Elevated basal cortisol level predicts lower hippocampal volume and cognitive decline in Alzheimer’s disease

Abstract Objective The concepts of mild cognitive impairment (MCI) and subjective cognitive decline (SCD) have been proposed to identify individuals in the early stages of Alzheimer’s disease (AD), or other neurodegenerative diseases. One approach to validate these concepts is to investigate the relationship between pathological brain markers and cognition in those individuals. Method We included 126 participants from the Consortium for the Early Identification of Alzheimer’s disease-Quebec (CIMA-Q) cohort (67 SCD, 29 MCI, and 30 cognitively healthy controls [CH]). All participants underwent a complete cognitive assessment and structural magnetic resonance imaging. Group comparisons were done using cognitive data, and then correlated with hippocampal volumes and white matter hyperintensities (WMHs). Results Significant differences were found between participants with MCI and CH on episodic and executive tasks, but no differences were found when comparing SCD and CH. Scores on episodic memory tests correlated with hippocampal volumes in both MCI and SCD, whereas performance on executive tests correlated with WMH in all of our groups. Discussion As expected, the SCD group was shown to be cognitively healthy on tasks where MCI participants showed impairment. However, SCD’s hippocampal volume related to episodic memory performances, and WMH to executive functions. Thus, SCD represents a valid research concept and should be used, alongside MCI, to better understand the preclinical/prodromal phase of AD.

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Interaction Between BDNF Val66Met and APOE4 on Biomarkers of Alzheimer’s Disease and Cognitive Decline

Journal of Alzheimer s Disease ◽

10.3233/jad-200132 ◽

2020 ◽

Vol 78 (2) ◽

pp. 721-734

Author(s):

Cynthia M. Stonnington ◽

Stefanie N. Velgos ◽

Yinghua Chen ◽

Sameena Syed ◽

Matt Huentelman ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Brain Activity ◽

Amyloid Β ◽

Hippocampal Volume ◽

Rate Of Change ◽

Plaque Burden ◽

Amyloid Burden ◽

Hippocampus Volume

Background: Whether brain-derived neurotrophic factor (BDNF) Met carriage impacts the risk or progression of Alzheimer’s disease (AD) is unknown. Objective: To evaluate the interaction of BDNF Met and APOE4 carriage on cerebral metabolic rate for glucose (CMRgl), amyloid burden, hippocampus volume, and cognitive decline among cognitively unimpaired (CU) adults enrolled in the Arizona APOE cohort study. Methods: 114 CU adults (mean age 56.85 years, 38% male) with longitudinal FDG PET, magnetic resonance imaging, and cognitive measures were BDNF and APOE genotyped. A subgroup of 58 individuals also had Pittsburgh B (PiB) PET imaging. We examined baseline CMRgl, PiB PET amyloid burden, CMRgl, and hippocampus volume change over time, and rate of change in cognition over an average of 15 years. Results: Among APOE4 carriers, BDNF Met carriers had significantly increased amyloid deposition and accelerated CMRgl decline in regions typically affected by AD, but without accompanying acceleration of cognitive decline or hippocampal volume changes and with higher baseline frontal CMRgl and slower frontal decline relative to the Val/Val group. The BDNF effects were not found among APOE4 non-carriers. Conclusion: Our preliminary studies suggest that there is a weak interaction between BDNF Met and APOE4 on amyloid-β plaque burden and longitudinal PET measurements of AD-related CMRgl decline in cognitively unimpaired late-middle-aged and older adults, but with no apparent effect upon rate of cognitive decline. We suggest that cognitive effects of BDNF variants may be mitigated by compensatory increases in frontal brain activity—findings that would need to be confirmed in larger studies.

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Sex and APOE genotype influence Alzheimer’s disease tau neuropathology

10.1101/2020.06.25.20139980 ◽

2020 ◽

Author(s):

Paula Duarte-Guterman ◽

Arianne Y. Albert ◽

Cindy K. Barha ◽

Liisa A.M. Galea

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Sex Differences ◽

Cognitive Decline ◽

Amyloid Beta ◽

Brain Atrophy ◽

Apoe Genotype ◽

Hippocampal Volume ◽

Amyloid Beta Protein ◽

Biological Sex

ABSTRACTAlzheimer’s disease (AD) is characterised by severe cognitive decline and pathological changes in the brain (brain atrophy, hyperphosphorylation of tau, and deposition of toxic amyloid-beta protein). Females have worse neuropathology (AD biomarkers and brain atrophy rates) and cognitive decline than males, however biological sex can interact with diagnosis (mild cognitive impairment (MCI) or AD) and APOE genotype (number of ε4 alleles), although there are discrepancies between studies. Using the ADNI database, we analysed the effect of sex and APOE genotype (number of ε4 alleles) and sex and diagnosis (cognitively normal (CN), MCI, AD) on cognition (memory and executive function), hippocampal volume, CSF amyloid beta, CSF tau and ptau. More males were diagnosed with MCI but there was no sex difference in those diagnosed with AD, suggesting the progression from CN, MCI to AD may be sex-specific. We found, consistent with some studies, that females had higher levels of CSF tau-pathology that was disproportionately affected by APOE genotype compared to males. These results suggest that sex and APOE genotype effects on AD biomarkers may influence sex differences in incidence and progression of MCI and AD. We also detected sex differences in hippocampal volume but the direction was dependent on the method of correction. Females had better memory (including verbal) scores than males, which may suggest a delay in the onset of cognitive decline or diagnosis.

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Higher CSF sTREM2 attenuates ApoE4-related risk for cognitive decline and neurodegeneration

Molecular Neurodegeneration ◽

10.1186/s13024-020-00407-2 ◽

2020 ◽

Vol 15 (1) ◽

Cited By ~ 1

Author(s):

Nicolai Franzmeier ◽

◽

M. Suárez-Calvet ◽

Lukas Frontzkowski ◽

Annah Moore ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Transmembrane Protein ◽

Hippocampal Volume ◽

Memory Decline ◽

Beneficial Effects ◽

Related Risk ◽

Ε4 Allele ◽

Open Question

Abstract Background The Apolipoprotein E ε4 allele (i.e. ApoE4) is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD). TREM2 (i.e. Triggering receptor expressed on myeloid cells 2) is a microglial transmembrane protein brain that plays a central role in microglia activation in response to AD brain pathologies. Whether higher TREM2-related microglia activity modulates the risk to develop clinical AD is an open question. Thus, the aim of the current study was to assess whether higher sTREM2 attenuates the effects of ApoE4-effects on future cognitive decline and neurodegeneration. Methods We included 708 subjects ranging from cognitively normal (CN, n = 221) to mild cognitive impairment (MCI, n = 414) and AD dementia (n = 73) from the Alzheimer’s disease Neuroimaging Initiative. We used linear regression to test the interaction between ApoE4-carriage by CSF-assessed sTREM2 levels as a predictor of longitudinally assessed cognitive decline and MRI-assessed changes in hippocampal volume changes (mean follow-up of 4 years, range of 1.7-7 years). Results Across the entire sample, we found that higher CSF sTREM2 at baseline was associated with attenuated effects of ApoE4-carriage (i.e. sTREM2 x ApoE4 interaction) on longitudinal global cognitive (p = 0.001, Cohen’s f2 = 0.137) and memory decline (p = 0.006, Cohen’s f2 = 0.104) as well as longitudinally assessed hippocampal atrophy (p = 0.046, Cohen’s f2 = 0.089), independent of CSF markers of primary AD pathology (i.e. Aβ1–42, p-tau181). While overall effects of sTREM2 were small, exploratory subanalyses stratified by diagnostic groups showed that beneficial effects of sTREM2 were pronounced in the MCI group. Conclusion Our results suggest that a higher CSF sTREM2 levels are associated with attenuated ApoE4-related risk for future cognitive decline and AD-typical neurodegeneration. These findings provide further evidence that TREM2 may be protective against the development of AD.

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Does Informant-Based Reporting of Cognitive Decline Correlate with Age-Adjusted Hippocampal Volume in Mild Cognitive Impairment and Alzheimer’s Disease?

Journal of Alzheimer s Disease Reports ◽

10.3233/adr-200260 ◽

2021 ◽

Vol 5 (1) ◽

pp. 207-211

Author(s):

Marwan Sabbagh ◽

Justin Miller ◽

Stephen Jones ◽

Aaron Ritter ◽

Jiong Shi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Cognitive Decline ◽

Hippocampal Volume ◽

Screening Tools ◽

Functional Impairments ◽

Diagnostic Status ◽

The Relationship

Background: Informant-based measures are effective screening tools for cognitive impairment. The Alzheimer’s Questionnaire (AQ) is a subjective, informant-based measure that detects amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) with high sensitivity and specificity and has been shown to predict amyloid burden. Objective: To determine whether informant-based report of cognitive decline correlates with hippocampal volume changes in MCI and AD. Methods: Retrospective chart review of 139 clinically referred patients with clinical diagnoses of aMCI or mild dementia due to AD was conducted. Diagnostic status (clinical diagnosis made by a neurologist), NeuroQuant measured MRI brain with percentile rank hippocampal volume, Montreal Cognitive Assessment (MoCA) total, AQ-Total score, and demographic variables were extracted from medical records. Spearman correlation was used to assess the relationship between hippocampal volume and AQ-Total. The AQ was used to assign diagnostic status. Thus, the relationship between the AQ and diagnostic status was excluded. Results: The sample include 88 female and 51 male participants. The mean age was 74.37±9.45, mean MOCA was 22.65±4.18, mean education was 14.80±3.35, and mean AQ score was 10.54±5.22. Hippocampal volume and the AQ correlation was r = –0.33 [95%CI –0.47 to –0.17], p < 0.0001. Conclusion: In a mixed-clinical sample of patients presenting to an outpatient memory disorders center, higher endorseme-nts of functional impairments by caregivers were significantly associated with smaller hippocampal volumes. When used in conjunction with other available measures, these findings further support the role of the AQ in clinical decision-making and demonstrate an additional relationship between clinical measures and volumetric MRI.

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Alzheimer’s disease profiled by fluid and imaging markers: tau PET best predicts cognitive decline

Molecular Psychiatry ◽

10.1038/s41380-021-01263-2 ◽

2021 ◽

Author(s):

Marco Bucci ◽

Konstantinos Chiotis ◽

Agneta Nordberg ◽

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Episodic Memory ◽

Cognitive Decline ◽

Clinical Manifestations ◽

Amyloid Β ◽

Hippocampal Volume ◽

Imaging Results ◽

Tau Pet ◽

Pet Amyloid

AbstractFor early detection of Alzheimer’s disease, it is important to find biomarkers with predictive value for disease progression and clinical manifestations, such as cognitive decline. Individuals can now be profiled based on their biomarker status for Aβ42 (A) or tau (T) deposition and neurodegeneration (N). The aim of this study was to compare the cerebrospinal fluid (CSF) and imaging (PET/MR) biomarkers in each ATN category and to assess their ability to predict longitudinal cognitive decline. A subset of 282 patients, who had had at the same time PET investigations with amyloid-β and tau tracers, CSF sampling, and structural MRI (18% within 13 months), was selected from the ADNI dataset. The participants were grouped by clinical diagnosis at that time: cognitively normal, subjective memory concern, early or late mild cognitive impairment, or AD. Agreement between CSF (amyloid-β-1-42(A), phosphorylated-Tau181(T), total-Tau(N)), and imaging (amyloid-β PET (florbetaben and florbetapir)(A), tau PET (flortaucipir)(T), hippocampal volume (MRI)(N)) positivity in ATN was assessed with Cohen’s Kappa. Linear mixed-effects models were used to predict decline in the episodic memory. There was moderate agreement between PET and CSF for A biomarkers (Kappa = 0.39–0.71), while only fair agreement for T biomarkers (Kappa ≤ 0.40, except AD) and discordance for N biomarkers across all groups (Kappa ≤ 0.14) was found. Baseline PET tau predicted longitudinal decline in episodic memory irrespective of CSF p-Tau181 positivity (p ≤ 0.02). Baseline PET tau and amyloid-β predicted decline in episodic memory (p ≤ 0.0001), but isolated PET amyloid-β did not. Isolated PET Tau positivity was only observed in 2 participants (0.71% of the sample). While results for amyloid-β were similar using CSF or imaging, CSF and imaging results for tau and neurodegeneration were not interchangeable. PET tau positivity was superior to CSF p-Tau181 and PET amyloid-β in predicting cognitive decline in the AD continuum within 3 years of follow-up.

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Age, vascular disease, and Alzheimer’s disease pathologies in amyloid negative elderly adults

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00913-5 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Tengfei Guo ◽

Susan M. Landau ◽

William J. Jagust ◽

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Fdg Pet ◽

Amyloid Β ◽

Hippocampal Volume ◽

Factors Associated ◽

Male Sex ◽

The Relationship

Abstract Background We recently reported that CSF phosphorylated tau (p-Tau181) relative to Aβ40 (CSF p-Tau/Aβ40 ratio) was less noisy and increased associations with Alzheimer’s disease (AD) biomarkers compared to CSF p-Tau181 alone. While elevations of CSF p-Tau/Aβ40 can occur in amyloid-β (Aβ) negative (Aβ-) individuals, the factors associated with these elevations and their role in neurodegeneration and cognitive decline are unknown. We aim to explore factors associated with elevated tau in CSF, and how these elevated tau are related to neurodegeneration and cognitive decline in the absence of Aβ positivity. Methods We examined relationships between CSF p-Tau/Aβ40, and CSF Aβ42/Aβ40, Aβ PET, and white matter hyperintensities (WMH) as well as vascular risk factors in 149 cognitively unimpaired and 52 impaired individuals who were presumably not on the Alzheimer’s disease (AD) pathway due to negative Aβ status on both CSF and PET. Subgroups had 18F-fluorodeoxyglucose (FDG) PET and adjusted hippocampal volume (aHCV), and longitudinal measures of CSF, aHCV, FDG PET, and cognition data, so we examined CSF p-Tau/Aβ40 associations with these measures as well. Results Elevated CSF p-Tau/Aβ40 was associated with older age, male sex, greater WMH, and hypertension as well as a pattern of hippocampal atrophy and temporoparietal hypometabolism characteristic of AD. Lower CSF Aβ42/Aβ40, higher WMH, and hypertension but not age, sex, Aβ PET, APOE-ε4 status, body mass index, smoking, and hyperlipidemia at baseline predicted CSF p-Tau/Aβ40 increases over approximately 5 years of follow-up. The relationship between CSF p-Tau/Aβ40 and subsequent cognitive decline was partially or fully explained by neurodegenerative measurements. Conclusions These data provide surprising clues as to the etiology and significance of tau pathology in the absence of Aβ. It seems likely that, in addition to age, both cerebrovascular disease and subthreshold levels of Aβ are related to this tau accumulation. Crucially, this phenotype of CSF tau elevation in amyloid-negative individuals share features with AD such as a pattern of metabolic decline and regional brain atrophy.

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