Current and Emerging Therapeutic Approaches for Vascular Cognitive Impairment and Dementia (JACC January 2026-1)-Article: Current and Emerging Therapeutic Approaches for Vascular Cognitive Impairment and Dementia

Article: Current and Emerging Therapeutic Approaches for Vascular Cognitive Impairment and Dementia

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This comprehensive 2026 JACC review by Goodall et al. addresses current and emerging therapies for vascular cognitive impairment and dementia (VCID), the second most common dementia subtype affecting 15-20% of cases. Differing from Alzheimer’s disease (AD), VCID treatments are limited, with no FDA-approved therapies specific to VCID, despite substantial cardiovascular risk factor contributions.<br /><br />Pharmacologic cognitive enhancers such as donepezil, galantamine, and memantine show modest cognitive benefits in vascular dementia (VaD), especially with AD overlap, though clinical relevance is limited. Cholinesterase inhibitors and memantine slightly slow cognitive decline; rivastigmine’s evidence is weaker. Nutraceuticals like cerebrolysin, butylphthalide, and ginkgo biloba demonstrate small gains, but require further validation. Behavioral and social interventions are first-line for neuropsychiatric symptoms including agitation and psychosis; antipsychotics (risperidone, quetiapine) may help when AD and VaD coexist but carry significant risks. Antidepressants show limited efficacy for depression in VaD, yet provide benefit post-stroke.<br /><br />Primary prevention focuses on addressing modifiable vascular risks including hypertension, diabetes, smoking, obesity, atrial fibrillation, and sedentariness, alongside management of covert cerebral small vessel disease (cSVD) detected by MRI. Intensive blood pressure lowering (target SBP ~120-130 mm Hg) reduces incident cognitive impairment and vascular events, especially if initiated midlife or early in VCID. Lipid-lowering therapies, though essential for cardiovascular and stroke prevention, have no demonstrated direct cognitive benefits or harms. Glycemic control must be individualized in diabetes to avoid hypoglycemia, with emerging interest in repurposing neuroprotective diabetes medications (metformin, GLP-1 receptor agonists, SGLT2 inhibitors), currently under clinical evaluation.<br /><br />Multimodal lifestyle interventions integrating diet (DASH/Mediterranean), physical activity, cognitive training, and vascular risk monitoring show promise in maintaining cognition and reducing vascular risk, with large trials like FINGER and Maintain Your Brain demonstrating mild cognitive improvements. Post-stroke cognitive decline prevention via intensive blood pressure control yields mixed results, underscoring the need for further research.<br /><br />Emerging pharmacologic agents target cholinergic, glutamatergic pathways, cerebral blood flow, and metabolic modulation. Novel therapies include stimulants such as methylphenidate, vasoactive peptides, epigenetic modulators like apabetalone, and nootropics like oxiracetam. The safety of recent anti-amyloid immunotherapies in AD-VCID overlap remains uncertain due to risks of amyloid-related imaging abnormalities. Nonpharmaceutical approaches like transcranial photobiomodulation are under investigation.<br /><br />In conclusion, VCID management requires a multimodal approach emphasizing vascular risk factor optimization, behavioral strategies, cautious pharmacotherapy for cognition and neuropsychiatric symptoms, and ongoing evaluation of emerging therapies. Cardiologists and primary care physicians play a pivotal role in early detection and prevention, providing a hopeful counter to therapeutic nihilism in this growing public health challenge.

Keywords

vascular cognitive impairment

dementia

vascular dementia

pharmacologic cognitive enhancers

cholinesterase inhibitors

primary prevention

vascular risk factors

lifestyle interventions

emerging therapies

neuropsychiatric symptoms