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. 2025 Apr 30:7067437251337627.
doi: 10.1177/07067437251337627. Online ahead of print.

Blood Angiogenesis Markers and Cognition in Older Adults at Risk for Dementia: Marqueurs sanguins de l'angiogenèse et cognition chez les personnes âgées à risque de démence

Bing Xin Song  1   2 , Erica Vieira  3   4 , Damien Gallagher  2   4   5 , Breno S Diniz  3   6 , Corinne E Fischer  4   7 , Alastair J Flint  4   8 , Nathan Herrmann  4   5 , Linda Mah  4   9 , Benoit H Mulsant  3   4   10 , Tarek K Rajji  3   4   11 , Clement Ma  3   12 , Krista L Lanctôt  1   2   3   4 ; PACt-MD Study Group
Affiliations

Blood Angiogenesis Markers and Cognition in Older Adults at Risk for Dementia: Marqueurs sanguins de l'angiogenèse et cognition chez les personnes âgées à risque de démence

Bing Xin Song et al. Can J Psychiatry. .

Abstract
in English, French

ObjectiveChanges in angiogenesis have been shown to contribute to cognitive decline and dementia. We aimed to identify angiogenesis blood markers associated with cognitive performance in older adults with mild cognitive impairment (MCI), remitted major depressive disorder (rMDD), or both (rMDD + MCI) who are at risk for dementia.MethodWe analyzed data from participants with MCI, rMDD, or rMDD + MCI in the Prevention of Alzheimer's Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation in Mild Cognitive Impairment and Depression study. Elastic net regression was used to select variables associated with cognitive performance among 19 angiogenesis markers and 6 covariates. Linear regressions were used to determine which of the selected angiogenesis markers were associated with cognitive performance, controlling for the selected covariates. Significant angiogenesis markers were independently analyzed without other angiogenesis markers, controlling for covariates, with subgroup analyses in those with and without rMDD.ResultsAngiogenin was the only selected marker associated with cognitive performance (β = 0.28, Padj = 0.03, f² = .02) when controlling for other selected markers (endothelial cell-specific molecule 1, e-selectin, interleukin-33 [IL-33], oncostatin M, platelet-derived growth factor-AB, IL-33 receptor, and tissue inhibitor of metalloproteinases-1) and selected covariates (age, education, apolipoprotein E ε4 status, diagnosis, and cardiovascular risk factors). When independently analyzed, angiogenin remained positively associated with cognitive performance (β = 0.21, P = 0.01, f² =.02), controlling for the covariates. In subgroup analyses, angiogenin was also associated with cognition in rMDD and rMDD + MCI participants (β =0.50, SE = 0.14, P < 0.001, f² = 0.08) and in MCI-only participants (β= 0.20, SE = 0.09, P = 0.02, f² = 0.02).ConclusionThe association of angiogenin with cognitive performance highlights a potentially novel biological pathway that could influence cognition in older adults at risk for dementia. Angiogenin may protect against cognitive decline, opening new avenues for innovative preventive, or therapeutic interventions.

Objectif:: Il a été démontré que les changements de l’angiogenèse contribuent au déclin cognitif et à la démence. Nous voulions identifier les marqueurs sanguins de l’angiogenèse associés aux performances cognitives chez les personnes âgées ayant un trouble cognitif léger (TCL), un trouble dépressif majeur en rémission (TDMr) ou les deux (TDMr + TCL) qui sont à risque de démence.

Méthode:: Nous avons analysé les données de participants à l’étude Prevention of Alzheimer's Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation in Mild Cognitive Impairment and Depression qui avaient un TCL, un TDMr, ou un TDMr + TCL. La régression Elastic Net a été utilisée pour sélectionner des variables associées aux performances cognitives parmi 19 marqueurs d’angiogenèse et 6 covariables. Des régressions linéaires ont été utilisées pour déterminer lesquels des marqueurs de l’angiogenèse sélectionnés étaient associés aux performances cognitives, en contrôlant les covariables sélectionnées. Les marqueurs de l’angiogenèse significatifs ont été analysés indépendamment sans les autres marqueurs de l’angiogenèse, en contrôlant les covariables, avec des analyses selon les sous-groupes avec et sans TDMr.

Résultats:: L’angiogénine était le seul marqueur sélectionné associé aux performances cognitives (β = .28; Padj = 0.03; f² = 0.02) lorsque l’on a contrôlé d’autres marqueurs sélectionnés [endocan, E-sélectine, interleukine-33 (IL-33), oncostatine M, facteur de croissance de dérivé plaquettaire-AB, récepteur IL-33, inhibiteur tissulaire des métalloprotéinases-1] et certaines covariables (âge, éducation, état de l’allèle ε4 l’apolipoprotéine E, diagnostic et facteurs de risque cardiovasculaire). Après une analyse indépendante, l’angiogénine est demeurée associée positivement aux performances cognitives (β = 0,21; P = 0,01; f² = 0,02), en contrôlant les covariables. Dans les analyses de sous-groupes, l’angiogénine était également associée à la cognition chez les participants TDMr et TDMr + TCL (β = 0,50; ET = 0,14; P < 0,001; f² = 0,08) et chez les participants TCL seulement (β = 0,20; ET = 0,09; P = 0,02; f² = 0,02).

Conclusion:: L’association de l’angiogénine avec les performances cognitives met en évidence une voie biologique potentiellement nouvelle qui pourrait influencer la cognition chez les personnes âgées à risque de démence. L’angiogénine peut protéger contre le déclin cognitif, ouvrant de nouvelles voies pour des interventions préventives, ou thérapeutiques innovantes.

Keywords: Mots clés; angiogenesis; angiogenin; angiogenèse; angiogénine; cognition; dementia; déficit cognitif léger (DCL); démence; major depressive disorder; mild cognitive impairment; trouble dépressif majeur.

Plain language summary

The relationship between blood markers and thinking/memory in older adults at risk for dementia.This study aimed to identify blood markers related to angiogenesis (the process of new blood vessel formation) that could predict cognitive function (memory and thinking abilities), in older adults at risk for dementia. Angiogenesis has been linked to dementia, and understanding its associated biological factors may help in predicting cognitive decline, particularly in individuals who are at risk for dementia. Participants included adults over 50 years of age with cognitive impairment and/or a history of depression. We used the elastic net regression model to select eight out of 19 angiogenesis markers while considering five out of the six other factors (covariates) that might influence cognition, such as age, education level, apolipoprotein E genotype, diagnosis, and cardiovascular health. Among the markers studied, angiogenin, a marker that can increase angiogenesis, stood out as the only one associated with cognitive function. When considering other factors, higher levels of angiogenin were linked to better cognition. This association was present even when angiogenin was examined on its own, independent of other angiogenesis markers. Angiogenin might play a protective role in cognition in older adults at risk for dementia. Overall, the findings highlight angiogenin as a potential biomarker for cognitive health in aging adults, who were at risk with early signs of cognitive impairment and a history of depression. This suggests that angiogenin could be a target for future research into treatments aimed at preventing or slowing cognitive decline in vulnerable populations.

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Conflict of interest statement

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: KLL has received consulting fees from Boehringer Ingelheim, Bristol Meyers Squibb, Eisai Co. Ltd., Exciva, Ironshore Pharmaceuticals, H Lundbeck A/S, Novo Nordisk, Otsuka and Praxis Therapeutics.

Figures

Figure 1.
Figure 1.
Partial regression plot of log angiogenin levels (residuals from its regression against other angiogenesis markers and covariates) and composite cognitive scores (residuals from its regression against other angiogenesis markers and covariates).
Figure 2.
Figure 2.
Boxplots of log angiogenesis levels in subgroups by (a) diagnosis, (b) presence of rMDD, (c) ApoE ε4 carrier status. (a) MCI and rMDD had higher angiogenin levels than rMDD + MCI (MCI: Z = 7.2, Padj < 0.001; rMDD: Z = 4.9, Padj < 0.001). No differences were observed between MCI and rMDD (Z = 1.7, P = 0.08, Padj = 0.2). (b) MCI alone had higher angiogenin levels than those with rMDD (both rMDD and rMDD + MCI groups; χ2KW(1) = 5.3, P < 0.001). (c) APoE ε4 carriers (those with one or two alleles) had lower angiogenin levels than non-carriers (Z = 4.6, P = 0.03). *P < 0.05; *** P < 0.001.
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