Interaction between Alzheimer’s Disease and Cerebral Small Vessel Disease: A Review Focused on Neuroimaging Markers

Alzheimer’s disease (AD) is characterized by the presence of β-amyloid (Aβ) and tau, and subcortical vascular cognitive impairment (SVCI) is characterized by cerebral small vessel disease (CSVD). They are the most common causes of cognitive impairment in the elderly population. Concurrent CSVD burden is more commonly observed in AD-type dementia than in other neurodegenerative diseases. Recent developments in Aβ and tau positron emission tomography (PET) have enabled the investigation of the relationship between AD biomarkers and CSVD in vivo. In this review, we focus on the interaction between AD and CSVD markers and the clinical effects of these two markers based on molecular imaging studies. First, we cover the frequency of AD imaging markers, including Aβ and tau, in patients with SVCI. Second, we discuss the relationship between AD and CSVD markers and the potential distinct pathobiology of AD markers in SVCI compared to AD-type dementia. Next, we discuss the clinical effects of AD and CSVD markers in SVCI, and hemorrhagic markers in cerebral amyloid angiopathy. Finally, this review provides both the current challenges and future perspectives for SVCI.


Introduction
Dementia is a progressive and deteriorative syndrome that affects memory and other cognitive domains, which interferes with a daily living [1]. Alzheimer's disease (AD) and vascular dementia (VaD) are the two most common causes of dementia in the elderly [2]. AD is characterized by senile plaques formed by β-amyloid (Aβ) and neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau. These changes, along with loss of neurons, contribute to the symptoms of dementia [3]. Based on these core AD pathological features, including Aβ [A], tau [T], and neurodegeneration [N] biomarkers, the National Institute on Aging-Alzheimer's Association (NIA-AA) proposed the AT(N) classification system [4]. A and T biomarkers are specific for the Aβ plaques and tau NFTs that constitute the hallmark neuropathologic signs of AD, respectively, while biomarkers of (N) (such as atrophy on magnetic resonance imaging, MRI) are not disease specific [4,5]. Brain atrophy is indicative (MCI) both show Aβ positivity on PET [43,44]. According to a previous study, tau PET positivity in the temporal region has been shown to be 6.1% for cognitively normal individuals, 46.5% for MCI, and 88.6% for AD-type dementia [45]. Tracers for paired helical filament tau have also been reported to correspond to Braak's pathological NFT stage and to be correlated with disease severity and symptom progression [46][47][48]. However, compared to AD, there has been relatively little interest in research using molecular imaging for SVCI.
In this review, we discuss the interaction between AD and CSVD biomarkers and the clinical effects of these two biomarkers using molecular imaging studies. More specifically, we discuss the following topics: (1) the frequency of AD imaging markers, including Aβ and tau in SVCI patients; (2) the relationship between AD markers and CSVD burdens; (3) potential distinct pathobiology of AD markers in SVCI compared to AD-type dementia; (4) the clinical effects of AD and CSVD markers in SVCI; (5) hemorrhagic markers in CAA and the clinical effects; and (6) current challenges and future perspectives.

Correlation between AD and CSVD Imaging Markers
Molecular imaging studies have enabled us to investigate the relationship between AD markers and CSVD MRI markers throughout the whole brain. There is increasing evidence from these studies showing that AD marker uptake is correlated with WMH volume, which is a characteristic MRI marker of CSVD. This has been observed prominently in the posterior regions of the brain. In our previous study of 53 SVCI patients, a relationship between Aβ uptake and WMH volume was observed in APOE4 non-carriers [53]. WMH volume is correlated with Aβ uptake in the posterior cerebral regions. Another study using clustering analyses classified SVCI patients and AD patients into the Aβ occipital-predominant and Aβ occipital-sparing groups. The frequency of the occipital-predominant group has been shown to be higher in SVCI patients (62.2%) than in AD patients (37.8%) [33]. Furthermore, the Aβ spreading pattern in patients with SVCI is quite different from in patients with ADCI. Specifically, the Aβ spreading pattern of patients with SVCI demonstrates that Aβ accumulates in the occipital area before the temporal and frontal regions, whereas in patients with ADCI, the parietal and fronto-temporal regions precede the occipital region. (Figure 1a) [33,[54][55][56][57]. The predominant Aβ deposition in the occipital region, mainly observed in patients with SVCI, may be related to the distribution pattern of CAA or ischemic vulnerability of the posterior circulation [53]. CAA is primarily found in the occipital region [53,58]. Moreover, ischemic injury and dysfunction of the endothelial layer may lead to disruption of the blood-brain barrier (BBB), which in turn leads to the deposition of Aβ. Since the vertebrobasilar system, which is responsible for the posterior circulation, may be vulnerable to ischemia, SVCI patients may show Aβ deposition primarily in the posterior region [53]. Figure 1a illustrates the spreading pattern of Aβ in AD, compared with that in SVCI. Interestingly, the Aβ spreading pattern in patients with ADCI developed using molecular imaging evidence seems to be different from that based on pathological studies. That is, a pathologic study conducted by Braak and Braak showed an early pattern of Aβ deposits in the basal parts of the frontal, temporal, and occipital lobes (Stage A) [46,59]. However, several molecular imaging studies suggest that there are diverse early Aβ accumulating regions such as the precuneus, posterior cingulate, isthmus cingulate, insula, and medial and lateral orbitofrontal cortices, in which several of the core regions of the default mode network are located [60][61][62].
In terms of the relationship between CSVD and tau, previous studies have suggested that ischemia might increase tau burdens regardless of the amyloid pathway [63]. Animal studies have also shown an association between increased cerebrovascular pathology and tau formation [64]. In vivo imaging studies have shown that CSVD burden may be associated with higher tau accumulation in the inferior temporal regions regardless of Aβ positivity [65]. Furthermore, in terms of tau spreading order, patients with SVCI are quite different from patients with ADCI. Unlike in ADCI, tau accumulates earlier in the fusiform gyrus and inferior temporal gyrus than in the parahippocampal cortex in SVCI (Figure 1b) [65,66]. . In the order of spreading Aβ in SVCI, unlike AD, Aβ accumulates in the occipital area before the temporal and frontal regions. In contrast to AD, tau accumulates in the fusiform gyrus and inferior temporal gyrus before the parahippocampal cortex in SVCI patients. Aβ-β-amyloid; SVCI-subcortical vascular cognitive impairment; AD-Alzheimer's disease.
In terms of the relationship between CSVD and tau, previous studies have suggested that ischemia might increase tau burdens regardless of the amyloid pathway [63]. Animal studies have also shown an association between increased cerebrovascular pathology and tau formation [64]. In vivo imaging studies have shown that CSVD burden may be associated with higher tau accumulation in the inferior temporal regions regardless of Aβ positivity [65]. Furthermore, in terms of tau spreading order, patients with SVCI are quite different from patients with ADCI. Unlike in ADCI, tau accumulates earlier in the fusiform gyrus and inferior temporal gyrus than in the parahippocampal cortex in SVCI ( Figure 1b) [65,66].

Potential Distinct Pathobiology of AD Markers in SVCI
Considering that SVCI and ADCI patients show different spreading patterns of AD imaging markers, there may be differences in the potential pathobiology of AD biomarkers between SVCI and ADCI patients. In patients with SVCI, vascular risk factors may lead to Aβ deposition. Several cohort studies have reported an association between vascular risk factors and Aβ deposition (Table 1) [67][68][69][70][71][72]. This Aβ deposition is increased by impaired Aβ clearance via a deficit in perivascular drainage of Aβ and breakdown of the BBB ( Figure 2) [73,74]. BBB breakdown causes faulty transport of Aβ through reduced levels of low-density lipoprotein receptor-related protein 1 (LRP1) and increased levels of receptor for advanced glycation end products (RAGE). These changes eventually lead to impaired clearance of toxic Aβ species [75,76]. Furthermore, Aβ accelerates the tau hyperphosphorylation by mediating the activation of protein kinases, including cyclindependent kinase 5 (CDK-5) and glycogen synthase kinase 3β (GSK-3β) [77,78]. In addition, Aβ induces the activation of caspase-3 and calpain-1 and the cleavage of tau, generating neurotoxic tau fragments ( Figure 2) [79,80]. The link between Aβ and tau aggregation may involve microglial activation [81]. Soluble Aβ oligomers are known to activate microglial cells [82]. Mouse studies on transgenic AD have revealed that the microglial activation precedes tau aggregation [83] and facilitates tau hyperphosphorylation through cytokine release with subsequent NFT formation [84]. There are two potential mechanisms that may explain how vascular risk factors induce tau accumulation. One hypothesis is that ischemia may activate CDK-5 and GSK-3β, resulting in tau phosphorylation [85]. Activation of CDK-5 occurs when ischemia inhibits the pumping of calcium ions out of cells and raises intracellular calcium levels [86,87]. GSK-3β is activated by ischemia through decreased activity of the phosphatidylinositol 3-kinase/Akt pathway [88,89]. Moreover, vascular risk factors and the accumulation of Aβ plaques lead to oxidative stress [90][91][92]. Oxidative stress may also be caused by several mechanisms, such as mitochondrial dysfunction or inflammatory responses [92]. It may manifest as damage to synapses and changes in Ca 2+ homeostasis, resulting in an apoptotic cascade and neurotoxicity [92] (Figure 2). Table 1. Cohort studies investigating the association between vascular risk factors and brain βamyloid deposition.

Study (Country)
Length of the Study

Results
Gottesman et al.  Abbreviations: Standard Deviation-SD; MCI-mild cognitive impairment; HTN-hypertension; DM-diabetes mellitus; BMI-body mass index; TC-total cholesterol; LDL-low-density lipoprotein; SUVR-standardized uptake value ratio; OR-odds ratio; SBP-systolic blood pressure; DBP-diastolic blood pressure; Aβ-βamyloid; DVR-distribution volume ratio; WMH-white matter hyperintensity; PREVENT-AD-Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimer Disease; FSRP-Framingham stroke risk profile; CAIDE-Cardiovascular risk factors, aging and incidence of dementia risk score; ASCVD-Atherosclerotic cardiovascular disease risk estimate from the pooled cohort equation.  Figure 2. Potential mechanism of Aβ and tau deposition in SVCI. The CSVD burden is associated with Aβ and tau deposition in SVCI. Ischemic events can lead to Aβ deposition by reducing Aβ clearance via BBB breakdown or deficits in perivascular drainage of Aβ from the brain interstitial fluid. BBB breakdown causes faulty transport of Aβ by reducing LRP1 levels and increasing RAGE levels, resulting in impaired clearance of toxic Aβ species. Aβ accelerates the tau hyperphosphorylation by mediating the activation of protein kinases, including CDK-5 and GSK-3β. In addition, Aβ induces the activation of caspase-3 and calpain-1, and the cleavage of tau generates neurotoxic tau fragments. The association between Aβ and tau aggregation may involve microglial activation. Soluble Aβ oligomers have been known to activate microglial cells. Microglial activation precedes tau aggregation and facilitates tau hyperphosphorylation through cytokine release and the subsequent NFT formation. Vascular risk factors can also induce tau accumulation. Ischemia caused by vascular injury may activate CDK-5 and GSK-3 β, resulting in tau phosphorylation. Moreover, vascular risk factors and the accumulation of Aβ plaques lead to oxidative stress. Oxidative stress may also be caused by several mechanisms, such as mitochondrial dysfunction or inflammatory responses. It may manifest as damage to synapses and changes in Ca2+ homeostasis, resulting in an apoptotic cascade and neurotoxicity. CSVD-cerebral small vessel disease; Aβ-β-amyloid; BBB-bloodbrain barrier; LRP1-low-density lipoprotein receptor-related protein 1; RAGE-receptor for advanced glycosylation end products; CDK-5-cyclin-dependent kinase 5; GSK-3β-glycogen synthase kinase 3β; NFTs-neurofibrillary tangles; ISF-interstitial fluid; CSF-cerebrospinal fluid; WMH-white matter hyperintensity; BM-basement membrane.

Figure 2.
Potential mechanism of Aβ and tau deposition in SVCI. The CSVD burden is associated with Aβ and tau deposition in SVCI. Ischemic events can lead to Aβ deposition by reducing Aβ clearance via BBB breakdown or deficits in perivascular drainage of Aβ from the brain interstitial fluid. BBB breakdown causes faulty transport of Aβ by reducing LRP1 levels and increasing RAGE levels, resulting in impaired clearance of toxic Aβ species. Aβ accelerates the tau hyperphosphorylation by mediating the activation of protein kinases, including CDK-5 and GSK-3β. In addition, Aβ induces the activation of caspase-3 and calpain-1, and the cleavage of tau generates neurotoxic tau fragments. The association between Aβ and tau aggregation may involve microglial activation. Soluble Aβ oligomers have been known to activate microglial cells. Microglial activation precedes tau aggregation and facilitates tau hyperphosphorylation through cytokine release and the subsequent NFT formation. Vascular risk factors can also induce tau accumulation. Ischemia caused by vascular injury may activate CDK-5 and GSK-3 β, resulting in tau phosphorylation. Moreover, vascular risk factors and the accumulation of Aβ plaques lead to oxidative stress. Oxidative stress may also be caused by several mechanisms, such as mitochondrial dysfunction or inflammatory responses. It may manifest as damage to synapses and changes in Ca 2+ homeostasis, resulting in an apoptotic cascade and neurotoxicity. CSVD-cerebral small vessel disease; Aβ-β-amyloid; BBB-blood-brain barrier; LRP1-low-density lipoprotein receptor-related protein 1; RAGE-receptor for advanced glycosylation end products; CDK-5-cyclin-dependent kinase 5; GSK-3β-glycogen synthase kinase 3β; NFTs-neurofibrillary tangles; ISF-interstitial fluid; CSF-cerebrospinal fluid; WMH-white matter hyperintensity; BM-basement membrane.
Notably, there are distinct effects of APOE genotyping on Aβ deposition between patients with SVCI and ADCI. Specifically, apolipoprotein E4 (APOE4) is a risk factor for Aβ positivity in patients with ADCI and SVCI. Apolipoprotein E2 (APOE2) is a protective factor in ADCI (OR = 0.43); however, it is a risk factor in SVCI (OR = 2.26) [93]. Thus, APOE2 might accelerate apolipoprotein E leakage in the vessel walls of patients with SVCI, which in turn leads to impaired vascular drainage of Aβ. This impaired drainage eventually results in increased Aβ burdens in the brain parenchyma [93]. Alternatively, APOE2 may contribute to the development of CAA, which in turn leads to increased CSVD [93].

Clinical Effects of AD and CSVD Markers in SVCI Patients
There has been some debate related to the clinical effects of Aβ and CSVD imaging markers. In fact, among patients with extensive WMHs, some tend to show severe dementia symptoms, while others have no symptoms. In this regard, our previous studies investigated which imaging markers might affect the clinical features of SVCI and found that AD biomarkers and CSVD independently affect cognition, abnormal behavior, and gait disturbances [29,32,51,65,[94][95][96]. A cross-sectional study has reported that Aβ uptake is only associated with memory dysfunction, whereas CSVD burden is associated with memory, visuospatial, and frontal executive functions [94]. Longitudinal cohort studies have also shown that Aβ positivity is associated with faster cognitive decline in patients with SVaD [51] and higher conversion to dementia in patients with svMCI [32]. In terms of abnormal behavior, Aβ predicts the signs of delusions and irritability, while CSVD burdens are associated with other behavioral symptoms, such as apathy and depression [97]. In addition, periventricular WMHs are the most important predictor of gait disturbances [98].
SVCI patients show distinct brain structural and cognitive trajectories based on AT (Aβ/tau) biomarker profiles [52]. A previous study showed that patients in the A+T+ group predicted a more rapid decline in structural and cognitive trajectories than those in the A+T− group, followed by those in the A−T− group [52]. Moreover, AD markers and CSVD burden have a synergistic effect on cognitive decline. In a cross-sectional study, significant interactions between WMHs and Aβ uptake were apparent in visuospatial function, suggesting that CSVD and Aβ synergistically affect cognitive impairment [29]. A longitudinal study comparing patients with SVCI and ADCI who had similar tau levels has shown that as Aβ turns positive, SVCI shows a steeper cognitive decline compared to the ADCI group [99]. In addition, as tau levels increase, the SVCI group shows a steeper cognitive decline than the ADCI group [99]. These findings indicate that there are interactive effects between AD markers and CSVD on cognitive decline. Furthermore, Aβ and CSVD affect specific downstream imaging markers, such as network changes and brain atrophy in specific regions, which in turn lead to the development of these corresponding clinical outcomes [32,95,100]. Specifically, Aβ uptake is associated with cortical thinning in the medial temporal regions including hippocampal changes, which in turn leads to memory dysfunction. In contrast, CSVD burdens are primarily associated with frontal thinning [101] and white matter network disruption [95], which in turn leads to frontal dysfunction. In addition, a three-year longitudinal study has shown that time-varying Aβ and CSVD affects the temporoparietal and frontal thinning, respectively, which in turn contributes to the corresponding cognitive decline [32]. Another cross-sectional study has demonstrated that Aβ positivity and CSVD severity are independently associated with higher tau uptake in the medial and inferior temporal regions, respectively [65]. Moreover, increased tau uptake can mediate the relationship between Aβ and CSVD uptake and cognitive impairment, indicating that tau is another important common downstream marker of Aβ and CSVD burdens. The overall mechanisms of SVCI are summarized in Figure 3. can lead to Aβ deposition by impairing Aβ clearance. SVCI is also related to widespread white ter hyperintensities or multiple lacunar infarctions, which have been gradually deposited in su tical regions for several decades. CAA is another factor known to be associated with SVCI. SV subcortical vascular cognitive impairment; APOE-apolipoprotein E; Aβ-β-amyloid; B blood-brain barrier; CAA-cerebral amyloid angiopathy.

Hemorrhagic Markers in Cerebral Amyloid Angiopathy (CAA) and the Clinical Effects
CAA is characterized by Aβ deposition in the small arteries of the meninges and tex, which causes vascular dysfunction and brain injury [102]. CAA is clinically and ologically characterized by lobar intracerebral hemorrhage (ICH), strictly lobar cere microbleeds (CMBs) and cortical superficial siderosis (CSS) [103]. CAA is generall lated to Aβ parenchymal aggregates, such as neuritic and diffuse plaques, although i also occur pathologically without evident AD neuropathological changes [104].
Generally, the anatomical location of CMBs reflects their underlying etiology. Sp ically, deep CMBs are presumed to be due to hypertensive CSVD, whereas lobar C may reflect CAA [105]. In a cross-sectional study, consistent with previous studies uptake has been shown to be associated with lobar CMBs [23]. CSVD is also assoc with lobar CMBs as well as deep CMBs [23]. Aβ uptake and CSVD synergistically a the development of lobar CMB [23]. Furthermore, a longitudinal study demonstrated longitudinal measures of Aβ uptake and lacunes synergistically affect the developme lobar CMBs [69]. According to Thal's CAA pathologic stage, CAA pathology extend quentially from leptomeningeal and cortical vessels to cerebellar vessels and eventu to the striatum and brainstem vessels [106]. Patients with both cerebellar and lobar C are more likely to present with CAA features, whereas deep CMBs, regardless of the p ence of both lobar and cerebellar CMBs, are more likely to represent underlying hy tensive angiopathy than CAA features [107]. Interestingly, restricted superficial cereb CMBs refer to CAA imaging markers, whereas the involvement of the cerebellar den nucleus might be equivalent to deep CMB [107].
Our previous study showed that the frequency of APOE4 was higher in Aβ (+) C than in Aβ (−) CAA, whereas APOE2 was associated with overt hemorrhagic marke CAA, such as lobar ICH and CSS [108]. These findings are consistent with other stu Figure 3. Mechanisms of SVCI. SVCI is caused by various factors, including increasing age, diabetes mellitus, hypertension, genetic predisposition such as APOE ε4 and ε2, and arteriosclerosis. This can lead to Aβ deposition by impairing Aβ clearance. SVCI is also related to widespread white matter hyperintensities or multiple lacunar infarctions, which have been gradually deposited in subcortical regions for several decades. CAA is another factor known to be associated with SVCI. SVCI-subcortical vascular cognitive impairment; APOE-apolipoprotein E; Aβ-β-amyloid; BBBblood-brain barrier; CAA-cerebral amyloid angiopathy.

Hemorrhagic Markers in Cerebral Amyloid Angiopathy (CAA) and the Clinical Effects
CAA is characterized by Aβ deposition in the small arteries of the meninges and cortex, which causes vascular dysfunction and brain injury [102]. CAA is clinically and radiologically characterized by lobar intracerebral hemorrhage (ICH), strictly lobar cerebral microbleeds (CMBs) and cortical superficial siderosis (CSS) [103]. CAA is generally related to Aβ parenchymal aggregates, such as neuritic and diffuse plaques, although it can also occur pathologically without evident AD neuropathological changes [104].
Generally, the anatomical location of CMBs reflects their underlying etiology. Specifically, deep CMBs are presumed to be due to hypertensive CSVD, whereas lobar CMBs may reflect CAA [105]. In a cross-sectional study, consistent with previous studies, Aβ uptake has been shown to be associated with lobar CMBs [23]. CSVD is also associated with lobar CMBs as well as deep CMBs [23]. Aβ uptake and CSVD synergistically affect the development of lobar CMB [23]. Furthermore, a longitudinal study demonstrated that longitudinal measures of Aβ uptake and lacunes synergistically affect the development of lobar CMBs [69]. According to Thal's CAA pathologic stage, CAA pathology extends sequentially from leptomeningeal and cortical vessels to cerebellar vessels and eventually to the striatum and brainstem vessels [106]. Patients with both cerebellar and lobar CMBs are more likely to present with CAA features, whereas deep CMBs, regardless of the presence of both lobar and cerebellar CMBs, are more likely to represent underlying hypertensive angiopathy than CAA features [107]. Interestingly, restricted superficial cerebellar CMBs refer to CAA imaging markers, whereas the involvement of the cerebellar dentate nucleus might be equivalent to deep CMB [107].
Our previous study showed that the frequency of APOE4 was higher in Aβ (+) CAA than in Aβ (−) CAA, whereas APOE2 was associated with overt hemorrhagic markers of CAA, such as lobar ICH and CSS [108]. These findings are consistent with other studies showing that APOE4 is related to the deposition of Aβ burdens [109,110], and APOE 2 is related to the breakdown of blood vessel walls [111]. In addition, the number of lobar CMB and the presence of CSS can predict Aβ (+), whereas ischemic CSVD markers can predict Aβ (−) [108].
A previous study investigating the clinical effects of CAA hemorrhagic markers has shown that multiple lobar CMBs are related to cortical thinning across all cortical regions, and that CSS is associated with frontal thinning, which in turn contributes to the corresponding cognitive decline [112]. Furthermore, path analyses have shown that the relationships between CAA hemorrhagic markers and cognitive impairments are partially mediated by thinning in cortical regions related to specific cognitive impairments [112]. A previous study investigated the clinical outcomes of parenchymal Aβ in patients with CAA, and showed that Aβ (+) CAA shows a steeper decline in multiple cognitive domains (including language, visuospatial, memory, and frontal dysfunctions) than Aβ (−) CAA [108].

Current Challenges and Future Perspectives
In SVCI, numerous potential biomarkers have been discovered using neuroimaging techniques, which were the focus of this review, as well as neuropathological research or genetic testing. These can be grouped broadly into the following categories: clinical biomarkers (neurobehavioral assessment); neuroimaging biomarkers, including WMHs and lacunes; biochemical biomarkers (serum, plasma, and CSF biomarkers); pathological biomarkers; and genetic biomarkers [113,114]. However, due to the lack of specific biomarkers for SVCI, additional extensive research on new biomarkers is necessary. Furthermore, the expansion of the AT(N) system to an ATV(N) framework is recommended [115,116]. Adopting vascular imaging biomarkers will improve the depth and accuracy of biomarker characterization in people along the AD continuum [115][116][117][118].
Research on dementia could further advance by recognizing and incorporating abundant knowledge on therapies to modulate vascular dysfunction and how to prevent and treat vascular illnesses. Treatment strategies for SVCI include slowing the progression of CSVD and improving clinical symptoms. For example, the modification of vascular risk factors, including hypertension and diabetes, has been recommended for the prevention of AD and SVCI [119][120][121][122][123]. Additionally, studying the pathways associated with Aβ deposition in SVCI may offer potential targets for treatment. For instance, strategies include cell-based therapies, which aim to promote the clearance of Aβ through the perivascular drainage pathway and BBB, such as upregulation of LRP1 and blockage of RAGE [124][125][126][127][128]. These strategies may provide important therapeutic applications that prevent the buildup of Aβ in the brain and protect vessels against damage in SVCI.

Conclusions
This review highlights the relationship between AD and SVCI. We focused on the interactions between AD and CSVD markers, potential distinct pathobiology, and clinical effects, based on molecular imaging studies. Therapeutic strategies are needed based on an understanding of the interactions between AD and CSVD markers in SVCI.