Trevor Lohman

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.

Increased blood pressure variability (BPV) is associated with increased risk for dementia, independent of hypertension. The increased risk for dementia associated with high BPV includes probable Alzheimer disease (AD) dementia, but high BPV is also associated with increased risk of stroke and cerebral small vessel disease, which are commonly comorbid with AD. This raises the question of whether high BPV is independently predictive of AD-specific pathophysiology and neurodegeneration, which could have significant clinical implications. Fewer studies have directly addressed this question by examining whether higher BPV predicts future AD biomarker abnormalities that are specific to AD pathophysiology within the amyloid/tau/neurodegeneration framework. This narrative review summarizes current studies on this topic and discusses future directions in the investigation of elevated BPV as a risk factor for AD, the most common cause of dementia in older adults.

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: Blood pressure variability is an age‐related hemodynamic risk factor for neurodegenerative disease, but it remains unclear whether distinct forms of BPV display independent or interactive effects on brain health. Increased pulse pressure variability combined with high beat‐to‐beat average real variability may indicate greater hemodynamic instability, potentially exacerbating neurodegeneration. Method: Older adults ( N = 105) underwent brain MRI and continuous BP monitoring to quantify beat‐to‐beat blood pressure variability using systolic average real variability (ARV) and pulse pressure variability through the ambulatory arterial stiffness index (AASI). The interactive effect of ARV and AASI on medial temporal lobe atrophy, plasma neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) was studied. Result: The interaction between higher ARV and higher AASI was associated with decreased left ( p = .01) and right ( p = .02) hippocampal volumes and decreased left entorhinal cortex volume ( p = .01) in a region of interest analysis adjusted for age, sex, total intracranial volume and average systolic blood pressure such that individuals with the highest ARV and AASI had the most adverse effects ( p = .0002, p = .001, p = .007 respectively, Figure 1). This finding was confirmed with a voxel‐based morphometry analysis (Figure 2) which revealed left‐sided medial temporal lobe atrophy associated with the ARV*AASI interaction term (uncorrected p = .007, FDR‐corrected p = .03). The interactive effect was also significantly associated with increased plasma NfL ( p = .009) such that individuals with the highest ARV and AASI had the highest NfL ( p = .01) adjusted for age, sex, and average systolic blood pressure, but not GFAP. Conclusion: The interaction between higher ARV and higher AASI is independently associated with increased neurodegenerative markers in independently living older adults. Participants with the highest ARV and highest AASI displayed the most adverse markers of medial temporal lobe neurodegeneration.

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.

Background: Blood pressure variability (BPV) is an age-related hemodynamic risk factor for neurodegeneration, but it remains unclear whether distinct forms of BPV display independent or interactive effects on brain health. Objective: Investigate whether high beat-to-beat BPV, when combined with increased pulse pressure variability, a form of BPV associated with arterial stiffness, exacerbates markers of neurodegeneration. Methods: Older adults (N = 105) without major neurological or systemic disease were recruited for brain magnetic resonance imaging and continuous blood pressure (BP) monitoring to quantify beat-to-beat BPV through systolic average real variability (ARV) and pulse pressure variability using arterial stiffness index (ASI). The interactive effect of ARV and ASI on medial temporal lobe atrophy, plasma neurofilament light chain (NfL), and plasma glial fibrillary acidic protein (GFAP) was studied using hierarchical linear regression in older adults . Voxel-based morphometry was used to confirm region-of-interest analysis findings. Results: The interaction between higher ARV and higher ASI was significantly associated with left-sided medial temporal lobe atrophy in both the region-of-interest (left hippocampus β = −252.79, p = 0.0002, right hippocampus β = −193.56, p = 0.001, left entorhinal cortex β = −0.13, p = 0.007), and false discovery rate-corrected voxel-based morphometry analysis (p = 0.03). The interactive effect was also significantly associated with increased plasma NfL (β = 3.88, p = 0.01), but not GFAP. Conclusions: The interaction between ARV and ASI is independently associated with neurodegenerative markers, including medial temporal lobe atrophy and plasma NfL, in older adults. These findings suggest that greater hemodynamic instability is associated with increased risk for neurodegenerative processes.

Background: Blood pressure variability (BPV) is associated with neurodegeneration and cognitive decline independent of average pressure. The effect of parasympathetic central autonomic network (CAN) impairment on this relationship has not been assessed. Objective: Determine whether parasympathetic CAN network function affects the relationship between BPV and neurodegenerative markers. Methods: 100 independently living older adults (55–89 years) underwent continuous blood pressure monitoring, neuropsychological testing, venipuncture, and brain MRI. Hippocampal volumes and entorhinal cortex thicknesses were assessed. Functional connectivity within a parasympathetic cardiovascular control network was used as a measure of parasympathetic CAN function. Plasma glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) were used as measures of glial and neuronal injury, respectively. Results: Elevated BPV was associated with left hippocampal atrophy (p = 0.03) and elevated plasma GFAP (p = 0.005) independent of age, sex, vascular risk factor burden, total intracranial volume (when applicable) and average blood pressure. These relationships were not mediated by parasympathetic central autonomic network impairment. Instead, parasympathetic CAN impairment conferred a vulnerability to elevated BPV. In participants with decreased parasympathetic CAN connectivity elevated BPV was associated with left entorhinal cortex atrophy (p = 0.0001), elevated plasma GFAP (p = 0.0001), elevated plasma NfL (p = 0.001), and memory impairment (p = 0.007). Conclusions: Findings suggest elevated beat-to-beat BPV is directly related to brain injury, and this effect is not mediated by CAN dysfunction. Instead, CAN impairment may confer a susceptibility to glial and neuronal injury in older adults with elevated beat-to-beat blood pressure variability. Mechanisms underlying increased susceptibility to BPV elevation in those with CAN dysfunction warrants further study.

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.