Arunima Kapoor

Introduction: Elevated blood pressure variability (BPV) is predictive of Alzheimers disease neuropathologic change observed with AD biomarkers. However, prior studies have largely focused on visit-to-visit BPV, which may be influenced by antihypertensive medication adherence and other external factors. Few studies have investigated beat-to-beat BPV, a reliable and direct measure of cardiovascular and autonomic function relevant to AD. Methods: Independently living older adults (N=132) were recruited from the community. Participants underwent continuous blood pressure monitoring and venipuncture. Plasma p-Tau217, p-Tau181, GFAP, NfL, and amyloid-β42/40 ratio were assessed. Linear regression examined the relationship between beat-to-beat systolic BPV and plasma AD biomarkers with and without adjustment for age, sex, systolic blood pressure, and apolipoprotein E4 (APOE4) carrier status. Results: Elevated beat-to-beat BPV was associated with elevated plasma p-Tau217 (β=0.32, p=0.008), plasma p-Tau181 (β=0.22, p=0.05), and plasma GFAP (β=0.41, p=0.00001). Elevated BPV was not associated with plasma amyloid-β42/40 ratio or plasma NfL. Discussion: Increased beat-to-beat BPV is associated with increased Core 1 T1 biomarkers of phosphorylated and secreted AD tau in blood plasma (i.e., pTau217, pTau181), but not with amyloid-β42/40 ratio, a biomarker more exclusively indexing cerebral amyloid retention alone. Elevated BPV was also associated with higher plasma GFAP, a marker of astrocyte reactivity. These findings are consistent with prior studies relating visit-to-visit BPV to AD biomarkers, suggesting that intrinsic cardiovascular and/or autonomic factors underlie links between BPV and AD.

INTRODUCTION: The locus coeruleus (LC) is one of the earliest sites of Alzheimer’s disease (AD) pathophysiological changes. LC magnetic resonance imaging (MRI) intensity may reflect effects of AD pathophysiology on the LC, providing a biomarker of early-stage AD. This study examined relationships among MRI-derived LC intensity, plasma phosphorylated tau 217 (pTau ₂₁₇ ), and memory in older adults without dementia. METHODS: Independently living adults aged 59–89 years ( N = 163) underwent neuropsychological assessment and T1-weighted fast spin-echo MRI. We quantified a bilateral LC contrast ratio relative to a pontine reference region, averaged across axial slices. Plasma pTau ₂₁₇ was measured using the Quanterix ALZpath p-Tau217 Advantage PLUS assay. For a subset ( n = 127), a memory composite score was calculated. RESULTS: After adjustment for age, sex, and APOE ɛ4 status, lower LC intensity was associated with higher plasma pTau ₂₁₇ concentrations (β = −0.17, P = .02). Each 1- SD decrease in LC intensity was associated with 53% higher odds of pTau ₂₁₇ positivity ( P = .03). In models additionally adjusted for education, a significant LC × pTau ₂₁₇ interaction for memory (β = −0.18, P = .009) indicated that lower LC intensity was associated with worse memory at low ( P = .01), but not high ( P = .64) pTau ₂₁₇ levels. DISCUSSION: These findings support MRI-derived LC intensity as a marker of early AD-related processes and suggest that LC intensity may provide complementary information not captured by plasma pTau ₂₁₇ alone. Longitudinal studies are warranted to determine how these relationships change across the early stages of AD.

Background: Low frequency oscillations in blood-oxygen-level-dependent signal (BOLD-LFOs) are generally considered nuisance signal in connectivity analysis and discarded. However, recent evidence suggests BOLD-LFOs shed light on cerebrovascular dysfunction and preclinical Alzheimer's disease, but the mechanisms remain unclear. No investigations have assessed the relationship between BOLD-LFOs and plasma pTau ₂₁₇ , or how it differs in apolipoprotein ε4 ( APOE4 ) carriers who are vulnerable to cerebrovascular dysfunction and genetically predisposed to AD. Objective: To study the relationship between BOLD-LFOs and plasma p-Tau ₂₁₇ in APOE4 carriers compared to non-carriers. Methods: Independently living older adults (N = 118) were recruited and underwent resting-state fMRI and venipuncture. BOLD-LFOs were quantified as signal power within the 0.01–0.10 Hz frequency range. Plasma pTau ₂₁₇ was assessed and linear regression quantified the interactive effect of APOE4 carrier status and BOLD-LFOs on plasma pTau ₂₁₇ . 2×2 ANCOVA was used to compare BOLD-LFOs across APOE4 carrier and amyloid positivity statuses based on previously reported pTau ₂₁₇ cutoffs. Results: The interactive effect of APOE4 carrier status and BOLD-LFO power was significantly associated with plasma pTau ₂₁₇ (β = -0.78, p = 0.001). This relationship was driven by an inverse relationship between BOLD-LFOs and plasma pTau ₂₁₇ in APOE4 carriers (β = −0.57, p = 0.0007). Amyloid-β (+) APOE4 carriers displayed lower BOLD-LFOs than amyloid-β (-) APOE4 carriers (p = 0.008) and amyloid-β (+) non-carriers (p = 0.03). Models were adjusted for age, sex, vascular risk factors, and total intracranial volume. Conclusions: Findings suggests BOLD-LFOs are implicated in preclinical AD in an APOE4 dependent manner, adding support for the continued study of BOLD-LFOs in the context of cerebrovascular contributions to AD genetic risk.

Background: Cerebrovascular dysfunction can contribute to the pathophysiology of Alzheimer's disease (AD) and trigger angiogenesis. To date, no prior systematic review and meta-analysis (SRMA) study has attempted to qualitatively and quantitatively review existing literature examining angiogenic factors in AD. Objective: In this review, we aimed to identify markers of angiogenesis in biofluids that can differentiate between individuals with AD and healthy older adults, and inform the role of angiogenesis in AD. Methods: Using Medline (1946 to August 4, 2021), the literature was systematically searched for articles according to PRISMA guidelines. Angiogenesis and AD terms were searched as keywords and mapped to MeSH headings. A total of 18 studies (including 28 dependent effect sizes) were included in the meta-analysis. Hedges’ g was selected as the effect size of interest. Results: A random-effects model including all eligible biofluid studies revealed a small and nonsignificant overall effect size (combined Hedges’ g = -0.26, 95% CI [-1.45, 0.92], p = 0.647), with significant heterogeneity (I ² = 98.6%, p < 0.0001). Moderator analysis revealed no significant difference based on which specific angiogenic biomarker was examined (i.e., vascular endothelial growth factor (VEGF) versus others). Conclusions: VEGF-related marker levels were not significantly different in AD and normal aging. Based on our findings, few studies have examined fibroblast growth factor and platelet-derived growth factor-related markers; however, we believe they warrant further investigation. Identifying novel angiogenic biomarkers could elucidate the role of vascular mechanisms in AD and reveal potential therapeutic targets.

Background: Enlarged perivascular spaces (ePVS) and white matter hyperintensities (WMH) are common and frequently co‐occurring features of cerebral small vessel disease. Few prior studies have examined the effect of cerebrovascular dysfunction on ePVS and WMH independently. In this study, we examined whether cerebrovascular reactivity (CVR)—an early and dynamic marker of cerebrovascular function—differs between individuals with no ePVS or WMH, only ePVS, only WMH and both ePVS and WMH to examine whether impaired cerebrovascular function confers appreciable risk to each of these pathologies. Method: Independently living older adults ( N = 118, mean age = 68.4 years; SD = 6.9; age range 55‐89 years; 34.7% male, mean education = 16.4 years; SD = 2.4) free of dementia or clinical stroke were recruited from the community and underwent brain MRI. pCASL MRI quantified whole brain cerebral perfusion during vasodilation (CVR to hypercapnia) induced by visually guided breathing exercises (15s breath holds) and indexed by capnography. ePVS were scored using a 5‐point scale in the centrum semiovale (CS). WMH were scored using the Fazekas scale. Result: One‐way ANOVA revealed a significant difference in CVR between groups (no ePVS/WMH, ePVS, WMH, ePVS + WMH), F (3,114) = 3.37, p = .021, with medium effect size (partial η ² = .08). Post‐hoc comparisons indicated that the overall effect was driven by the difference between individuals with no ePVS or WMH (M = 9.89, SD = 3.65) and those with both (M = 6.57, SD = 2.40). Higher CVR was associated with decreased risk of ePVS + WMH, compared to all other groups, even after accounting for age, and sex (OR = 0.78, 95% CI (0.62, 0.98), p = .035). Conclusion: We explored the contribution of CVR to ePVS and WMH distinctly. These findings suggest that higher CVR substantially decreases risk of having combined WMH and ePVS‐CS. CVR deficits may represent early‐stage changes which contribute to the development of both ePVS‐CS and WMH. The cross‐sectional design of this study limits examination of directionality or bidirectionality. Future studies could explore how regional differences in CVR are associated with each pathology and whether that may differentially affect cognitive functioning in the long‐term.

Background: Enlarged perivascular spaces (ePVS) and white matter hyperintensities (WMH) are common and frequently co‐occurring features of cerebral small vessel disease. Few prior studies have examined the effect of cerebrovascular dysfunction on ePVS and WMH independently. In this study, we examined whether cerebrovascular reactivity (CVR)—an early and dynamic marker of cerebrovascular function—differs between individuals with no ePVS or WMH, only ePVS, only WMH and both ePVS and WMH to examine whether impaired cerebrovascular function confers appreciable risk to each of these pathologies. Method: Independently living older adults ( N = 118, mean age = 68.4 years; SD = 6.9; age range 55‐89 years; 34.7% male, mean education = 16.4 years; SD = 2.4) free of dementia or clinical stroke were recruited from the community and underwent brain MRI. pCASL MRI quantified whole brain cerebral perfusion during vasodilation (CVR to hypercapnia) induced by visually guided breathing exercises (15s breath holds) and indexed by capnography. ePVS were scored using a 5‐point scale in the centrum semiovale (CS). WMH were scored using the Fazekas scale. Result: One‐way ANOVA revealed a significant difference in CVR between groups (no ePVS/WMH, ePVS, WMH, ePVS + WMH), F (3,114) = 3.37, p = .021, with medium effect size (partial η ² = .08). Post‐hoc comparisons indicated that the overall effect was driven by the difference between individuals with no ePVS or WMH (M = 9.89, SD = 3.65) and those with both (M = 6.57, SD = 2.40). Higher CVR was associated with decreased risk of ePVS + WMH, compared to all other groups, even after accounting for age, and sex (OR = 0.78, 95% CI (0.62, 0.98), p = .035). Conclusion: We explored the contribution of CVR to ePVS and WMH distinctly. These findings suggest that higher CVR substantially decreases risk of having combined WMH and ePVS‐CS. CVR deficits may represent early‐stage changes which contribute to the development of both ePVS‐CS and WMH. The cross‐sectional design of this study limits examination of directionality or bidirectionality. Future studies could explore how regional differences in CVR are associated with each pathology and whether that may differentially affect cognitive functioning in the long‐term.

Background Intrinsic low frequency oscillations in BOLD signal (BOLD-LFOs) are generally considered nuisance signal in connectivity analysis and discarded. However, recent evidence suggests BOLD-LFOs may shed light on cerebrovascular dysfunction and early Alzheimer’s disease pathophysiology, but the mechanisms remain unclear. No investigations to date have assessed the relationship between BOLD-LFOs and plasma pTau₂₁₇, or how this relationship differs in apolipoprotein-e4 (APOE4) carriers who are vulnerable to cerebrovascular dysfunction and predisposed to AD pathophysiology. Methods Independently living older adults (N=118) without major neurological or psychiatric disorder were recruited from the community. Participants underwent resting-state brain functional MRI and venipuncture. Total BOLD-LFOs were quantified as signal power within the 0.01–0.10 Hz frequency range. Plasma level of pTau₂₁₇ was assessed and linear regression was used to quantify the interactive effect of APOE4 carrier status and BOLD-LFOs on plasma pTau₂₁₇. 2×2 ANCOVA was used to compare BOLD-LFOs across APOE4 carrier and amyloid positivity statuses based on previously reported pTau₂₁₇ cutoffs. Results The interactive effect of APOE4 carrier status and BOLD-LFO power was significantly associated with plasma pTau₂₁₇ (β=−.65, p=.004). This relationship was driven by an inverse relationship between BOLD-LFOs and plasma pTau₂₁₇ in APOE4 carriers (β=−.49, p=.003). Amyloid-β (+) APOE4 carriers displayed lower BOLD-LFOs than amyloid-β (−) APOE4 carriers (p=.02) and amyloid-β (+) APOE4 non-carriers (p=.04). All models were adjusted for age and sex. Conclusion Present study findings suggests that BOLD-LFOs are implicated early in AD pathophysiology in an APOE4 dependent manner, adding support for the continued study of BOLD-LFOs in the context of cerebrovascular contributions to AD genetic risk.

Progressive decline in episodic memory is a hallmark of Alzheimer’s disease (AD). Emotional arousal is known to enhance memory. Enhanced encoding of emotionally arousing stimuli or events may improve memory in patients with AD; however, whether this effect is present in patients with AD remains unclear. Here we conducted a systematic search of the literature to identify relevant literature on emotional enhancement of memory in AD. Inclusion criteria were studies that (1) included individuals with Alzheimer’s disease and (2) assessed emotional memory, particularly episodic memory. Thirty-five studies were included. Twelve out of 35 studies (34.3%) showed clear emotional enhancement of memory for episodic memory among participants with mild AD, while 13 studies (37.1%) found no effect. Ten studies (28.6%) found that emotional enhancement of memory was influenced by stimuli type, valence of emotion, level of encoding or intensity of emotion. Studies including brain imaging showed that amygdala and hippocampus volume are strong predictors of emotional enhancement of memory in AD, regardless of level of cognitive impairment. Evaluating volumes or networks of brain regions known to be involved in emotional memory processing may be a key factor influencing the preservation of enhanced encoding of emotional information. Future studies are needed to confirm whether atrophy of memory-related brain regions diminishes emotional enhancement of memory in AD.

Cerebrovascular reactivity (CVR) represents the ability of cerebral blood vessels to regulate blood flow in response to vasoactive stimuli and is related to cognition in cerebrovascular and neurodegenerative conditions. However, few studies have examined CVR in the medial temporal lobe, known to be affected early in Alzheimer disease and to influence memory function. We aimed to examine whether medial temporal CVR is associated with memory function in older adults with and without mild cognitive impairment (MCI). In this observational study, independently living older adults free of dementia or stroke were recruited from the community and underwent brain MRI, neuropsychological assessment, and blood draw in an academic research setting. pCASL MRI quantified medial temporal lobe cerebral perfusion during CVR response to hypercapnia. Hypercapnia was induced by visually guided breathing exercises (15 seconds breath holds) during capnographic monitoring. MCI diagnosis and memory performance were assessed through comprehensive neuropsychological assessment. Aβ42/40 and pTau181 levels were quantified in blood plasma. Logistic and hierarchical linear regression examined medial temporal CVR in relation to MCI diagnosis and memory function. In a sample of 144 older adults (mean age = 69.6 years; SD = 7.4%; 34.7% male; mean education = 16.6 years, SD = 2.3), CVR to hypercapnia in the medial temporal lobe was attenuated in individuals with MCI after adjusting for age, sex, education, apolipoprotein ε4 carrier status, Aβ42/40 and pTau181 levels, and vascular risk factors (OR = 0.87, 95% CI [0.77-0.97], p = 0.013). Cerebrovascular reactivity to hypercapnia was associated with verbal memory performance for stories (B = 0.33, 95% CI [0.09-0.57], p = 0.009), a word list (B = 0.10, 95% CI [0.001-0.20], p = 0.048), and visual memory (B = 0.33, 95% CI [0.09-0.57], p = 0.008). Deficits in medial temporal CVR are observed in older adults with MCI and are related to worse memory function. Findings suggest that medial temporal cerebrovascular dysfunction is related to cognition and memory before the onset of dementia, independent of changes in Alzheimer pathophysiologic markers. Limitations of the study include the cross-sectional design. Future longitudinal studies are warranted to examine whether early cerebrovascular changes can predict progressive memory decline.