We cannot control our age and genetics, which are significant drivers of late-onset Alzheimer’s disease. However, experts believe addressing modifiable risk factors, including lifestyle choices, would prevent up to 40% of all dementia cases. Among these modifiable risks, cardiovascular factors—particularly hypertension (high blood pressure)—consistently rank at the top. The traditional explanation for hypertension’s impact on cognition centers on blood vessel damage. High blood pressure leads to fatty plaques in arteries, small blood vessel lesions, and ultimately reduced cerebral blood flow, sometimes causing strokes. This vascular damage provides a clear pathway from hypertension to cognitive decline, making blood pressure medications logical candidates to promote cognitive health. However, hypertension is a recognized risk factor for Alzheimer’s disease (AD), not just dementia generally, yet researchers still know surprisingly little about how hypertension increases AD risk.
Drs. Iadecola and Faraco are investigating a provocative hypothesis: hypertension may trigger AD through immune system dysfunction and tau accumulation, not just blood vessel disruptions. Their hypothesis builds on evidence from both humans and animal models showing that hypertension correlates with increased accumulation of pathological tau protein. In AD, cognitive symptoms emerge concurrently with the development and spread of tau pathology. In previous CureAlz-supported work, the Iadecola and Faraco team demonstrated that high dietary salt (a leading cause of hypertension) impairs cognitive function in mice by increasing pathological tau. They identified IL17, an immune signaling molecule, as a potential mediator of this process. Building on these findings, they now propose that hypertension causes cognitive decline through direct effects on immune cells and the IL-17 signaling pathway, which leads in turn to accumulation of phosphorylated tau and consequent cognitive impairment.
This distinction between vascular and immune mechanisms has important therapeutic implications. If hypertension promotes AD primarily through immune dysfunction rather than reduced blood flow, then simply lowering blood pressure with conventional medications may have limited effects on cognition. Effective prevention and treatment strategies would need to target the immune pathways that drive pathological tau accumulation. This underscores a fundamental challenge in AD prevention: understanding not just which risk factors matter, but how they cause the disease. Only by understanding the underlying mechanisms can researchers develop targeted interventions that address the root causes of cognitive decline.
Drs. Iadecola and Faraco proposed three experimental aims to test their hypothesis. In the first aim, they are mapping the events leading from hypertension to tau pathology in relation to neurovascular and cognitive impairments using an established protocol (DOCA-salt) that triggers hypertension in mice. They will perform several assessments, including cognition, vascular functions (such as cerebral blood flow), and markers of tau pathology, at three time points after initiation of hypertension. They are also treating the animals with losartan (a drug used to treat human hypertension) or a drug that increases blood pressure to test how other changes impact tau-related pathologies. In the second aim, they are assessing whether mice lacking IL17 still develop hypertension but without consequent tau pathology and cognitive deficits, and whether the source of IL17 changes its impact. IL17 circulates in the bloodstream after being made in the periphery of the body, but it is also made in the brain’s dura mater layer. Determining which source of production is relevant would inform future therapeutic investigations. Finally, in the last aim, the team will assess the relative contribution of neurovascular dysfunction and tau pathology to the cognitive deficits observed with hypertension. They will eliminate or lower total tau protein in the hypertension mouse model and measure the same outcomes described in aims 1-2 to determine whether blocking tau pathology improves cognition independent of the neurovascular effects of hypertension.
