDade E.
      • Martins R.N.
      • Saykin A.J.
      • Masters C.L.
      • Ringman J.M.
      • Frster S.
      • Schofield P.R.
      • Sperling R.A.
      • Johnson K.A.
      • Chhatwal J.P.
      • Salloway S.
      • Correia S.
      • Jack Jr., C.R.
      • Weiner M.
      • Bateman R.J.
      • Morris J.C.
      • Mayeux R.
      • Brickman A.M.
      Dominantly Inherited Alzheimer Network
      White matter hyperintensities and the mediating role of cerebral amyloid angiopathy in dominantly-inherited Alzheimer's disease.
      Besides posterior dominant WMH, the radiological features of CAA include lobar microbleeds, dilated perivascular spaces, and multiple areas of superficial siderosis (Figure 1). Mutation carriers are more likely to have cerebral microbleeds than noncarriers, and patients with microbleeds have higher WMH volumes. Although there is some codependency between WMH and microbleeds, these observations highlight that WMH represents a core feature of AD independent of vascular forms of Aβ.
      • Lee S.
      • Zimmerman M.E.
      • Narkhede A.
      • Nasrabady S.E.
      • Tosto G.
      • Meier I.B.
      • Benzinger T.L.S.
      • Marcus D.S.
      • Fagan A.M.
      • Fox N.C.
      • Cairns N.J.
      • Holtzman D.M.
      • Buckles V.
      • Ghetti B.
      • McDade E.
      • Martins R.N.
      • Saykin A.J.
      • Masters C.L.
      • Ringman J.M.
      • Frster S.
      • Schofield P.R.
      • Sperling R.A.
      • Johnson K.A.
      • Chhatwal J.P.
      • Salloway S.
      • Correia S.
      • Jack Jr., C.R.
      • Weiner M.
      • Bateman R.J.
      • Morris J.C.
      • Mayeux R.
      • Brickman A.M.
      Dominantly Inherited Alzheimer Network
      White matter hyperintensities and the mediating role of cerebral amyloid angiopathy in dominantly-inherited Alzheimer's disease.
      In another imaging study, the peak skeletonized mean diffusivity, a measure of cerebral WM microstructural disruption as a simple marker of diffuse global WM heterogeneity, was increased in CAA suggesting a role for WM disruption in causing cognitive impairment in CAA.
      • McCreary C.R.
      • Beaudin A.E.
      • Subotic A.
      • Zwiers A.M.
      • Alvarez A.
      • Charlton A.
      • Goodyear B.G.
      • Frayne R.
      • Smith E.E.
      Cross-sectional and longitudinal differences in peak skeletonized white matter mean diffusivity in cerebral amyloid angiopathy.

      Conclusions and Future Directions

      There is a wealth of evidence from neuroimaging and pathologic studies demonstrating that various features of cerebral SVD are inherent to the AD continuum. The presence of greater burdens of SVD pathology in normal aging are evident, not only in late-onset AD, but also in mutation carriers with familial AD. Thus, vascular brain injury and consequent tissue changes in both grey matter and WM, particularly in the latter, are the norm rather than the exception. It is further apparent that vascular lesions or SVD modify the progression of disease and increase the odds of dementia (Figure 3). Hypertension-induced arteriosclerotic disease is an important index in AD as is CAA, which is irrefutably conditional to age-related changes in the cerebral intracranial vasculature. It is thought that vascular brain injury occurs concomitantly with neurodegenerative changes and that these are parallel processes without much mechanistic interaction between them. The fallacy of this argument is that in many studies, vascular brain injury used as a surrogate for SVD is assessed by overt lesions, such as infarcts,
      • Kalaria R.N.
      Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer's disease.
      evident both radiologically and pathologically. However, it is more likely that clinically silent lesions or covert changes characteristic of SVD contribute to precipitate AD type of pathology over long periods of time (Figure 3). Robust proof of this and of vascular risk factors including history of hypertension increasing the burden of Aβ or neurofibrillary pathology are generally lacking. It is plausible that some of the evidence is confounded by selection bias of participants whose vascular risk factors are well-controlled, and markers of SVD such as WMH may not be evident in those at risk.
      • Ramirez J.
      • McNeely A.A.
      • Scott C.J.M.
      • Masellis M.
      • Black S.E.
      Alzheimer's Disease Neuroimaging Initiative
      White matter hyperintensity burden in elderly cohort studies: the Sunnybrook Dementia Study, Alzheimer's Disease Neuroimaging Initiative, and Three-City Study.
      However, such evidence can be derived from large, comprehensive, prospectively followed longitudinal studies where SVD features including indices assessing BBB damage
      • Nation D.A.
      • Sweeney M.D.
      • Montagne A.
      • Sagare A.P.
      • D'Orazio L.M.
      • Pachicano M.
      • Sepehrband F.
      • Nelson A.R.
      • Buennagel D.P.
      • Harrington M.G.
      • Benzinger T.L.S.
      • Fagan A.M.
      • Ringman J.M.
      • Schneider L.S.
      • Morris J.C.
      • Chui H.C.
      • Law M.
      • Toga A.W.
      • Zlokovic B.V.
      Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction.
      are carefully monitored in both individuals at risk and those in the early stages of clinical disease. Evidence of early SVD and WM damage in familial AD reinforces the certainty of AD as a multifactorial disorder. From this perspective, it is conceivable that the presence of SVD is either part of the pathologic processes that lead to AD, or that in some patients, SVD coexists with some other possible AD trigger, lowering the threshold for cognitive dysfunction and eventual dementia. It is probable that other cellular effects of familial AD mutations independent of Aβ deposition also contribute to early SVD in familial AD cases (Figure 3). In the absence of any strong support for therapeutic approaches that lower Aβ deposition or reduce neurofibrillary pathology, it is timely to strongly implement therapeutic and preventative measures that improve or retain functional properties of cerebral small vessels in the context of AD pathologies including CAA.
      Figure thumbnail gr3
      Figure 3Proposed modification of risk factors and biomarkers of AD in older age. Early changes include vascular disease factors associated with SVD in the progression of AD. SVD incorporates covert vascular brain injury including arteriolosclerosis in the early phase that may alter cerebral perfusion to cause WM changes and lead to the recognized biomarkers of AD. Fluctuations in CBF, blood pressure variability, perfusion pressure, PWV, and BBB damage may contribute to prodromal stages in the AD continuum. Vascular factors increase conversion of mild cognitive impairment (MCI) to dementia in the form of frank or clinical AD. These changes also promote changes in CSF and brain Aβ and tau pathophysiology. The y axis represents increasing severity or accumulation of the biomarkers. The horizontal dashed line represents lower threshold changes in markers with minimal impact on clinical symptoms. Neurodegeneration is depicted as a late phase, but it is likely that tissue atrophy occurs concomitantly or as a consequence of SVD or small infarct pathology.
      • Kalaria R.N.
      Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer's disease.
      Aβ, amyloid β protein; AD, Alzheimer disease; BBB, blood-brain barrier; CBF, cerebral blood flow; CSF, cerebrospinal fluid; Max, maximum; Min, minimum; PVW, pulse wave velocity; SVD, small vessel disease; WM, white matter.

      Acknowledgments

      We thank Drs. Yumi Yamamoto and Yoshiki Hase for their help with some images in Figures 1 and 2.

      Author Contributions

      Both authors critically revised the manuscript for important intellectual content and approved the final version of the manuscript for submission.

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