Hypertension and hyperhomocysteinemia as modifiable risk factors for Alzheimer's disease and dementia: New evidence, potential therapeutic strategies, and biomarkers

Abstract

This review summarizes recent evidence on how mid-life hypertension, hyperhomocysteinemia (HHcy) and blood pressure variability, as well as late-life hypotension, exacerbate Alzheimer's disease (AD) and dementia risk. Intriguingly, HHcy also increases the risk for hypertension, revealing the importance of understanding the relationship between comorbid cardiovascular risk factors. Hypertension-induced dementia presents more evidently in women, highlighting the relevance of sex differences in the impact of cardiovascular risk. We summarize each major antihypertensive drug class's effects on cognitive impairment and AD pathology, revealing how carbonic anhydrase inhibitors, diuretics modulating cerebral blood flow, have recently gained preclinical evidence as promising treatment against AD. We also report novel vascular biomarkers for AD and dementia risk, highlighting those associated with hypertension and HHcy. Importantly, we propose that future studies should consider hypertension and HHcy as potential contributors to cognitive impairment, and that uncovering the underlying molecular mechanisms and biomarkers would aid in the identification of preventive strategies.

Serum PAI-1/BDNF Ratio Is Increased in Alzheimer’s Disease and Correlates with Disease Severity

“…It has been shown that hyperhomocysteinemia can inhibit the binding of tPA with its receptor annexin II, thereby reducing plasmin synthesis. [54][55][56] In line with these findings, in a recent meta-analysis and meta-regression of case-…”

“…Furthermore, it should be noted that reduced tPA/plasmin activity in Alzheimer may also occur through mechanisms independent of inhibitory action of PAI-1. It has been shown that hyperhomocysteinemia can inhibit the binding of tPA with its receptor annexin II, thereby reducing plasmin synthesis. - In line with these findings, in a recent meta-analysis and meta-regression of case-control studies, it has been reported that in Alzheimer patients, there is an approximate one-third increase in blood homocysteine, independently of disease severity …”

Autonomic nervous system and cardiac neuro-signaling pathway modulation in cardiovascular disorders and Alzheimer’s disease

“…Although the application of neurotrophins in cardiovascular diseases is still debated and technical concerns have been raised about their administration, parallel findings demonstrate the key role played by NTFs in the modulation of the brain/heart axis, with possible preventive value. Since cardiovascular disease is known to increase AD/dementia risk and pathology ( Carey and Fossati, 2022 ), the proposed strategies may also reveal to have invaluable therapeutic or preventive potential in AD, as well as vascular dementias and related neurodegenerative disorders.…”

“…In line with our hypothesis of a link between heart and brain dysfunction, recent clinical investigations, as well as studies in animal models, have highlighted the beneficial effects promoted by different cardioprotective drugs (i.e., Beta-blockers, Angiotensin Converting Enzyme (ACE) inhibitors, sartans, and Aldosterone receptor antagonists) in Alzheimer’s disease and cognitive dementia. The cardioprotective drugs, in addition to providing preventive effects ( Carey and Fossati, 2022 ), also appear to prevent the neuronal accumulation of Aβ aggregates and result in a significant improvement in memory impairment in some clinical studies as well as in multiple animal models ( Chen et al, 2020 ; Lee et al, 2020 ; Drews et al, 2021 ; Ouk et al, 2021 ; Wang et al, 2021 ; Beaman et al, 2022 ; Deng et al, 2022 ; Mehdipour et al, 2022 ). This evidence points to the possibility that combination therapies containing these compounds may have efficacy for the treatment and prevention of both cardiac diseases and dementia in older adults.…”

Engineering Exosomes to Specifically Target the Mitochondria of Brain Cells

“…The final product was purified by flash column chromatography on silica gel (hexane/EtOAc, 4:1) to produce compound 1 (0.86 g, 80%) as a light pink solid. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 1.14 (t, J = 7.2 Hz, 12 H), 1.74 (t, J = 2.4 Hz, 1H), 3.32 (q, J = 7. 21 To a stirring solution of compound 1 (0.5 g, 1.00 mmol) and 2-azidoethyl 4-methylbenzene-sulfonate (0.45 g, 1.25 mmol) in THF/tertbutanol/water = 3:1:1, copper(II) sulfate (0.21 mmol, 40 mg) and sodium ascorbate (0.42 mmol, 82 mg) were subsequently added.…”