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Mid-life hypertension and cerebral hypoperfusion may be preclinical abnormalities in people who later develop Alzheimer’s disease. Although accumulation of amyloid-beta (Aβ) is characteristic of Alzheimer’s disease and is associated with upregulation of the vasoconstrictor peptide endothelin-1 within the brain, it is unclear how this affects systemic arterial pressure. We have investigated whether infusion of Aβ40 into ventricular cerebrospinal fluid modulates blood pressure in the Dahl salt-sensitive rat. The Dahl salt-sensitive rat develops hypertension if given a high-salt diet. Intracerebroventricular infusion of Aβ induced a progressive rise in blood pressure in rats with pre-existing hypertension produced by a high-salt diet (p < 0.0001), but no change in blood pressure in normotensive rats. The elevation in arterial pressure in high-salt rats was associated with an increase in low frequency spectral density in systolic blood pressure, suggesting autonomic imbalance, and reduced cardiac baroreflex gain. Our results demonstrate the potential for intracerebral Aβ to exacerbate hypertension, through modulation of autonomic activity. Present findings raise the possibility that mid-life hypertension in people who subsequently develop Alzheimer’s disease may in some cases be a physiological response to reduced cerebral perfusion complicating the accumulation of Aβ within the brain. [ABSTRACT FROM AUTHOR]

The earliest decline in cerebral perfusion in Alzheimer's disease (AD) is in the medial parietal cortex (precuneus). We have analyzed precuneus in post-mortem tissue from 70 AD and 37 control brains to explore the pathophysiology of the hypoperfusion: the contribution of arteriolosclerotic small vessel disease (SVD) and cerebral amyloid angiopathy (CAA), and of the vasoconstrictors endothelin-1 (EDN1) and angiotensin II (Ang II), and the association with Aβ. The myelin-associated glycoprotein:proteolipid protein-1 ratio (MAG:PLP1) was used as an indicator of oxygenation of the precuneus prior to death. MAG:PLP1 was reduced ∼50% in early AD (Braak stage III-IV). Although MAG:PLP1 remained low in advanced AD (stage V-VI), the reduction was less pronounced, possibly reflecting falling oxygen demand. Reduction in cortical MAG:PLP1 correlated with elevation in vascular endothelial growth factor (VEGF), another marker of hypoperfusion. Cortical MAG:PLP1 declined nonsignificantly with increasing SVD and CAA, but significantly with the concentration of EDN1, which was elevated approximately 75% in AD. In contrast, with reduction in cortical MAG:PLP1, Ang II level and angiotensin-converting enzyme (ACE) activity declined, showing a normal physiological response to hypoperfusion. MAG:PLP1 was reduced in the parietal white matter (WM) in AD but here the decline correlated positively (ie, physiologically) with WM EDN1. However, the decline of MAG:PLP1 in the WM was associated with increasing cortical EDN1 and perhaps reflected vasoconstriction of perforating arterioles, which traverse the cortex to perfuse the WM. EDN1 in the cortex correlated highly significantly with both soluble and insoluble Aβ42, shown previously to upregulate neuronal endothelin-converting enzyme-2 (ECE2), but not with Aβ40. Our findings demonstrate reduced oxygenation of the precuneus in early AD and suggest that elevated EDN1, resulting from Aβ42-mediated upregulation of ECE2, is a contributor. [ABSTRACT FROM AUTHOR]

Background: Depression in individuals with Alzheimer's disease (AD) is common, distressing, difficult to treat, and inadequately understood. It occurs more frequently in AD than in older adults without dementia. The reasons why some patients develop depression during AD and others do not remain obscure., Objective: We aimed to characterize depression in AD and to identify risk factors., Methods: We used data from three large dementia focused cohorts: ADNI ( n  = 665 with AD, 669 normal cognition), NACC ( n  = 698 with AD, 711 normal cognition), and BDR ( n  = 757 with AD). Depression ratings were available using the GDS and NPI and in addition for BDR the Cornell. A cut-off of≥8 was used for the GDS and the Cornell Scale for Depression in Dementia,≥6 for the NPI depression sub-scale, and≥2 for the NPI-Q depression sub-scale. We used logistic regression to examine potential risk factors and random effects meta-analysis and an interaction term to look for interactions between each risk factor and the presence of cognitive impairment., Results: In individual studies there was no evidence of a difference in risk factors for depressive symptoms in AD. In the meta-analysis the only risk factor which increased the risk of depressive symptoms in AD was previous depression, but information on this was only available from one study (OR 7.78 95% CI 4.03-15.03)., Conclusion: Risk factors for depression in AD appear to differ to those for depression per se supporting suggestions of a different pathological process, although a past history of depression was the strongest individual risk factor., Competing Interests: LS has no relevant conflicts of interest to disclose. She has previously received a travel award from the RCPsych/Gatsby Foundation and is the finance office for the Academic Faculty of the Royal College of Psychiatrists. She has received research funding in the past from the Mason Medical Research Foundation, the David Telling Charitable Trust, BRACE Alzheimer’s Research and the British Neuropathological Society. ML has no relevant conflicts of interest to disclose. He has received research funding from the MS Society, Parkinson’s UK and the NIHR HTA. JP has no relevant conflicts of interest to disclose. During the last 3 years, Clive Ballard has received consulting fees from Acadia pharmaceutical company, AARP, Addex pharmaceutical company, Eli Lily, Enterin pharmaceutical company, GWPharm, H.Lundbeck pharmaceutical company, Novartis pharmaceutical company, Janssen Pharmaceuticals, Johnson and Johnson pharmaceuticals, Novo Nordisk pharmaceutical comapny, Orion Corp pharmaceutical company, Otsuka America Pharm Inc, Sunovion Pharm. Inc, Suven pharmaceutical company, Roche pharmaceutical company, Biogen pharmaceutical company, Synexus clinical research organization and tauX pharmaceutical company and research funding from synexus clinical research organization, Roche pharmaceutical company, Novo Nordisk pharmaceutical company, Novartis pharmaceutical company, Medical research council (UK), Wellcome trust (UK), National Institute for Health Research (UK), National Institute for Health (US), IMI (Eu), Michael J Fox foundation (US), Alzheimer’s Disease Drug Discovery foundation (US), Alzheimer’s Society (UK), Parkinson’s Society (UK), Alzheimer’s Research UK, the Gilling’s foundation and BRACE (UK), (© 2023 – The authors. Published by IOS Press.)

Mid-life hypertension and cerebral hypoperfusion may be preclinical abnormalities in people who later develop Alzheimer's disease. Although accumulation of amyloid-beta (Aβ) is characteristic of Alzheimer's disease and is associated with upregulation of the vasoconstrictor peptide endothelin-1 within the brain, it is unclear how this affects systemic arterial pressure. We have investigated whether infusion of Aβ 40 into ventricular cerebrospinal fluid modulates blood pressure in the Dahl salt-sensitive rat. The Dahl salt-sensitive rat develops hypertension if given a high-salt diet. Intracerebroventricular infusion of Aβ induced a progressive rise in blood pressure in rats with pre-existing hypertension produced by a high-salt diet ( p < 0.0001), but no change in blood pressure in normotensive rats. The elevation in arterial pressure in high-salt rats was associated with an increase in low frequency spectral density in systolic blood pressure, suggesting autonomic imbalance, and reduced cardiac baroreflex gain. Our results demonstrate the potential for intracerebral Aβ to exacerbate hypertension, through modulation of autonomic activity. Present findings raise the possibility that mid-life hypertension in people who subsequently develop Alzheimer's disease may in some cases be a physiological response to reduced cerebral perfusion complicating the accumulation of Aβ within the brain.