Cognition in Cardiovascular Disease

Abstract

Purpose of Review

Acute cerebrovascular events once dominated efforts to protect the brain from cardiovascular disease. As stroke prevention and treatment have advanced, attention has broadened to the more continuous vascular processes that contribute to cognitive decline across later life. This review organizes cardiovascular brain injury by route, direct structural injury versus indirect mediated pathways, and tempo, acute events versus chronic processes, with vessel caliber determining lesion topography.

Recent Findings

Vascular and Alzheimer pathology commonly coexist in older adults with cognitive impairment, and their relationship appears bidirectional but asymmetric: Alzheimer pathology can directly injure the cerebral vasculature, while vascular dysfunction may facilitate Alzheimer pathology and, more clearly, accumulated vascular injury lowers the threshold at which Alzheimer pathology becomes clinically expressed. Covert infarction, microbleeds, white matter disease, and blood-brain barrier disruption accumulate into a cumulative vascular substrate that erodes cognition over decades without requiring a recognized clinical event, and the clinical syndrome follows the lesion, with the subcortical dysexecutive phenotype the modal presentation. Evidence from SPRINT MIND, FINGER, US POINTER, BRAIN-AF, LACI-2, CREST-2, and Mendelian randomization identifies blood pressure control as the best-established intervention, uses discordant and null findings to refine presumed mechanisms, and frames the emerging dilemma of anti-amyloid therapy in patients with substantial vascular disease.

Summary

In the mixed vascular and Alzheimer disease that dominates late-life dementia, the vascular component is often the more modifiable, and cardiovascular risk management remains among the most actionable strategies for preserving cognition.

Introduction

As longevity and survival from chronic disease have increased, cognitive decline and dementia have become increasingly prominent clinical and public-health challenges. An estimated 57.4 million people were living with dementia worldwide in 2019, with prevalence projected to reach 152.8 million by 2050 [1]. Two developments have transformed the clinical response. Disease-modifying therapy for Alzheimer disease has made biological diagnosis a clinical need, and prevention science has shown that a large fraction of dementia is modifiable: the 2024 Lancet Commission estimates that approximately 45% of dementia cases are potentially attributable to fourteen modifiable risk factors, many cardiovascular or cardiometabolic [2].

The bulk of the modifiable risks relate to cardiovascular disease. Protecting the brain from these risks once meant preventing stroke. As stroke prevention and treatment have advanced, attention has broadened to more continuous vascular processes. Illustratively, atrial fibrillation is associated with cognitive decline even without recognized stroke; heart failure produces a fluctuating cognitive fog; hypertension and arterial stiffening injure the cerebral microvasculature over decades; myocardial infarction is followed by cognitive decline that unfolds over years rather than at the event [3]; and treatment itself, from cardiac surgery and transcatheter procedures to anticoagulation, overtreated blood pressure, and accumulating medication burden, can add iatrogenic injury.

Here we organize the review around three propositions:

1. Cardiovascular cognitive injury occurs through distinguishable routes and tempos: direct structural injury, which may be acute or chronic, and indirect mediated pathways, with vessel caliber determining where the lesions land.

2. Repeated covert lesions and chronic microvascular dysfunction accumulate into a cumulative vascular substrate that erodes cognition silently, over years, without requiring any clinical event; the recognized stroke is only the visible part of a much larger vascular burden.

3. In mixed vascular and Alzheimer disease, which dominates late-life dementia, the two pathologies may reinforce one another biologically while vascular injury independently gates the clinical expression of a given Alzheimer burden.

The sections that follow trace these propositions through mechanism, syndrome, evaluation, and treatment, and end with the controversies they generate, including the newly urgent question of anti-amyloid therapy in the patient whose vascular disease has helped bring Alzheimer pathology to clinical expression. These relationships are summarized in Fig. 1. Table 1 summarizes the major cardiovascular conditions considered in this review, their dominant mechanisms, cognitive consequences, evaluation, interventions, and principal uncertainties.

Fig. 1.

Mechanisms of cardiovascular cognitive injury. Direct structural routes (solid) and indirect mediated routes (dashed) converge on the cumulative vascular substrate, which erodes cognition in its own right. Vessel caliber is not a third route; it determines lesion topography. Impaired perivascular clearance is shown as a mechanism upstream of the substrate rather than a component of it. The substrate and Alzheimer pathology may reinforce one another biologically, with asymmetric confidence in the two directions and cerebral amyloid angiopathy as the physical interface; separately, and on firmer evidence, accumulated vascular injury gates the clinical expression of a given Alzheimer burden

Table 1.

Cardiovascular conditions, mechanism, and cognitive consequence

Condition	Dominant mechanism	Cognitive consequence	Key evaluation	Intervention	Key controversy
Chronic hypertension	Chronic direct: pulsatility, endothelial dysfunction, SVD	WMH, lacunes, dysexecutive and slowed-processing decline	Midlife and current BP, orthostatic vitals, MRI SVD markers	BP control, individualized targets	Late-life BP lowering, J-curve, timing of benefit
Atrial fibrillation	Acute direct embolic plus chronic substrate	Overt and covert infarcts, cognitive decline independent of recognized stroke	Rhythm monitoring, MRI for covert infarction, LA structure/function	Anticoagulation when indicated, rate/rhythm control	BRAIN-AF negative; tension with MR mediation through stroke/low CO
Atrial cardiopathy	Mixed direct and indirect	Cognitive decline or embolic risk without documented AF	ECG, rhythm monitoring, LA size/function, emerging biomarkers	Risk-factor treatment; anticoagulation uncertain	Whether atrial disease is causal independent of AF
Heart failure	Chronic direct hypoperfusion plus indirect neurohormonal/inflammatory	Brain fog, slowed processing, attentional and executive dysfunction	EF, HF phenotype, orthostatics, sleep apnea, renal function	GDMT, perfusion optimization, rehabilitation	Reversibility; HFpEF versus HFrEF mechanisms
Coronary disease and MI	Mixed: shared substrate, inflammation, hypoperfusion, procedural injury	Post-MI cognitive change, accelerated long-term decline	Vascular risk profile, delirium screen, cognitive baseline	Secondary prevention, cardiac rehabilitation	Shared burden versus hypoperfusion versus microembolism
Aortic stenosis and TAVR	Chronic hypoperfusion plus acute procedural embolic injury	Pre-procedural impairment; possible improvement or decline after intervention	Echo, frailty/cognition baseline, pre/post neuroimaging	Valve replacement, cerebral embolic protection	Whether intervention improves cognition net of embolic risk
Carotid stenosis	Chronic hypoperfusion plus microembolic injury	Modest contribution to dysexecutive decline	Carotid imaging, cerebral perfusion, cognitive baseline	Intensive medical therapy; revascularization on stroke-risk grounds	CREST-2: no cognitive benefit in asymptomatic stenosis
Cardiac surgery/bypass	Acute direct embolic and hypoperfusion plus delirium	Perioperative neurocognitive disorder, delirium, long-term decline	Baseline cognition, delirium risk, vascular burden	Perfusion/anesthesia management, delirium prevention	Attribution of post-CABG decline versus expected aging
Cardiac arrest	Acute direct hypoxic-ischemic injury	HIE, amnestic and executive deficits	Exam, EEG, MRI, biomarkers, serial neuroprognostication	Post-arrest care, TTM, rehabilitation	Prognostic accuracy and selective regional vulnerability

Foundational Considerations

Conceptual Framework and Nomenclature

Route-Tempo-Caliber Classification

The mechanisms by which cardiovascular disease injures the brain can be understood along two dimensions. The first is the route of injury. Direct injury leaves a structural lesion: infarction, hemorrhage, hypoxic-ischemic damage, white matter disease, microbleeds, disruption of the blood-brain barrier. Indirect injury is mediated by systemic inflammation, neuroendocrine and autonomic dysregulation, and impaired perivascular clearance, which influence brain structure and function without a primary lesion. The direct mechanisms are well-established; many of the indirect mechanisms are biologically plausible but have not been proven in humans to cause cognitive decline independently of the structural injury they accompany. The second dimension is tempo, which divides direct injury into acute events, such as cardioembolic infarction, hemorrhage, and anoxic-ischemic injury, and chronic processes, such as persistent hypoperfusion, pulsatile microvascular injury, barrier breakdown, and progressive white matter disease. Vessel caliber is not a third dimension but a determinant of topography: Large-vessel disease injures gray and white matter along defined arterial territories (Fig. 2), governed by proximal occlusion dynamics [4]. Conversely, small-vessel disease predominantly affects deep white matter and basal ganglia, reflecting the vulnerability of regions supplied by long, non-collateralized perforating arterioles [5, 6].

Fig. 2.

Magnetic resonance angiography co-registered with a coronal T1 image, showing the circle of Willis, the proximal middle cerebral arteries in the Sylvian fissures, and the ascending anterior cerebral vessels

Reinforcement-Gating Framework

Downstream of both routes lies the cumulative vascular substrate: the accumulated burden of covert injury, comprised of silent infarcts, microinfarcts, microbleeds, white matter disease, and blood-brain barrier disruption. Whether accrued as a stepwise series of silent lesions or as a continuous process, the substrate erodes cognition in its own right, silently, over years.

Vascular pathology’s relationship to coexisting Alzheimer disease is captured by the reinforcement-gating framework: vascular and Alzheimer pathology may mutually reinforce one another biologically, while accumulated vascular injury independently gates the clinical expression of a given Alzheimer burden, i.e., vascular injury reduces the threshold for Alzheimer pathology to cause dementia [7–9].

Amyloid Vascular Reinforcement Hypothesis

Two physiological features sit at the base of this hypothesis: glymphatic flow and cerebral amyloid angiopathy. The glymphatic concept proposes that perivascular cerebrospinal fluid (CSF) acts like lymphatics elsewhere to remove large molecules. Experimental work shows that cerebral arterial pulsation contributes to perivascular CSF-interstitial fluid exchange and amyloid-beta clearance [10, 11]; whether age-related arterial stiffening causally impairs this pathway in humans remains less certain. Cerebral amyloid angiopathy (CAA) provides a plausible physical interface between vascular dysfunction and amyloid biology [12]. Cerebral amyloid angiopathy may present without microhemorrhage and be indistinguishable from other forms of white matter disease. The blood-brain barrier normally excludes inflammogenic plasma proteins; when disrupted, fibrinogen can enter the parenchyma and trigger perivascular microglial activation and axonal injury [13], while human imaging demonstrates blood-brain barrier breakdown in aging and cognitive impairment [14]. A single abnormality such as arterial stiffening may therefore express itself as both direct vascular injury and indirect clearance failure. The categories are mechanisms of injury, not diseases.

Perfusion Window and Survival Triage

Cerebral perfusion is held within an autoregulated window (Fig. 3a), and chronic injury arises at both of its extremes: insufficient flow on one side, excess pressure and pulsatile load on the other. Catastrophic circulatory disruptions initiate acute injury, which is completed by a cascade that is not purely hemodynamic: excitotoxicity and spreading depolarizations, edema that can itself compromise perfusion, local inflammation, and cell death ranging from necrosis to programmed death. With sustained low flow, the cell triages short-term survival over long-term maintenance, preserving ionic gradients while relinquishing protein synthesis, repair, and plasticity; [15, 16] the deferred cost of that triage, accruing as “incomplete infarction”, is one way the substrate is built without any clinical event [17, 18].

Fig. 3.

The perfusion window and the cycle that narrows it. a Cerebral blood flow is held constant across the autoregulatory plateau; below the lower limit flow becomes pressure-passive and falls, and above the upper limit pressure breaks through. The dashed curve shows the rightward shift of chronic hypertension, so that pressures normal for others fall below the shifted lower limit. b The self-amplifying cycle of pulsatile injury; each turn stiffens the vessel further, and the cycle exits both into the hypoperfusion arm and, ultimately, into intracerebral hemorrhage

Evidence and Causal Inference

Biases

The evidence linking cardiovascular disease to cognition is largely observational and carries the classic biases of that design:

• Confounding by shared risk: Upstream causes for Alzheimer and vascular pathologies, such as age, vascular risk factors, education, and APOE epsilon4 drive both exposure and outcome [19].

• Reverse causation in its protopathic form: It operates because early, undiagnosed cognitive decline degrades self-care, adherence, and health behavior years before diagnosis [20].

• Measurement confound: Vascular cognitive impairment preferentially affects executive function, attention, and processing speed, domains that brief screening instruments sample poorly, and trial follow-up is short relative to decades of accumulation [21].

• Confounding by indication (and contraindication): The bias cuts both ways, and its scale was demonstrated when the observational cognitive benefit of anticoagulation in atrial fibrillation failed to survive randomization in BRAIN-AF [22].

• Healthy adherence: Current adherence may be a sign of good health-related behavior in the past and thus a difference in phenotype [23].

• Outcome misclassification: This arises from screening instruments insensitive to executive function and processing speed, and from follow-up short relative to the decades over which vascular injury accumulates [24].

Recent Methodological Advances

Three developments have improved the situation: life-course cohorts with serial imaging [25], causal-inference methods including Mendelian randomization and target-trial emulation [26], and mechanistic biology of the neurovascular unit together with plasma biomarkers that allow Alzheimer pathology to be measured rather than assumed [27]. Observational associations should be interpreted through triangulation among longitudinal imaging, randomized trials, and genetic causal inference, and disagreement among these methods is informative rather than something to be averaged away. Where the three converge, as they do for blood pressure, causal confidence is high. Where they diverge, as they currently do for atrial fibrillation, the divergence itself points to the mechanism (see below).

Mechanisms of Brain Injury

Acute Injury

Acute direct injury is well characterized. Ischemic infarctions are brought about by cardioembolism (from atrial fibrillation, left ventricular thrombus, valvular and prosthetic disease, endocarditis, cardiac tumor, and procedures), by large-artery atherosclerosis and arterio-arterial embolism from unstable plaque, and through lacunar infarction from the obstruction of the small penetrating vessels. The loss of access to oxidative metabolism due to obstruction, which is the bulk of the brain’s energy source, causes depolarization of the neuronal plasma membrane, activation of calcium currents, which lead to activation of endonucleases, proteases, and lipases, which then damage the cell [4]. Secondary mechanisms, such as increased intracranial pressure and inflammation, exacerbate the damage to the brain. The cognitive consequences depend on location and network [28] (see Clinical Syndromes).

Atrial fibrillation is the prototypical embolic etiology. It is associated with cognitive decline and dementia seemingly even in patients without recognized stroke [29], which may suggest covert infarction, microembolism, beat-to-beat perfusion variability, inflammation, and a shared atrial-and-vascular substrate as potential contributors. In cohorts with atrial fibrillation, magnetic resonance imaging (MRI) demonstrates a high burden of clinically silent vascular brain lesions and links incident silent infarcts to cognitive decline [30, 31]. Disappointingly, Mendelian randomization complicates this picture by pointing in the opposite direction: it finds genetic liability to atrial fibrillation causally associated with dementia, with mediation running almost entirely through ischemic stroke and low cardiac output and no residual pathway through small vessel disease or brain volume [32], while a second bidirectional analysis finds no signal to vascular dementia at all [33]. The genetics therefore point back toward the embolic and low-output mechanisms that the randomized trials, discussed under management, seemed to disfavor. The most economical reconciliation is temporal: Mendelian randomization integrates lifetime exposure, plausibly operating through decades of accumulated subclinical infarction that a few years of anticoagulation in low-risk patients can neither undo nor measurably prevent, and anticoagulation does nothing for the low-output pathway. Note, the substrate view captures the part of the association unaffected by anticoagulation; it does not deny the role of embolism.

Hemorrhage too contributes at every scale, from symptomatic intracerebral hemorrhage to individually silent microbleeds that count toward the burden of disease, with hemorrhagic transformation, anticoagulation-associated bleeding, and cerebral amyloid angiopathy as recurring clinical contexts. Hemorrhage marks the acute pole of the high-pressure arm of the perfusion window. When pressure acutely overwhelms autoregulation, the result is hypertensive encephalopathy often with vasogenic edema, seen in the posterior reversible encephalopathy syndrome for example. When a chronically remodeled small vessel finally yields under load, the result is intracerebral hemorrhage, the catastrophic endpoint of the remodeling cycle described below [5, 34]. Excess pressure is the predisposing load acting on vulnerable vessel biology rather than the whole mechanism, and aneurysmal subarachnoid hemorrhage, whose proximate cause is rupture of a structural lesion, lies largely outside this framework [35].

Hypoxic-ischemic injury completes the acute category. Cardiac arrest produces selective vulnerability, with delayed neuronal death in areas of high energy consumption, the hippocampal CA1 sector, cortex, and basal ganglia [36]. Watershed injury occurs in parts of the vascular tree farthest from the main cerebral arteries and thus most vulnerable to hypoperfusion [37]. Profound hypotension, shock, arrhythmia, or pulmonary embolism produce watershed or diffuse injury by the same physiology. These lesions are classified as direct because the brain injury is structural regardless of its extracranial origin.

Chronic Injury

Direct Mechanisms

Chronic Hypoperfusion- Short Term Survival at the Expense of Long Term Maintenance Leading to Eventual Failure

Chronic hypoperfusion affects the brain by an accumulation of lesions over time. Heart failure is the paradigm: patients describe a cognitive fog that tracks hemodynamic status, and the mechanisms differ by phenotype, with reduced cardiac output driving cerebral hypoperfusion in heart failure with reduced ejection fraction, while heart failure with preserved ejection fraction operates through its comorbidity cluster and the microvascular inflammation it generates [38, 39].

The effects of ischemia are graded by its severity and duration, and the classic ischemic-threshold physiology, extended cautiously to chronic hypoperfusion, may be used to explain it. As flow falls, the cell relinquishes expensive functions sequentially before it relinquishes viability: protein synthesis and repair are suppressed at relatively modest reductions, synaptic and electrical function and intermediary metabolism fail at deeper ones, and only at severe reductions does energy homeostasis collapse and membrane integrity fail [15, 16, 40]. Severity and duration interact: flow that is survivable briefly becomes structurally damaging when sustained, and the threshold for irreversible injury migrates upward with time [41]. The hypoperfused cell therefore triages survival at the expense of maintenance, preserving ionic gradients by giving up protein turnover, repair, synaptic maintenance, plasticity, and axonal and myelin support, and survival on those terms has a long-term cost. Within surviving tissue, irreversible loss accrues as selective neuronal, axonal, and myelin loss that never amounts to frank infarction, the lesion Lassen named incomplete infarction [17, 18], and modern neuropathology identifies exactly this continuum, rarefaction, incomplete infarction, and diffuse demyelination, beneath the white matter hyperintensities of imaging [5]. Extending thresholds established in acute experimental ischemia to chronic hypoperfusion over months and years is a conceptual extrapolation of this review, explicitly marked as such in Fig. 4; it is not a directly measured chronic human threshold model. The pathology nevertheless supports the central inference: the substrate can be built entirely from tissue that never died all at once.

Fig. 4.

Survival triage across flow and time. As perfusion falls the cell relinquishes expensive functions before it relinquishes viability, and as the deficit is sustained the threshold for irreversible injury climbs to meet it. The brackets separate empirically established acute ischemic thresholds from the chronic extrapolation proposed in this review

Where that injury localizes to, is set by vascular architecture interacting with metabolic demand. Gray matter is preferentially supplied by the cerebral vasculature at the expense of the white matter, through a dense pial network and short cortical branches, but is metabolically fragile; deep white matter is metabolically frugal but vascularly exposed, sitting at the distal ends of long medullary arteries with sparse interconnections, the last territory of the arterial supply [6]. The crossing explains the topography: acute severe perfusion failure takes the demanding gray matter first, which is why arrest injures hippocampus and cortex, while chronic modest hypoperfusion takes the exposed white matter first, and white matter’s lower acute infarction thresholds [42] are the same frugality seen at the other tempo. Deep gray structures obey the same principle differently, metabolically demanding and therefore served by direct proximal perforators, but perforators without collateral redundancy, which is why lacunes take the basal ganglia and thalamus as well as white matter. At the cellular level, oligodendrocytes and their precursors are the selectively vulnerable elements of chronically hypoperfused white matter [43]. Two clinical corollaries follow. Orthostatic hypotension and overtreated blood pressure impose episodic hypoperfusion that is modifiable, and orthostatic hypotension predicts incident dementia in prospective cohorts [44]; the argument is for individualized targets, not against treatment. Aortic stenosis combines chronic low flow with the procedural embolic risk of its correction, and the cognitive outcome of transcatheter replacement is the balance of restored perfusion against periprocedural injury [45].

Pressure and Pulsatility

The brain is injured at the other extreme of its perfusion by pressure and pulsatility rather than scarcity. In the healthy circulation, the compliant aorta cushions each systole, and an impedance mismatch at the interface between stiff and elastic vessels reflects pulse energy away from the microcirculation. Aortic stiffening attenuates this protection: pulse wave velocity rises, wave reflection at the aorta-carotid interface falls, and greater pulsatile energy is transmitted into the cerebral circulation, where it is associated with microvascular brain injury and worse cognitive performance [46]. Endothelial dysfunction and blood-brain barrier leakage provide a mechanistic bridge from this hemodynamic load to white matter injury [5]. The chronic injury is a cycle, not a one-way insult. Excess pulse pressure provokes an adaptive reaction of the vessel wall, smooth muscle hypertrophy, inward remodeling, collagen deposition, and elastin fragmentation, which reduces compliance; the stiffened vessel cushions the pulse less, so the same cardiac output delivers a harder mechanical knock downstream, provoking further remodeling. The cycle is self-amplifying, which explains the nonlinear, accelerating course of small-vessel injury in long-standing hypertension, and its exits run in both directions: the remodeled, narrowed vessel with impaired autoregulation feeds the hypoperfusion arm, and the same vessel may ultimately yield as intracerebral hemorrhage [5, 34] (Fig. 3b).

Small vessel disease is the principal manifestation, defined by the Standards for Reporting Vascular changes on Neuroimaging (STRIVE-2) lesion set [47], and is a major cause of lacunar ischemic stroke, spontaneous intracerebral hemorrhage, and vascular cognitive impairment [34]. Its two signature lesions arise differently: lacunes are genuine small infarcts, whereas most white matter hyperintensity reflects the leak, incomplete ischemia, demyelination, and gliosis of a failing endothelium rather than infarction [5], the imaging face of the incomplete infarction described above. Quantitative segmentation adds spatial information, dissociating the anterior and periventricular predominance of hypertensive arteriolosclerosis from the posterior predominance of cerebral amyloid angiopathy in vivo [48], (Table 2) and CAA holds its special position at the interface, a vascular lesion that is simultaneously a clearance-dependent expression of amyloid biology [12]. Genetic evidence closes the loop on causation: genetically predicted blood pressure is associated with adverse small-vessel and white matter phenotypes that track cognition [49], and with all-cause dementia through this substrate route [50], while the paradoxical inverse estimates for Alzheimer disease itself [51] are most plausibly reverse causation, the prodrome lowering pressure. The genetic evidence, like the trials, acts on the vascular route rather than on Alzheimer biology directly.

Table 2.

Pantoni etiologic classification of cerebral small vessel disease.

(adapted from [34])

Type	Designation	Key vessel pathology	Representative causes	Relevance to cognition
1	Arteriolosclerosis	Hyaline wall thickening, fibrinoid necrosis, lipohyalinosis	Aging, hypertension, diabetes	Most common form; driver of WMH, lacunes, subcortical dysexecutive syndrome
2	Cerebral amyloid angiopathy	Amyloid-beta in media/adventitia of cortical/leptomeningeal vessels	Aging, APOE	Lobar microbleeds, siderosis, lobar hemorrhage; vascular-neurodegenerative interface
3	Inherited/genetic SVD distinct from CAA	Genetically determined arteriopathy	CADASIL, CARASIL, COL4A1/A2, Fabry, MELAS	Pure SVD models without cardiac risk factors
4	Inflammatory/immune-mediated	Vessel-wall inflammation	Primary CNS angiitis, systemic vasculitides, infection	Part of systemic disease; potentially reversible
5	Venous collagenosis	Noninflammatory collagenous venular thickening	Advanced age	Implicated in periventricular white matter change
6	Other	Miscellaneous	Postradiation angiopathy; nonamyloid microvessel degeneration	Includes microvascular degeneration in AD

Indirect Mechanisms

Three pathways may connect cardiovascular disease to cognition independent of primary structural lesion, and all three remain less established than the direct routes. Systemic inflammation is the most developed: endothelial activation, barrier dysfunction, microglial priming, and altered synaptic function provide a coherent chain from the inflamed circulation to the brain [52]. Experimental evidence that extravasated fibrinogen can activate perivascular microglia and promote axonal injury supplies one concrete link in that chain [13]. Neuroendocrine and autonomic dysregulation, with sustained sympathetic activation and altered cortisol dynamics, is toxic in principle to hippocampal and frontal systems, and neurohumoral activation is a shared feature of heart failure and cognitive impairment [53]. Impaired perivascular clearance may degrade the environment in which protein aggregation occurs, and is the forward limb of the reinforcement loop developed in the next section; the strongest direct evidence that arterial pulsation drives this exchange remains experimental [10, 11]. The honest take on all three is the same: none has been shown in humans to cause cognitive decline independently of the structural injury it accompanies. They may explain cognition that seems disproportionate to lesion burden, and they identify therapeutic targets, but on present evidence they are modifiers of the direct account, not alternatives to it.

Vascular and Alzheimer Pathology: Reinforcement-Gating Framework

Mixed pathology is common in late-life dementia, and vascular lesions frequently coexist with Alzheimer pathology; clinical impairment often emerges from their combined burden [7, 8].

The relationship between the two pathologies has two components, and they carry different evidential weight. The first is reinforcement, and it is bidirectional with asymmetric confidence. In the forward direction, vascular dysfunction may promote or facilitate Alzheimer pathology: perivascular clearance of amyloid-beta and tau depends partly on healthy arterial pulsatility, and the stiffened, dysregulated circulation that builds the substrate also impairs clearance. This direction is mechanistically plausible, but its human causal evidence is weaker than the association, and the genetic data reviewed above, which locate cardiovascular effects on the substrate route rather than on Alzheimer biology, counsel restraint. In the reverse direction the evidence is stronger: amyloid-beta injures the vasculature directly, depositing in vessel walls as cerebral amyloid angiopathy, impairing vascular reactivity and clearance, and thereby closing a self-reinforcing loop whose physical interface is CAA itself [12]. The second component is gating, and it is the better supported clinicopathologic claim: whatever the causal traffic between the pathologies, accumulated vascular injury lowers the clinical threshold at which a given Alzheimer burden expresses as dementia [8]. The Nun Study showed that infarction markedly increased the clinical expression of dementia among participants with Alzheimer pathology, and subsequent autopsy cohorts likewise support additive, largely independent contributions of vascular and Alzheimer lesions rather than requiring biological synergy [7–9]. No trial has tested whether reducing vascular burden shifts that threshold; a biomarker-stratified design holding amyloid fixed could.

Plasma biomarkers operationalize part of this reasoning. High-performing phosphorylated tau 217 (p-tau217) assays can identify Alzheimer pathology with high diagnostic accuracy, but the probability attached to a positive or negative result remains assay-, threshold-, and prevalence-dependent [27, 54]. Extensive small vessel disease neither excludes Alzheimer disease nor is excluded by it, so a positive result should establish that Alzheimer pathology is likely to be present without automatically settling causal attribution in a vascular-heavy phenotype; confirmatory CSF or amyloid positron emission tomography (PET) remains appropriate for indeterminate, discordant, or treatment-defining cases. Read together, p-tau217, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) describe complementary aspects of neurodegenerative injury, but neither GFAP nor NfL is specific and no validated multi-analyte index yet apportions the vascular share [27].

Clinical Correlations

Clinical Syndromes

Table 3 maps the major vascular cognitive impairment phenotypes onto the route-tempo-caliber framework. The cognitive syndrome of cardiovascular disease is determined by the caliber, tempo, and location of the injury. Acute large-vessel injury produces focal, often cortical syndromes dictated by lesion site: an embolic infarct of the Broca area makes aphasia part of that patient’s vascular syndrome. The chronic small-vessel process produces an insidious subcortical, dysexecutive picture, and this is the modal presentation, the most frequently missed, and the one most often entangled with Alzheimer disease. Table 4 maps the correspondence.

Table 3.

Subtypes of vascular cognitive impairment and dementia, mapped onto route, tempo and caliber

Subtype	Tempo	Caliber	Imaging signature	Cognitive profile
Multi-infarct dementia	Acute, repeated	Large, sometimes mixed	Multiple cortical and cortico-subcortical infarcts	Stepwise and patchy; deficits follow territories, with aphasia, neglect, apraxia
Strategic infarct dementia	Acute, single event	Large or small	One lesion in thalamus, angular gyrus, caudate, genu of the internal capsule or medial temporal region	Disproportionate to lesion volume; amnesia, abulia or executive failure by site
Subcortical ischemic vascular dementia (lacunar state, Binswanger type)	Chronic, insidious	Small	Confluent white matter hyperintensity, multiple lacunes, enlarged perivascular spaces	Slowed processing, dysexecutive syndrome, early gait disorder and urinary urgency, depression
Hypoperfusion and hypoxic-ischemic dementia	Acute or chronic	Systemic or watershed territory	Watershed infarction, laminar necrosis, hippocampal or basal ganglia injury, delayed leukoencephalopathy	Amnestic after CA1 injury; visuospatial after posterior watershed; executive and transcortical aphasia after anterior watershed
Hemorrhagic vascular cognitive impairment	Acute on chronic	Small	Lobar or deep intracerebral hemorrhage, microbleeds, cortical superficial siderosis	Depends on site and burden; amyloid angiopathy adds posterior and visuospatial features
Mixed vascular and Alzheimer disease	Chronic	Mixed	Any of the above with medial temporal atrophy and positive amyloid biomarkers	Combined amnestic and dysexecutive; the most common late-life substrate

Note. Complements Table 2, which classifies small vessel disease by vessel pathology, and Table 4, which maps lesion location to syndrome

Table 4.

Lesion location, cognitive syndrome, and cardiovascular etiology

Location or territory	Cognitive syndrome and features	Memory pattern	Cardiovascular etiology
Anterior cerebral artery (medial frontal, cingulate, supplementary motor area, anterior corpus callosum)	Abulia, akinetic mutism if bilateral, transcortical motor aphasia (dominant), apathy and executive impairment, contralateral leg-predominant weakness, alien limb with callosal involvement	Retrieval and organizational (frontal) pattern, lesion-dependent	Cardioembolic or large-artery atherosclerotic infarct; anterior watershed hypoperfusion
Middle cerebral artery (lateral fronto-temporo-parietal cortex; deep territory via lenticulostriates)	Dominant: Broca, Wernicke, or global aphasia, apraxia. Nondominant: hemispatial neglect, anosognosia, aprosodia. Either: contralateral hemiparesis, hemianopia	Lesion-dependent, not primarily amnestic	Cardioembolic (the most common recipient territory, the principal atrial fibrillation link), large-artery atherosclerosis, carotid artery-to-artery embolism
Posterior cerebral artery (occipital cortex, medial temporal and hippocampus, splenium, thalamic perforators)	Homonymous hemianopia, visual agnosia, prosopagnosia, alexia without agraphia (dominant, with splenium), Balint syndrome and Anton syndrome if bilateral	Encoding-type amnesia if medial temporal involved, dense and Alzheimer-like when bilateral	Cardioembolic, including top-of-basilar embolism; vertebrobasilar atherosclerosis
Paramedian thalamus, with or without rostral midbrain	Amnesia, executive impairment, fluctuating arousal, apathy, vertical gaze palsy	Encoding-type	Small-vessel occlusion of thalamoperforators, or embolic occlusion of the artery of Percheron
Caudate or anterior capsular genu	Abulia, dysexecutive syndrome, psychomotor slowing	Retrieval-type	Small-vessel lacunar infarct, or cardioembolic
Dominant angular gyrus	Alexia, agraphia, acalculia, finger agnosia, left-right disorientation (Gerstmann), can mimic Alzheimer disease	Variable	Cardioembolic or large-artery infarct in the MCA inferior division (angular branch)
Deep frontal-subcortical white matter	Slowed processing, executive dysfunction, apathy, early gait disorder, urinary urgency	Retrieval-type, cueing helps	Small vessel disease (arteriolosclerosis), chronic and insidious
Posterior (parieto-occipital) watershed	Balint syndrome: simultanagnosia, optic ataxia, ocular apraxia; visual disorientation	Not a distinguishing feature	Global hypoperfusion: cardiac arrest, severe hypotension, low output
Anterior (frontal) watershed	Executive impairment, transcortical motor aphasia, proximal-predominant (man-in-a-barrel) weakness	Not a distinguishing feature	Global hypoperfusion
Hippocampus (CA1)	Dense anterograde amnesia mimicking Alzheimer disease	Encoding-type, poor cueing benefit	Global hypoxic-ischemic injury (cardiac arrest), selective CA1 vulnerability
Basal ganglia and cerebellum	Parkinsonism, dystonia, action myoclonus	Not a distinguishing feature	Global hypoxic-ischemic injury

Multi-infarct and strategic infarct dementia show the lesion-dependence most plainly. The classic multi-infarct course is stepwise with focal signs and temporal linkage to events, and its profile is patchy: cortical strokes produce aphasia, neglect, and apraxia. Strategic infarcts can produce disproportionate cognitive impairment from single lesions, particularly in the thalamus, angular gyrus, caudate, and connected frontal-subcortical networks. Large pooled lesion-symptom mapping now supports the strategic-location concept beyond the older case-series literature [28].

The subcortical syndrome of small vessel disease is insidious and often strokeless. Processing speed fails earliest and worst; executive function and set-shifting follow; gait disorder and urinary urgency arrive early; and depression is common [34]. Memory is often involved differently than in Alzheimer disease: retrieval and executive organization are disproportionately affected in subcortical vascular disease, while cueing and recognition are relatively better preserved than in typical Alzheimer disease [55, 56], although this is a probabilistic rather than absolute bedside distinction.

Heart failure contributes a fluctuating fog of low output, underrecognized because it is attributed to age or illness, tracking hemodynamic status and partially reversible with optimization [38], a reminder that vascular cognitive injury is not uniformly fixed. Anoxic-ischemic injury contributes the memory-dominant exception: hippocampal CA1 vulnerability produces amnesia that can mimic Alzheimer disease [36], posterior watershed injury produces visuospatial syndromes, anterior watershed injury produces executive impairment and transcortical aphasia, and a delayed leukoencephalopathy can follow apparent recovery [57]. In the mixed vascular and Alzheimer patient, the bedside apportioning runs on the same distinctions: an encoding-type memory deficit unhelped by cueing points toward Alzheimer disease, while disproportionate slowing, early executive impairment, early gait disorder, and heavy white matter disease point toward the vascular contribution.

Evaluation

The aim of evaluation is not to assign a single cause but to characterize contributions and identify what is modifiable. The history should establish midlife as well as current vascular risk; the cardiac record, atrial fibrillation, heart failure, infarction, valve disease, arrest; and a medication review directed at anticholinergic, sedative, and orthostatic burden, which degrades cognition directly and is often reversible [58, 59]. Orthostatic vital signs and gait observation are informative and frequently omitted.

Bedside testing should generally favor the Montreal Cognitive Assessment (MoCA) over the Mini-Mental State Examination (MMSE) in suspected vascular cognitive impairment because it better samples executive function, attention, and processing speed and has greater sensitivity for mild vascular deficits; an explicit cueing and recognition check helps characterize the memory phenotype, while formal neuropsychology resolves ambiguous cases [60]. MRI is the central investigation, read for the full STRIVE-2 lesion set (Fig. 5) [47], increasingly with quantitative segmentation, whose spatial output carries etiologic information: anterior and periventricular predominance suggests hypertensive arteriolosclerosis, while posterior lobar hemorrhagic markers with cortical superficial siderosis suggest cerebral amyloid angiopathy, assessed against the Boston 2.0 criteria [61]. The cardiac workup comprises electrocardiography, extended rhythm monitoring for occult atrial fibrillation where the imaging suggests embolism, echocardiography, and a low threshold for cardiology referral.

Fig. 5.

Imaging of cerebral small vessel disease. a Transverse T2 image showing enlarged perivascular spaces, the vessels travelling perpendicular to the page. b Transverse T2 image showing perivascular space enlargement in the plane of the image, appearing as parallel streaks. c Transverse susceptibility weighted image of the basal ganglia and thalamus showing several microhemorrhages. d FLAIR image showing a right thalamic lacune with a hypointense core and a slightly hyperintense rim. e FLAIR image showing periventricular and deep white matter hyperintensities. f Susceptibility weighted image showing superficial siderosis. g to i Fazekas grades 1, 2 and 3: punctate hyperintensities, early confluence, and confluent disease

Plasma biomarkers have entered practice, with regulatory clearance of a p-tau217-based ratio for symptomatic patients [62] and guideline support in specialty care [54]. High-performing p-tau217 assays can function as triage or, when validated to sufficiently high accuracy thresholds, as confirmatory tests; interpretation must remain assay-specific and anchored to pre-test probability [27, 54]. In a presentation dominated by vascular disease, a positive blood result increases the probability of concomitant Alzheimer pathology but does not by itself apportion the cause of impairment. Indeterminate or discordant results, and cases in which treatment eligibility requires definitive amyloid attribution, should proceed to CSF biomarkers or amyloid PET. Renal function and age can modify circulating biomarker concentrations [63], and should be considered when results are near decision thresholds. Current diagnostic criteria differ primarily in how tightly they require the cognitive syndrome to be linked to documented cerebrovascular disease (Table 5).

Table 5.

Diagnostic criteria for vascular cognitive impairment, and what separates them

Criteria	Cognitive requirement	Vascular requirement	Required link
DSM-5, major or mild vascular neurocognitive disorder	Decline in one or more domains, major or mild	Cerebrovascular disease on history, examination or imaging sufficient to account for the deficits	Either a temporal relationship to a cerebrovascular event, or prominent decline in complex attention and executive function
VASCOG 2014	Graded, permitting mild as well as major impairment	Specified imaging burden: a large-vessel infarct, a strategic single infarct, two or more lacunes outside the brainstem, or extensive confluent white matter lesions	Profile-based or temporal; the imaging threshold is explicit
NINDS-AIREN 1993	Dementia	Cerebrovascular disease on examination and imaging	Onset within three months of stroke, or abrupt deterioration, or stepwise progression

All three require both the cognitive deficit and the vascular lesion, and differ in how tightly they require the two to be linked. NINDS-AIREN demands a temporal or stepwise link and therefore performs poorly for the insidious small vessel disease that is the modal presentation described here. None apportions the vascular and degenerative contributions in mixed disease.

The evaluation should end where treatment begins, by surfacing the treatable: orthostatic hypotension, medication burden, sleep apnea, depression, and suboptimal control of blood pressure, rhythm, and heart failure.

Management

The main avenue for intervention available for vascular cognitive impairment is the management of modifiable vascular risk factors, i.e., secondary prevention. We order these interventions by strength of evidence (Table 6). Blood pressure control is the best established. SPRINT MIND found that intensive lowering reduced mild cognitive impairment (MCI) and the combined endpoint of MCI or probable dementia, with probable dementia alone not reaching significance after early termination [64], and its imaging substudy tied the effect to the substrate by showing slowed white matter hyperintensity progression [65]. Benefit appears greatest for midlife control, and the autoregulation physiology reviewed above supplies the caveat: in the chronically hypertensive, rigid circulation, aggressive lowering and orthostatic drops can hypoperfuse, so targets should be individualized rather than abandoned.

Table 6.

Randomized trials with cognitive endpoints relevant to cardiovascular prevention

Trial (year)	Design	Population	Cognitive endpoint	Result	Implication
SPRINT MIND (2019)	RCT substudy, intensive (< 120) vs. standard (< 140 mmHg)	Hypertensive adults without diabetes or prior stroke	Probable dementia; MCI (secondary)	No significant dementia reduction; significant MCI and combined MCI + dementia reduction; likely underpowered after early termination	BP lowering reduces MCI and slows WMH progression
FINGER (2015)	RCT, multidomain lifestyle vs. health advice	At-risk older adults, Finland	Neuropsychological composite	Improved or maintained cognition vs. control	Multidomain risk reduction benefits cognition
US POINTER (2025)	Phase 3 single-blind RCT, structured vs. self-guided lifestyle, 2 years	2111 adults aged 60–79 at risk	Global cognitive composite	Both arms improved; structured arm greater; consistent across subgroups	Lifestyle intervention protects cognition in diverse population; no usual-care control
BRAIN-AF (2026)	Double-blind RCT, rivaroxaban vs. placebo/aspirin	Adults < 65 with nonvalvular AF at low stroke risk	Composite of stroke, TIA, cognitive decline (MoCA)	Stopped for futility; HR 1.10	Anticoagulating low-risk AF does not prevent cognitive decline
LACI-2 (2023)	Phase 2b RCT, ISMN and/or cilostazol vs. guideline care, 2 × 2 factorial, 12 months	363 adults with lacunar stroke	Cognitive impairment (DSM-5 7-level ordinal), tMoCA	Combination aOR 0.44, improved tMoCA, reduced low mood; cilostazol alone reduced impairment at 6 months	Substrate-directed endothelial therapy feasible and promising; phase 3 warranted
CREST-2 cognitive substudy (2026)	Substudy of RCT, revascularization + intensive medical vs. intensive medical alone	> 2000 adults with asymptomatic carotid stenosis	Longitudinal cognitive trajectory	No divergence; no benefit even with worse baseline cognition	Revascularization does not protect cognition; decline is multifactorial

Atrial fibrillation is where the evidence is most instructively discordant. BRAIN-AF randomized 1,235 relatively young, low-stroke-risk patients to rivaroxaban or placebo specifically to test prevention of stroke, transient ischemic attack, or cognitive decline and was stopped for futility; primary events occurred at 7.0 versus 6.4% per year (hazard ratio 1.10, 95% confidence interval 0.86–1.40) [22]. Observational cohorts report less dementia after catheter ablation [66], yet the randomized cognitive readout of early rhythm control in EAST-AFNET 4 was null at two years [67]. The synthesis this review presents is provisional: lifetime cognitive risk may reflect combinations of covert embolism, low output, and a shared atrial-and-vascular substrate that short-duration anticoagulation or rhythm-control trials incompletely capture, while Mendelian randomization places much of the lifetime causal pathway through ischemic stroke and low cardiac output [32]. Current evidence does not support anticoagulation below established stroke-prevention thresholds solely for cognitive protection. The next trials should begin earlier in the disease course, use cognition as a primary endpoint, and incorporate serial silent-infarct and substrate imaging as mediators.

In heart failure, the brain is protected by restoring its supply: guideline-directed therapy, decongestion, and output optimization, with partial cognitive reversibility documented after mechanical support [68], and attention to sleep-disordered breathing, anemia, renal function, and polypharmacy.

For lipids and metabolic risk, the Lancet Commission added low-density lipoprotein (LDL) cholesterol to the modifiable factors [2], drug-target Mendelian randomization supports lipid lowering most clearly for vascular and unspecified dementia via the stroke route [69], and the signals for sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists remain hypothesis-generating [70].

Multidomain lifestyle intervention is consistent: FINGER established the model [71], US POINTER found improvement in both arms with greater gains in the structured arm, though the absence of a usual-care control limits attribution [72]. Life’s Essential 8 (diet, exercise, non-smoking, sleep, and the control of weight, cholesterol, blood sugar, and blood pressure) reflects how far cardiovascular and cognitive prevention overlap [73].

Substrate-directed pharmacotherapy has an encouraging phase 2 signal in LACI-2: isosorbide mononitrate reduced recurrent stroke and cognitive impairment, cilostazol reduced functional dependence, and the combination improved a composite vascular-functional-cognitive outcome, with both drugs generally well tolerated [74]. These exploratory findings support endothelial-targeted therapy as a testable strategy rather than establish efficacy; definitive phase 3 trials are required.

Donepezil yields small cognitive gains without global benefit in vascular populations, and the CADASIL trial, null on its primary with positive executive secondaries, suggests that pure small vessel disease has only a modest cholinergic deficit, so apparent benefit in mixed populations likely reflects undiagnosed Alzheimer disease [75].

Carotid revascularization has not shown a cognitive advantage: the CREST-2 cognitive analysis presented at the 2026 International Stroke Conference reported no benefit from carotid stenting or endarterectomy over intensive medical management, including among patients with worse baseline cognition [76]. These results are currently conference-level evidence and await full publication; stroke prevention remains the established rationale for revascularization, and the wider question the null raises is taken up in the final section.

Deprescribing is a cognitive intervention in its own right, given some preliminary evidence linking cumulative anticholinergic exposure to incident dementia [58, 59], and perioperative care (embolic protection, perfusion management, delirium prevention) offers immediately achievable gains. The remaining decision, anti-amyloid therapy in the patient with substantial vascular disease, is difficult enough to warrant its own section, which follows.

Anti-Amyloid Therapy: Challenges and Future Directions

Anti-amyloid therapy in patients with substantial vascular disease is the most controversial topic this review addresses, because the same substrate that helps bring Alzheimer pathology to clinical expression also constrains treating it. The difficulty is less a dispute between camps than a challenge of deciding where evidence is thin, and the eligibility criteria are not all of one kind. That hemorrhagic markers carry hemorrhagic risk is well founded: cortical superficial siderosis, more than four microbleeds, and probable cerebral amyloid angiopathy identify vessels already demonstrating their fragility, and these are the criteria on firmest ground [61, 77]. The other two exclusions are extrapolations. That a heavy white matter burden or concurrent anticoagulation increases the risk of amyloid-related imaging abnormalities (ARIA) or hemorrhage is mechanistically plausible and clinically prudent, but it is not established: the trials excluded severe white matter disease at enrollment, so they could not measure its effect, The criteria exclude the evidence that would test them, since the patients who would generate the evidence are the patients the criteria exclude. Best-practice recommendations steer away from both, and reasonably so, but clinicians should understand that on these two points they are following prudence rather than data [77, 78].

The lack of clinico-radiological correlation on MR imaging complicates this picture. Visual white matter rating shows only modest interrater agreement [79], volumetric quantification discriminates somewhat better but is not the regulatory standard [80], and the exclusion for a “major vascular contribution” has no widely accepted operational definition at all, so the criterion most likely to apply to the patients this review describes is the one least specified.

Anticoagulation is another gray area. Drug-specific appropriate-use recommendations (AURs) and the 2026 Alzheimer’s Association Amyloid-Related Imaging Abnormalities workgroup treat concomitant anticoagulation as a major safety concern, and current AURs generally exclude patients receiving therapeutic anticoagulation from initiating or continuing amyloid-targeting therapy until better safety data are available [77, 78, 81]. Donanemab trial exposure to anticoagulation was too limited to establish safety, and APOE epsilon4, especially homozygosity, further raises ARIA risk [77]. The case for treating includes evidence that clinical separation can persist and enlarge after finite-course donanemab treatment; in the long-term extension, early-start participants differed from a weighted external Alzheimer’s Disease Neuroimaging Initiative (ADNI) control by approximately 1.2 Clinical Dementia Rating Sum of Boxes (CDR-SB) points at three years [82]. The case for restraint rests on modest average treatment effects [83] and on a hemorrhagic tail that mean effects cannot represent. The defensible class-level principle is therefore not to withdraw medically necessary anticoagulation merely to create eligibility for anti-amyloid therapy; when anticoagulation is required, vascular and thromboembolic indications should generally take precedence over elective amyloid-targeting treatment.

Five questions organize the future. First, rhythm-directed and anticoagulant cognitive protection needs trials with cognition as the primary endpoint and substrate imaging as a mediator. The reconciliation offered here for the discordance between BRAIN-AF and the Mendelian randomization evidence remains conjectural, and the proposed trials could falsify it. Second, the vascular exclusions themselves need direct testing, whether through registries of treated patients stratified by quantified white matter burden and anticoagulant status, or through trials that deliberately enroll the moderately vascular patient. Third, whether flow-directed intervention can improve cognition remains unsettled beyond the asymptomatic carotid case, which CREST-2 has now largely closed [76], a null consistent with the possibility that by the time a flow-limiting lesion is treated, most of what is injuring the brain is small-vessel, inflammatory, and degenerative rather than hemodynamic; the symptomatic population has not been tested on cognitive endpoints. Fourth, whether any indirect mechanism causes decline independently of structural injury remains the mechanistic frontier, with the metabolic agents an early test [70]. Fifth, the field lacks its most needed instrument: a measure that quantifies the vascular contribution in vivo as p-tau217 quantifies the amyloid one. Nothing would do more for the mixed-disease patient, in whom the treatable component currently cannot be numerically apportioned. The LACI-2 successors will meanwhile decide whether the substrate can be treated and not merely prevented [74].

Conclusion

Cardiovascular disease injures the brain through a multitude of mechanisms which may be understood along two dimensions of routes and tempos rather than through any single mechanism: direct structural injury, acute and chronic, shaped in its topography by vessel caliber and by the crossing of vascular architecture with metabolic demand, and indirect pathways that remain plausible modifiers rather than established causes. The covert majority of that injury accumulates into the cumulative vascular substrate, which erodes cognition without requiring an event, and which stands in a double relationship to Alzheimer disease: possible mutual reinforcement biologically, and clinicopathologically supported gating of clinical expression. The typical clinical result follows the lesion: focal cortical syndromes when large vessels fail acutely, and, most commonly and most missed, the subcortical dysexecutive picture of the chronic small-vessel process, entangled with Alzheimer disease in the mixed dementia that dominates late life.

The practical consequences are concrete. Neuropsychology will need a better grasp of what categories of testing best characterize early vascular cognitive impairment, vascular pathology burden, and related disabilities. Orthostatic vitals and gait deserve routine attention, and the MRI should be read for the full small-vessel lesion set. Plasma biomarkers should be interpreted against pre-test probability, and every evaluation should end by identifying what can be treated. Among interventions, blood pressure control has the strongest convergent support, multidomain lifestyle intervention is consistent, endothelial-directed therapy is the most promising frontier, and deprescribing and perioperative care are available today. Managing cardiovascular risk is among the most actionable strategies medicine currently has for preserving cognition.

Key References

• Livingston G, Huntley J, Liu KY, et al. Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. Lancet. 2024;404:572–628. https://doi.org/10.1016/S0140-6736(24)01296-0.

  • ○ The 2024 Lancet Commission update attributes roughly 45% of dementia to fourteen modifiable risk factors, most of them cardiovascular or cardiometabolic, and provides the epidemiologic foundation for treating cardiovascular risk as cognitive protection.
• Rivard L, Khairy P, Talajic M, et al. Anticoagulation to prevent ischemic stroke and neurocognitive impairment in atrial fibrillation: the BRAIN-AF randomized clinical trial. Nat Med. 2026;32:297–305. https://doi.org/10.1038/s41591-025-04101-y.

  • ○ The BRAIN-AF randomized trial in younger, low-stroke-risk patients with atrial fibrillation found no cognitive benefit of anticoagulation and was stopped for futility; its null result anchors the separation of observational association from causal effect.
• Baker LD, Espeland MA, Whitmer RA, et al. Structured vs. self-guided multidomain lifestyle interventions for global cognitive function: the US POINTER randomized clinical trial. JAMA. 2025;334:681–691. https://doi.org/10.1001/jama.2025.12923.

  • ○ The US POINTER randomized trial found cognitive improvement with both structured and self-guided multidomain lifestyle intervention, with greater gains in the structured arm, strengthening the case for multidomain prevention while illustrating the limits of attribution without a usual-care control.
• Wardlaw JM, Woodhouse LJ, Mhlanga II, et al. Isosorbide mononitrate and cilostazol treatment in patients with symptomatic cerebral small vessel disease: the Lacunar Intervention Trial-2 (LACI-2) randomized clinical trial. JAMA Neurol. 2023;80:682–692. https://doi.org/10.1001/jamaneurol.2023.1526.

  • ○ The LACI-2 phase 2b trial found isosorbide mononitrate and cilostazol well tolerated in symptomatic small vessel disease, with exploratory signals of benefit on recurrent stroke, cognition, and dependence, the most direct randomized support to date for therapy aimed at the endothelium rather than at risk factors.
• Zimmer JA, Sims JR, Evans CD, et al. Donanemab in early symptomatic Alzheimer’s disease: results from the TRAILBLAZER-ALZ 2 long-term extension. J Prev Alzheimers Dis. 2026;13:100446. https://doi.org/10.1016/j.tjpad.2025.100446.

  • ○ The TRAILBLAZER-ALZ 2 long-term extension shows that clinical separation can persist and enlarge after a finite course of donanemab, the strongest evidence for durable disease modification that must be weighed against hemorrhagic risk in vascular patients.

Author Contributions

The paper was written jointly by the authors, one being a behavioral neurologist and the other a cardiologist, to bring together the role of vascular disease in cognitive medicine.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Human and Animal Rights and Informed Consent

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Competing interests

AS is on the speakers bureau for Lily and have been invited to an advisory committee for Biogen. SA is the Medical Director and part owner of Indigo Infusions in San Antonio.