A featured review published in Alzheimer’s & Dementia discussed the current understanding of the role cardiovascular (CV) risk factors, such as hypertension, play in the development of dementia.
As the baby boomer population is aging, it is expected that cases of dementia will rapidly increase. There is currently no cure for dementia and few effective preventative strategies have been found, so it is important to better understand the underlying pathology of disease such that more effective treatments may be developed.
This featured review article, written by investigators from Temple University Lewis Katz School of Medicine in the United States, discussed recent evidence about the relationship between hypertension, hyperhomocysteinemia (HHcy), blood pressure variability, and hypotension and Alzheimer disease (AD) and dementia risk.
Increasingly, evidence has suggested that AD is a multifactorial disease in which several processes contribute to cerebral pathology and eventually, cognitive decline.
One study published in 2022 found that patients with a CV risk trajectory that was progressing were associated with elevated AD and vascular dementia risk whereas patients with stable or controlled CV risk were not.
Hypertension in midlife has been recognized as an AD risk factor. More specifically, elevated systolic blood pressure may be the underlying cause of the association. The Honolulu-Asia Aging Study found that a systolic blood pressure of >140 mmHg in midlife associated with a 1.77-times higher risk for dementia in later life. Similarly, a study that evaluated data from the Whitehall II Cohort reported an association between a systolic blood pressure of ≥130 mmHg with a higher incidence for dementia, but there was no such relationship in later life.
Hypotension in late life may also contribute to dementia risk as late-life hypotension and low diastolic blood pressure were found to show a greater risk for the development of AD and cognitive impairment.
The same study found that patients who had a diastolic blood pressure of 90-100 mmHg in later life were associated with a 23% lower risk for dementia. There may also be a longitudinal relationship between hypertension and hypotension, in which individuals with hypertension in midlife may be more sensitive to the effects of later-life hypotension with regard to AD risk.
Similarly, variability in blood pressure has been associated with AD and/or cognitive decline risk in multiple studies. However, additional study is needed to explore the biological mechanisms underpinning these relationships.
Another potentially relevant CV risk factor is HHcy, which is a disorder that causes excess plasma homocysteine levels due to disrupted metabolism, typically caused by low folate, vitamin B12, and/or vitamin B6 or high methionine. Between 5% and 7% of individuals living in the US have HHcy, and its prevalence increases with age. A study published in 2018 and a meta-analysis found that patients with AD, dementia, or vascular dementia had elevated homocysteine compared with healthy controls. Furthermore, serum homocysteine levels have been found to correlate with dementia severity.
Review authors hypothesized the following mechanism of how these CV risk factors contribute to AD and dementia risk and pathology. Hypertension in midlife affects the cerebrovascular environment, including a loss of cerebral autoregulation, which increases pressure to the cerebral vessels and increases cell apoptosis. These changes increase permeability of the blood-brain barrier, which increases infiltration of toxins and immune cells that lead to neuroinflammation and oxidative stress. Hypertension also impairs amyloid-β clearance and promotes processes which induce hypoperfusion.
These processes likely exacerbate or accelerate the onset of AD.
Review authors concluded, “Both midlife hypertension and HHcy, which also increases the risk for hypertension, play a prominent role in increasing AD risk and CV pathology in the aging population. This review clearly demonstrates that regardless of amyloid-β and tau pathology levels, the consequences of CV risk factors […] lead to increased synaptic loss and eventually cognitive impairment.”
Carey A, Fossati S. Hypertension and hyperhomocysteinemia as modifiable risk factors for Alzheimer’s disease and dementia: new evidence, potential therapeutic strategies, and biomarkers. Alzheimers Dement. Published online November 19, 2022. doi:10.1002/alz.12871