Posterior Cingulate Glucose Metabolism, Hippocampal Glucose Metabolism, and Hippocampal Volume in Cognitively Normal, Late-Middle-Aged Persons at 3 Levels of Genetic Risk for Alzheimer Disease

ObjectiveTo determine the ordering of changes in Alzheimer disease (AD) biomarkers among cognitively normal individuals.MethodsCross-sectional data, including CSF analytes, molecular imaging of cerebral fibrillar β-amyloid (Aβ) with PET using the [11C] benzothiazole tracer Pittsburgh compound B (PiB), MRI-based brain structures, and clinical/cognitive outcomes harmonized from 8 studies, collectively involving 3,284 cognitively normal individuals 18 to 101 years of age, were analyzed. The age at which each marker exhibited an accelerated change (called the change point) was estimated and compared across the markers.ResultsAccelerated changes in CSF Aβ1-42 (Aβ42) occurred at 48.28 years of age and in Aβ42/Aβ40 ratio at 46.02 years, followed by PiB mean cortical standardized uptake value ratio (SUVR) with a change point at 54.47 years. CSF total tau (Tau) and tau phosphorylated at threonine 181 (Ptau) had a change point at ≈60 years, similar to those for MRI hippocampal volume and cortical thickness. The change point for a cognitive composite occurred at 62.41 years. The change points for CSF Aβ42 and Aβ42/Aβ40 ratio, albeit not significantly different from that for PiB SUVR, occurred significantly earlier than that for CSF Tau, Ptau, MRI markers, and the cognitive composite. Adjusted analyses confirmed that accelerated changes in CSF Tau, Ptau, MRI markers, and the cognitive composite occurred at ages not significantly different from each other.ConclusionsOur findings support the hypothesized early changes of amyloid in preclinical AD and suggest that changes in neuronal injury and neurodegeneration markers occur close in time to cognitive decline.

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Genetic risk for Alzheimer disease predicts hippocampal volume through the human lifespan

Neurology Genetics ◽

10.1212/nxg.0000000000000506 ◽

2020 ◽

Vol 6 (5) ◽

pp. e506 ◽

Cited By ~ 2

Author(s):

Kristine B. Walhovd ◽

Anders M. Fjell ◽

Øystein Sørensen ◽

Athanasia Monika Mowinckel ◽

Céline Sonja Reinbold ◽

...

Keyword(s):

Alzheimer Disease ◽

Genetic Risk ◽

Hippocampal Volume ◽

Older Age ◽

Polygenic Risk Score ◽

Polygenic Risk ◽

Human Lifespan ◽

Negative Effect ◽

Additive Mixed Models ◽

Age Range

ObjectiveTo test the hypothesis that genetic risk for Alzheimer disease (AD) may represent a stable influence on the brain from early in life, rather than being primarily age dependent, we investigated in a lifespan sample of 1,181 persons with a total of 2,690 brain scans, whether higher polygenic risk score (PGS) for AD and presence of APOE ε4 was associated with lower hippocampal volumes to begin with, as an offset effect, or possibly faster decline in older age.MethodsUsing general additive mixed models, we assessed the relations of PGS for AD, including variants in APOE with hippocampal volume and its change in a cognitively healthy longitudinal lifespan sample (age range: 4–95 years, mean visit age 39.7 years, SD 26.9 years), followed for up to 11 years.ResultsAD-PGS and APOE ε4 in isolation showed a significant negative effect on hippocampal volume. The effect of a 1 sample SD increase in AD-PGS on hippocampal volume was estimated to –36.4 mm3 (confidence interval [CI]: –71.8, –1.04) and the effect of carrying ε4 allele(s) –107.0 mm3 (CI: –182.0, –31.5). Offset effects of AD-PGS and APOE ε4 were present in hippocampal development, and interactions between age and genetic risk on volume change were not consistently observed.ConclusionsEndophenotypic manifestation of polygenic risk for AD may be seen across the lifespan in cognitively healthy persons, not being confined to clinical populations or older age. This emphasizes that a broader population and age range may be relevant targets for attempts to prevent AD.

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Is this phishing? Older age is associated with greater difficulty discriminating between safe and fraudulent emails

10.31234/osf.io/upf6c ◽

2020 ◽

Author(s):

Matthew D. Grilli ◽

Katelyn S. McVeigh ◽

Ziad M. Hakim ◽

Aubrey Anne Ladd Wank ◽

Sarah J. Getz ◽

...

Keyword(s):

Older Adults ◽

Genetic Risk ◽

Ecological Validity ◽

Identity Theft ◽

Older Age ◽

Social Worlds ◽

Middle Aged ◽

Cognitively Normal ◽

Online Fraud ◽

Laboratory Task

As our social worlds become increasingly digitally connected, so too has concern about older adults falling victim to so-called “phishing” emails, which attempt to deceive a person into identity theft and fraud. In 65 cognitively normal middle-aged to older adults, we investigated whether older age was associated with reduced accuracy in judging the suspiciousness of phishing and genuine emails that commonly populate an inbox, using a novel laboratory task with established ecological validity, combined with computational modeling. We found that older age was related to a suboptimal shift in the discrimination of safe from malicious emails. Lower episodic memory and increased genetic risk for Alzheimer’s disease also contributed to higher risk profiles. These findings suggest that among cognitively normal middle-aged and older adults, older age, lower cognition, and increased Alzheimer’s genetic risk may elevate a person’s susceptibility to online fraud because of difficulty detecting phishing emails.

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Cognitively Normal APOE ε4 Carriers Have Specific Elevation of CSF SNAP-25

10.21203/rs.3.rs-122858/v1 ◽

2020 ◽

Author(s):

Omar Hameed Butt ◽

Justin M Long ◽

Rachel L. Henson ◽

Elizabeth Herries ◽

Courtney L. Sutphen ◽

...

Keyword(s):

Alzheimer Disease ◽

Genetic Risk ◽

Carrier Status ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Cognitively Normal ◽

Disease Research ◽

Total Tau ◽

T Tau ◽

Phosphorylated Tau 181

Abstract Background: Cerebrospinal fluid (CSF) synaptosomal-associated protein 25 (SNAP-25) and neurogranin are recently described biomarkers for synaptic integrity that are known to be elevated in the CSF of symptomatic Alzheimer disease (AD). Their relationship with Apolipoprotein E (APOE) ε4 carrier status, the major genetic risk factor for AD, remains unclear.Methods: In this study, CSF SNAP-25 and neurogranin were compared in cognitively normal APOE ε4 carriers and non-carriers (n=274, mean age 65.0 ± 9.0 years, 39% APOE ε4 carriers, 58% female) enrolled at the Knight Alzheimer Disease Research Center, and in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database.Results: SNAP-25, a biomarker of pre-synaptic integrity, was specifically elevated in APOE ε4 carriers versus non-carriers (5.95 ± 1.72 pg/ml, 4.44 ± 1.40 pg/ml, p <0.0001), even after adjusting for age, sex, years of education, and amyloid status (p <0.0001). In contrast, CSF neurogranin, a biomarker of post-synaptic integrity, did not vary by APOE ε4 status. Further, CSF total tau (t-tau), phosphorylated-tau-181 (ptau181), and neurofilament light chain (NfL) also did not vary by APOE ε4 status. Similar results were observed in the ADNI cohort. Conclusion: Our findings suggest APOE ε4 carriers have both amyloid-related and amyloid-independent presynaptic disruption as reflected by elevated CSF SNAP-25 levels. In contrast, post-synaptic disruption as reflected by elevations in CSF neurogranin is related to amyloid status.

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Faculty Opinions recommendation of Relationships between tau and glucose metabolism reflect alzheimer's disease pathology in cognitively normal older adults.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.733457144.793547250 ◽

2018 ◽

Author(s):

Daniela Perani

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

Glucose Metabolism ◽

Cognitively Normal

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Cerebrospinal Fluid Hypocretin and Nightmares in Dementia Syndromes

Dementia and Geriatric Cognitive Disorders Extra ◽

10.1159/000509585 ◽

2021 ◽

pp. 19-25

Author(s):

Lynn Marie Trotti ◽

Donald L. Bliwise ◽

Glenda L. Keating ◽

David B. Rye ◽

William T. Hu

Keyword(s):

Cerebrospinal Fluid ◽

Alzheimer Disease ◽

Cholinesterase Inhibitor ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Cognitively Normal ◽

Dementia Patients ◽

Sleep Questionnaires ◽

Sleep Alterations ◽

Normal Controls

Background/Aims: Hypocretin promotes wakefulness and modulates REM sleep. Alterations in the hypocretin system are increasingly implicated in dementia. We evaluated relationships among hypocretin, dementia biomarkers, and sleep symptoms in elderly participants, most of whom had dementia. Methods: One-hundred twenty-six adults (mean age 66.2 ± 8.4 years) were recruited from the Emory Cognitive Clinic. Diagnoses were Alzheimer disease (AD; n = 60), frontotemporal dementia (FTD; n = 21), and dementia with Lewy bodies (DLB; n = 20). We also included cognitively normal controls (n = 25). Participants and/or caregivers completed sleep questionnaires and lumbar puncture was performed for cerebrospinal fluid (CSF) assessments. Results: Except for sleepiness (worst in DLB) and nocturia (worse in DLB and FTD) sleep symptoms did not differ by diagnosis. CSF hypocretin concentrations were available for 87 participants and normal in 70, intermediate in 16, and low in 1. Hypocretin levels did not differ by diagnosis. Hypocretin levels correlated with CSF total τ levels only in men (r = 0.34; p = 0.02). Lower hypocretin levels were related to frequency of nightmares (203.9 ± 29.8 pg/mL in those with frequent nightmares vs. 240.4 ± 46.1 pg/mL in those without; p = 0.05) and vivid dreams (209.1 ± 28.3 vs. 239.5 ± 47.8 pg/mL; p = 0.014). Cholinesterase inhibitor use was not associated with nightmares or vivid dreaming. Conclusion: Hypocretin levels did not distinguish between dementia syndromes. Disturbing dreams in dementia patients may be related to lower hypocretin concentrations in CSF.

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Financial Capacity and Regional Cerebral Tau in Cognitively Normal Older Adults, Mild Cognitive Impairment, and Alzheimer’s Disease Dementia

Journal of Alzheimer s Disease ◽

10.3233/jad-201122 ◽

2020 ◽

pp. 1-10

Author(s):

Christopher Gonzalez ◽

Nicole S. Tommasi ◽

Danielle Briggs ◽

Michael J. Properzi ◽

Rebecca E. Amariglio ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Early Stage ◽

Cognitively Normal ◽

Financial Capacity ◽

Posterior Cingulate ◽

Dorsolateral Prefrontal

Background: Financial capacity is often one of the first instrumental activities of daily living to be affected in cognitively normal (CN) older adults who later progress to amnestic mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia. Objective: The objective of this study was to investigate the association between financial capacity and regional cerebral tau. Methods: Cross-sectional financial capacity was assessed using the Financial Capacity Instrument –Short Form (FCI-SF) in 410 CN, 199 MCI, and 61 AD dementia participants who underwent flortaucipir tau positron emission tomography from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Linear regression models with backward elimination were used with FCI-SF total score as the dependent variable and regional tau and tau-amyloid interaction as predictors of interest in separate analyses. Education, age sex, Rey Auditory Verbal Learning Test Total Learning, and Trail Making Test B were used as covariates. Results: Significant associations were found between FCI-SF and tau regions (entorhinal: p < 0.001; inferior temporal: p < 0.001; dorsolateral prefrontal: p = 0.01; posterior cingulate: p = 0.03; precuneus: p < 0.001; and supramarginal gyrus: p = 0.005) across all participants. For the tau-amyloid interaction, significant associations were found in four regions (amyloid and dorsolateral prefrontal tau interaction: p = 0.005; amyloid and posterior cingulate tau interaction: p = 0.005; amyloid and precuneus tau interaction: p < 0.001; and amyloid and supramarginal tau interaction: p = 0.002). Conclusion: Greater regional tau burden was modestly associated with financial capacity impairment in early-stage AD. Extending this work with longitudinal analyses will further illustrate the utility of such assessments in detecting clinically meaningful decline, which may aid clinical trials of early-stage AD.

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