Complex interactions between external environmental stimuli and internal conditions cause blood pressure (BP) fluctuations. Visit-to-visit BP variability (VVV) refers to dynamic BP fluctuations across months and years [1, 2]. These dynamics reflect the integrated effects of autonomic nervous activity, vascular resistance, or arterial stiffness on VVV, which is a predictor of adverse events, independent of mean BP [1].

Earlier studies have demonstrated a strong relationship between hypertension and Alzheimer’s disease (AD). Vascular factors often coexist and interact with AD pathology [2]. While VVV has been associated with cognitive impairment and dementia, the impact of VVV on incident and prevalent AD has garnered attention. In addition to apoE ε4 carriers, amyloid beta or tau protein, increased VVV has emerged as a modifiable cardiovascular factor contributing to AD risk [2].

In the recent issue of Hypertens Res, two papers remind us how VVV is associated with cognitive impairment and dementia [3, 4].

In the study by Cui et al. [3], the 362 non-demented elderly were included with a median follow-up of 4.9 years. Elevated VVV in SBP was a pivotal factor for worsening cognitive function, and was associated with white matter hyperintensities, cortical infarction, and lateral ventricle volume. Those associations between VVV and cognitive function were partially mediated by structural cerebrovascular disease and brain atrophy, whereas pre-existing AD pathology, plasma p-tau181, had little mediation effects. Furthermore, no significant interaction was observed between VVV and apoE genotype on global cognitive decline [3].

On the other hand, in the study by Satoh et al. [4], the association between VVV and dementia risk was evaluated using insurance data from the 301,448 elderly. To define dementia outcome, the first prescription of anti-dementia medication, which is primarily taken by AD patients, was used as a proxy for dementia diagnosis. During a follow-up period of approximately 2 years, elevated VVV in SBP as well as DBP were associated with the risk of dementia, regardless of antihypertensive treatment [4].

In that issue, AD pathology was not involved in the association between VVV and cognitive decline [3], while VVV was probably involved in the onset of AD [4]. Immediately, those two results seem contradictory.

Although numerous studies have reported that VVV is involved in cognitive decline [5], there is no consensus to clearly determine the relationship between VVV and cognitive decline in AD. Increased VVV was associated with a significant decrease in Mini-Mental State Examination score during the 12-month follow-up in those with established AD diagnosis [6]. On the other hand, the Doxycycline and Rifampicin in the Treatment of Alzheimer’s Disease (DARAD) trial found no association between VVV and cognitive decline in mild to moderate AD patients [7]. Similarly, the current publication by Cui et al. reported that neither mediation nor interaction between VVV and cognitive decline was observed by AD pathology or genotype [3]. In the Swedish Kungsholmen project, a SBP drop of more than 15 mmHg occurring 3 to 6 years before diagnosis significantly increased the risk of developing AD [8]. Regarding the onset of AD, BP variability around before onset might be important. A recent meta-analysis has shown that VVV in SBP and DBP are significantly associated with the incidence of AD [2]. In a two-sample mendelian randomization study, a significant causal effect between BP variability and AD was observed [9]. Therefore, increased VVV could serve as a predictor for the incident development of AD.

AD pathology itself contributes to the increased VVV via disruption of central autonomic network comprised of the insular cortex, amygdala, hypothalamus, periaqueductal gray matter, parabrachial complex, nucleus tractus solitarius, and ventrolateral medulla [10]. Among these, the relationship between insular cortex damage and the autonomic nervous system dysregulation is particularly important when considering AD pathology in relation to VVV.

In 1998, Braak and Braak [11] showed the highly structured progression of neurofibrillary tangles through the brain in a sequence that starts in the mesiotemporal cortex. A more likely origin of the autonomic dysregulation in early AD is the AD pathology in the insular cortex [12, 13]. The insular cortex is affected at stage III of the six stages in the Braak sequence, and stage III is a preclinical stage. AD pathology reaches the insular cortex at a preclinical stage, before ‘dementia’ could be diagnosed. The pathology of AD should thus also be considered as a possible explanation for non-demented elderly individuals’ autonomic morbidity and mortality such as impaired BP regulation, cardiac conduction disorders, and sudden unexpected death [12, 13]. Thus, preclinical AD pathology may explain the increased BP variability in the elderly. These findings suggest the relationship between insular cortex damage due to AD pathology and exaggerated BP variability. In a large-scale study of the Alzheimer’s Disease Neuroimaging Initiative (ADNI), baseline plasma p-tau181 levels were 15.4 and 23.7 pg/mL in healthy controls and AD patients, respectively [14]. In the study by Cui et al. [3], the median value for all participants was 2.2 pg/mL, a much lower value than that noted in the ADNI study, suggesting that this population might represent a group with low AD pathology.

Because increased VVV could have a bidirectional association with arterial remodeling concomitant with autonomic instability in patients with AD susceptibility, higher VVV could further contribute to promote AD pathology in the cerebral neurovascular coupling [15]. In this case, damage to the insular cortex would be an important clinical landmark (Fig. 1). There is a complex and unexplored interplay linking autonomic dysregulation and pathological abnormalities within the insular cortex, which may increase VVV, and contribute to the development of AD. Therefore, the mechanisms linking VVV and the development of AD are an area of active research. In this context, the two studies [3, 4] in the issue of Hypertens Res can be further expanded in the future, to better elucidate the underlying mechanisms of the relationship between VVV and AD.

Fig. 1
figure 1

A possible scheme for the relationship between blood pressure variability and Alzheimer’s disease. CV indicates cardiovascular, BP blood pressure, AD Alzheimer’s disease

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