Elevated Β-amyloid Research Articles

Early Detection of Amyloid-Related Changes in Memory among Cognitively Unimpaired Older Adults with Daily Digital Testing.

This study was undertaken to determine whether assessing learning over days reveals Alzheimer disease (AD) biomarker-related declines in memory consolidation that are otherwise undetectable with single time point assessments. Thirty-six (21.9%) cognitively unimpaired older adults (aged 60-91 years) were classified with elevated β-amyloid (Aβ+) and 128 (78%) were Aβ- using positron emission tomography with 11C Pittsburgh compound B. Participants completed the multiday Boston Remote Assessment for Neurocognitive Health (BRANCH) for 12 min/day on personal devices (ie, smartphones, laptops), which captures the trajectory of daily learning of the same content on 3 repeated tests (Digit Signs, Groceries-Prices, Face-Name). Learning is computed as a composite of accuracy across all 3 measures. Participants also completed standard in-clinic cognitive tests as part of the Preclinical Alzheimer's Cognitive Composite (PACC-5), with 123 participants undergoing PACC-5 follow-up after 1.07 (standard deviation = 0.25) years. At the cross-section, there were no statistically significant differences in performance between Aβ+/- participants on any standard in-clinic cognitive tests (eg, PACC-5) or on day 1 of multiday BRANCH. Aβ+ participants exhibited diminished 7-day learning curves on multiday BRANCH after 4 days of testing relative to Aβ- participants (Cohen d = 0.49, 95% confidence interval = 0.10-0.87). Diminished learning curves were associated with greater annual PACC-5 decline (r = 0.54, p < 0.001). Very early Aβ-related memory declines can be revealed by assessing learning over days, suggesting that failures in memory consolidation predate other conventional amnestic deficits in AD. Repeated digital memory assessments, increasingly feasible and uniquely able to assess memory consolidation over short time periods, have the potential to be transformative for detecting the earliest cognitive changes in preclinical AD. ANN NEUROL 2024;95:507-517.

Clinical Manifestations.

Accelerated Long-term Forgetting (ALF) is the phenomenon whereby material is retained normally over short intervals (minutes or hours) but forgotten abnormally rapidly over longer periods (days or weeks). ALF may be an early marker of cognitive decline, but little is known about its relationships with preclinical Alzheimer's disease pathology in older adults, and how memory selectivity may influence which material is forgotten. Participants in 'Insight 46', a sub-study of the MRC National Survey of Health and Development (British 1946 birth cohort), completed cognitive and neuroimaging assessments at two time-points (baseline at age ∼70; follow-up ∼2.4 years later). At follow-up, we assessed Complex Figure Drawing (copy; immediate recall; 30-minute recall; 7-day recall). Complex Figure items were categorized as 'outline' or 'detail' (Fig1), to test the hypothesis that forgetting the outline of the structure would be more sensitive to the effect of brain pathologies. ALF scores were calculated as the proportion of material retained after 7 days, relative to 30 minutes. Rates of cerebral atrophy between baseline and follow-up were quantified from T1-weighted MRI using the Brain Boundary Shift Integral (BBSI). β-amyloid status (positive/negative) was determined from 18F-Florbetapir-PET. Baseline serum neurofilament light (NfL) was quantified (Quanterix Simoa assay). Multivariable regression models were used to investigate the effects (mutually adjusted) of β-amyloid status, BBSI and NfL on ALF in n = 316 clinically-normal individuals (50% female; 22% β-amyloid positive; 30% APOE-ε4 carriers), and to explore interactions between these predictors, adjusting for potential confounders including prospectively-collected childhood cognitive ability and education. 'Outline' items were better retained than 'detail' (Fig1). β-amyloid-positive participants had poorer ALF scores for 'outline' (but not 'detail') items (Fig1C; Table 1). Unexpectedly, higher NfL was associated with scores for 'outline' items (Table 1). Greater rate of cerebral atrophy predicted poorer retention among participants with elevated β-amyloid and higher NfL (Table 1; Fig2). These results provide evidence of associations between biomarkers of brain pathologies and ALF in 73-year-olds. Interactions between different biomarkers merit further exploration. ALF may be a sensitive outcome measure for therapeutic trials in preclinical AD. Better retention of 'outline' (vs. 'detail') items illustrates the strategic role of memory selectivity.

Prevalence and incidence of depressive symptoms and diagnosis of depression as associated with elevated amyloid among Medicare beneficiaries with cognitive impairment

BackgroundDepression and cognitive impairment commonly co-occur, and it has been hypothesized that the two share pathological processes. Our objective for this study was to determine the relationship between elevated β-amyloid level and the prevalence and incidence of depressive symptoms and diagnosed depression over two years among fee-for-service Medicare beneficiaries with cognitive impairment. MethodsWe utilized data from the CARE-IDEAS cohort study (N = 2078) including two measures of depressive symptoms (PHQ-2) and administrative claims data to identify pre-scan and incident depression diagnosis in subsample of fee-for-service Medicare beneficiaries (N = 1443). We used descriptive statistics and Poisson regression models with robust covariance. ResultsBeneficiaries whose scan results indicated not-elevated β-amyloid were significantly more likely to have been diagnosed with depression pre-scan (46.4 % vs. 33.1 %). There was no significant association between elevated amyloid and the incidence of depressive symptoms or diagnosed depression. LimitationsThe sample was limited to Medicare beneficiaries with cognitive impairment. Race/ethnic composition and education levels were not representative of the general population and there was substantial loss to follow-up. Mixed depressive / anxious episodes were captured as diagnoses of depression, potentially overestimating depression in this population. ConclusionsThere was a high prevalence and incidence of diagnosed depression in this cohort of Medicare beneficiaries, but the incidence of depressive symptoms and diagnosed depression was not associated with elevated β-amyloid.

DIFFERENCES IN PHYSICAL ACTIVITY AMOUNT AND FRAGMENTATION OVER 24 HOURS BY B-AMYLOID STATUS AND AGE

Abstract β-amyloid is a hallmark of Alzheimer’s disease and can be measured in vivo by PET imaging. Whether PiB+ (elevated β-amyloid) individuals exhibit distinct physical activity patterns throughout the day (i.e., activity amount or fragmentation) is unknown. Using data from 125 BLSA participants (56-95 years) with PET imaging and ≥3 days of wrist accelerometry, we examined associations between PiB status and activity patterns daily and during 6-hour time blocks using multivariable linear regression models. Modification by age was also examined. Daily total activity counts and activity fragmentation did not differ by PiB status (p=0.34 and p=0.70, respectively). Yet, per each additional year of age, PiB+ individuals were more active during early morning (p=0.04) and evening (p=0.029) but trended towards less active in mid-morning (p=0.069) than PiB- individuals. Though replication of findings is needed, older PiB+ participants appeared more active in the late evening/early morning, possibly reflecting altered sleep-time, agitation, or restlessness.

β-Amyloid and Tau Imaging in Chronic Traumatic Brain Injury: A Cross-sectional Study.

Traumatic brain injury (TBI) has been promoted as a risk factor for Alzheimer disease (AD). There is evidence of elevated β-amyloid (Aβ) and tau, the pathologic hallmarks of AD, immediately following TBI. It is not clear whether Aβ and tau remain elevated in the chronic period. To address this issue, we assessed Aβ and tau burden in long-term TBI survivors and healthy controls using PET imaging. Using a cross-sectional design, we recruited individuals following a single moderate to severe TBI at least 10 years previously from an inpatient rehabilitation program. A demographically similar healthy control group was recruited from the community. PET data were acquired using 18F-NAV4694 (Aβ) and 18F-MK6240 (tau) tracers. Aβ deposition was quantified using the Centiloid scale. Tau deposition was quantified using the standardized uptake value ratio (SUVR) in 4 regions of interest (ROIs). As a secondary measure, PET scans were also visually read as positive or negative. We examined PET data in relation to time since injury and age at injury. PET data were analyzed in a series of regression analyses. The sample comprised 87 individuals with TBI (71.3% male; 28.7% female; mean 57.53 years, SD 11.53) and 59 controls (59.3% male; 40.7% female; mean 60.34 years, SD 11.97). Individuals with TBI did not have significantly higher 18F-NAV4694 Centiloid values (p = 0.067) or 18F-MK6240 tau SUVRs in any ROI (p ≤ 0.001; SUVR greater for controls). Visual assessment was consistent with the quantification; individuals with TBI were not more likely than controls to have a positive Aβ (p = 0.505) or tau scan (p = 0.221). No associations were identified for Aβ or tau burden with time since injury (p = 0.057 to 0.332) or age at injury. A single moderate to severe TBI was not associated with higher burden of Aβ or tau pathologies in the chronic period relative to healthy controls. Aβ and tau burden did not show a significant increase with years since injury, and burden did not appear to be greater for those who were older at the time of injury.

Association of β-Amyloid and Vascular Risk on Longitudinal Patterns of Brain Atrophy.

Vascular risk factors and elevated β-amyloid (Aβ) are commonly observed together among older adults. Here, we examined the interactive vs independent effects of systemic vascular risk and Aβ burden on longitudinal gray matter atrophy and how their co-occurrence may be related to cognitive decline in a cohort of clinically normal adults. A secondary goal was to examine whether vascular risk influences gray matter atrophy independently from markers of white matter injury. Participants were 196 adults (age 73.8 ± 6.1 years) from the Harvard Aging Brain Study. Baseline Aβ burden was quantified with Pittsburgh compound B PET. Baseline vascular risk was measured with the Framingham Heart Study cardiovascular disease risk score. Brain atrophy was quantified longitudinally with structural MRI over a median of 4.50 (±1.26) years. Cognition was assessed yearly with the Preclinical Alzheimer Cognitive Composite over a median of 6.25 (±1.40) years. Linear mixed-effects models examined vascular risk and Aβ burden as interactive vs independent predictors of gray matter atrophy, with adjustment for age, sex, years of education, APOE ε4 status, intracranial volume (when appropriate), and their interactions with time. In subsequent models, we adjusted for markers of white matter injury to determine whether vascular risk accelerated brain atrophy independently from diffusion- and fluid-attenuated inversion recovery (FLAIR)-based markers. Mediation analyses examined whether brain atrophy mediated the interactive association of vascular risk and Aβ burden on cognitive decline. Higher vascular risk and elevated Aβ burden interacted to predict more severe atrophy in frontal and temporal lobes, thalamus, and striatum. Higher Aβ burden, but not vascular risk, was associated with more severe atrophy in parietal and occipital lobes, as well as the hippocampus. Adjusting for diffusion- and FLAIR-based markers of white matter injury had little impact on the above associations. Gray matter atrophy mediated the association between vascular risk and cognitive decline at higher levels of Aβ burden. We observed an interaction between elevated vascular risk and higher Aβ burden with longitudinal brain atrophy, which in turn influenced cognitive decline. These results support vascular risk factor management as a potential intervention to slow neurodegeneration and cognitive decline in preclinical Alzheimer disease.

Divergent Cortical Tau Positron Emission Tomography Patterns Among Patients With Preclinical Alzheimer Disease

Characterization of early tau deposition in individuals with preclinical Alzheimer disease (AD) is critical for prevention trials that aim to select individuals at risk for AD and halt the progression of disease. To evaluate the prevalence of cortical tau positron emission tomography (PET) heterogeneity in a large cohort of clinically unimpaired older adults with elevated β-amyloid (A+). This cross-sectional study examined prerandomized tau PET, amyloid PET, structural magnetic resonance imaging, demographic, and cognitive data from the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study from April 2014 to December 2017. Follow-up analyses used observational tau PET data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Harvard Aging Brain Study (HABS), and the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center (together hereinafter referred to as Wisconsin) to evaluate consistency. Participants were clinically unimpaired at the study visit closest to the tau PET scan and had available amyloid and tau PET data (A4 Study, n = 447; ADNI, n = 433; HABS, n = 190; and Wisconsin, n = 328). No participants who met eligibility criteria were excluded. Data were analyzed from May 11, 2021, to January 25, 2022. Individuals with preclinical AD with heterogeneous cortical tau PET patterns (A+T cortical+) were identified by examining asymmetrical cortical tau signal and disproportionate cortical tau signal relative to medial temporal lobe (MTL) tau. Voxelwise tau patterns, amyloid, neurodegeneration, cognition, and demographic characteristics were examined. The 447 A4 participants (A+ group, 392; and normal β-amyloid group, 55), with a mean (SD) age of 71.8 (4.8) years, included 239 women (54%). A total of 36 individuals in the A+ group (9% of the A+ group) exhibited heterogeneous cortical tau patterns and were further categorized into 3 subtypes: asymmetrical left, precuneus dominant, and asymmetrical right. A total of 116 individuals in the A+ group (30% of the A+ group) showed elevated MTL tau (A+T MTL+). Individuals in the A+T cortical+ group were younger than those in the A+T MTL+ group (t61.867 = -2.597; P = .03). Across the A+T cortical+ and A+T MTL+ groups, increased regional tau was associated with reduced hippocampal volume and MTL thickness but not with cortical thickness. Memory scores were comparable between the A+T cortical+ and A+T MTL+ groups, whereas executive functioning scores were lower for the A+T cortical+ group than for the A+T MTL+ group. The prevalence of the A+T cortical+ group and tau patterns within the A+T cortical+ group were consistent in ADNI, HABS, and Wisconsin. This study suggests that early tau deposition may follow multiple trajectories during preclinical AD and may involve several cortical regions. Staging procedures, especially those based on neuropathology, that assume a uniform trajectory across individuals are insufficient for disease monitoring with tau imaging.

The prospective association between periodontal disease and brain imaging outcomes: The Atherosclerosis Risk in Communities study.

We investigate if periodontal disease is prospectively associated with cerebrovascular and neurodegenerative markers of dementia and Alzheimer's pathology. N=1306 participants (Visit 5 mean age=76.5 [standard deviation=5.4] years) in the Atherosclerosis Risk in Communities study with completed dental exams at Visit 4 underwent brain magnetic resonance imaging scans at Visit 5 while N=248 underwent positron emission tomography scans. Participants were classified as edentulous or, among the dentate, by the modified Periodontal Profile Class. Brain volumes were regressed on periodontal status in linear regressions. Cerebrovascular measures and β-amyloid positivity were regressed on periodontal status in logistic regressions. Periodontal disease was not associated with brain volumes, microhaemorrhages, or elevated β-amyloid. Compared with periodontally healthy individuals, odds ratios [95% confidence interval] for all-type infarcts were 0.37 [0.20, 0.65] for severe tooth loss and 0.56 [0.31, 0.99] for edentulous participants. Within the limitations of this study, periodontal disease was not associated with altered brain volumes, microhaemorrhages, or β-amyloid positivity. Tooth loss was associated with lower odds of cerebral infarcts.

Abstract 13659: Cerebral Small Vessel Disease is a Potent Independent Risk Factor for Alzheimer’s Disease

Alzheimer’s Disease (AD) is the leading cause of dementia worldwide. Current treatments may slow the progression of the disease but cannot reverse the pathology, thereby confirming the medical need for measures of prevention and early detection. Recent studies established a connection between cardiovascular disease (CVD) risk factors and AD. Small vessel disease, which shares similar risk factors and pathology as CVD, is receiving attention as a potential risk factor for AD as well. We sought to quantify the risk associated with confirmed diagnosis of cerebral small vessel disease (CSVD) for the development of AD as a first step to defining the condition as a treatment target for preventing AD. We hypothesized patients with image-based evidence of CSVD would have a greater risk of having AD.In this retrospective clinical study, we selected patients from the National Alzheimer’s Coordinating Center database with image-based evidence of CSVD including lacunar infarction, microhemorrhage, and white matter hyperintensity (n=3,895). We quantified the risk of each of these conditions for association with clinical AD, elevated β-amyloid, and tau protein accumulation. In addition, we compared the rates of AD development between men and women within these CSVD populations. Using a linear regression analysis, we controlled for shared comorbidities between CSVD and AD. We observed an increased risk as defined by odds ratio (OR) of AD in patients with microhemorrhage (OR=1.32, p=0.04). Patients with white matter hyperintensity also exhibited increased risk of developing AD, which increased with disease severity (Moderate: OR= 1.63, p&lt;0.01; Extensive: OR=2.72, p&lt;0.01). Lacunar infarction did not demonstrate independent risk for developing AD. CSVD did not confer any additional risk for increased tau protein or amyloid based on imaging. The risk of AD was not higher for women as compared to men with confirmed CSVD. Here we elucidate a clear association between CSVD and risk of AD and observe increased risk with the extent of the disease. With a more comprehensive understanding of these relationships, CSVD imaging could be used as an early biomarker for accelerated AD and provide an opportunity to test methods for controlling CSVD as a novel early intervention.

Abstract P123: Prospective Association Between Periodontal Disease And Brain Imaging Markers Of Cerebrovascular And Neurodegenerative Disease: The Atherosclerosis Risk In Communities Study

Background: Periodontal disease (PD) is associated positively with neurocognitive outcomes. Few studies have investigated the relationship between PD and indicators of brain aging and vascular changes. Hypothesis: PD is associated with greater cerebral small vessel disease, lower total and regional brain volumes and elevated β-amyloid (Aβ) deposition. Methods: We included 6,793 participants who received full-mouth periodontal examinations and tooth counts at Visit 4 (1996-1998) of the Atherosclerosis Risk in Communities Study. We used a modified 3-level version of the Periodontal Profile Class to categorize PD based on severity and extent of gingival inflammation and tissue loss. Among participants who attended Visit 5 (2011-2013), n=1,306 received a brain MRI and n=248 received a PET scan. Total brain volume, Alzheimer’s disease signature volume, and presence of microhemorrhages and cerebral infarctions were ascertained via 3T MRI; Aβ deposition was assessed from PET. We regressed brain volumes on baseline PD status using weighted multivariable linear regression. Presence of cerebrovascular microhemorrhages, infarctions, or elevated Aβ (standardized uptake value ratio&gt;1.2) were regressed on PD category using logistic models. We examined the interaction between Apolipoprotein E ε4 ( APOE ) allele possession and PD categories on the Aβ outcome. Results: Prevalence of baseline periodontal disease was 73% (959/1306) and 87% (206/248) among the MRI and PET subgroups, respectively. PD was not associated with volumetric brain measures nor microhemorrhages. PD was inversely associated with the odds of subcortical and lacunar infarctions. PD and Aβ were not associated in main effect or interaction analyses, although there was a notably stronger association among carriers of APOE . Conclusion: PD was not associated with altered brain structure, cerebral microhemorrhages or elevated Aβ deposition. Counter to the hypothesis, PD and complete tooth loss were inversely associated with cerebral infarctions.

Apolipoprotein E4 Moderates the Association Between Vascular Risk Factors and Brain Pathology.

The strongest genetic risk factor for late-onset Alzheimer disease (AD), Apolipoprotein E4 (APOE4), increases cardiovascular disease risk and may also act synergistically with vascular risk factors to contribute to AD pathogenesis. Here, we assess the interaction between APOE4 and vascular risk on cerebrovascular dysfunction and brain pathology. This is an observational study of cognitively normal older adults, which included positron emission tomography imaging and vascular risk factors. We measured beat-to-beat blood pressure and middle cerebral artery velocity at rest and during moderate-intensity exercise. Cerebrovascular measures included cerebrovascular conductance index and the cerebrovascular response to exercise. There was a significant interaction between resting cerebrovascular conductance index and APOE4 carrier status on β-amyloid deposition (P=0.026), with poor conductance in the cerebrovasculature associated with elevated β-amyloid for the APOE4 carriers only. There was a significant interaction between non-high-density lipoprotein cholesterol and APOE4 carrier status (P=0.014), with elevated non-high-density lipoprotein cholesterol predicting a blunted cerebrovascular response to exercise in APOE4 carriers and the opposite relationship in noncarriers. Both cerebral and peripheral vascular risk factors are preferentially associated with brain pathology in APOE4 carriers. These findings provide insight into pathogenic vascular risk mechanisms and target strategies to potentially delay AD onset.

Gene- and age-informed screening for preclinical Alzheimer's disease trials.

Elevated β-amyloid is used to enroll individuals into preclinical Alzheimer's disease trials, but the screening process is inefficient and expensive. Novel enrichment methods are needed to improve efficiency of enrollment. Alzheimer's disease incidence rates and a polygenic hazard score were used to create a gene- and age-defined ADAge. An ADAge cutpoint was chosen to optimally predict β-amyloid positivity among clinically normal Alzheimer's Disease Neuroimaging Initiative participants and applied to an independent Alzheimer's Disease Research Center validation cohort. The impact of ADAge enrichment on screening costs was evaluated in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease trial data. In the validation cohort, the ADAge-enriched sample had a higher proportion of individuals with elevated β-amyloid (difference [95% CI] 0.19[0.07 to 0.33]) than the unenriched sample. ADAge enrichment lowered screening costs by $4.41 million (31.00%) in the real-world clinical trial scenario. ADAge enrichment provides for a more efficient and cost-effective means to enroll clinically normal individuals with elevated β-amyloid in clinical trials.

SNX8 Enhances Non-amyloidogenic APP Trafficking and Attenuates Aβ Accumulation and Memory Deficits in an AD Mouse.

Dysregulation of various APP trafficking components in the endosome has been previously implicated in Alzheimer’s disease (AD). Although single nucleotide polymorphisms within the gene locus encoding the endosomal component, SNX8 have been previously associated with AD, how SNX8 levels are altered and its contribution to AD onset is currently unknown. Here, we observe decreased expression of SNX8 in human AD and AD mouse brain. SNX8 predominantly localized to early and late endosomes, where SNX8 overexpression enhanced total APP levels, cell surface APP distribution and consequent soluble APPα cleavage. SNX8 depletion resulted in elevated β-amyloid (Aβ) levels, while SNX8 overexpression reduced Aβ levels in cells and in an APP/PS1 AD mouse model. Importantly, SNX8 overexpression rescued cognitive impairment in APP/PS1 mice. Together, these results implicate a neuroprotective role for SNX8 in enhancing non-amyloidogenic APP trafficking and processing pathways. Given that endosomal dysfunction is an early event in AD, restoration of dysfunctional endosomal components such as SNX8 may be beneficial in future therapeutic strategies.

Brain expression of the vascular endothelial growth factor gene family in cognitive aging and alzheimer\u2019s disease

Vascular endothelial growth factor (VEGF) is associated with the clinical manifestation of Alzheimer’s disease (AD). However, the role of the VEGF gene family in neuroprotection is complex due to the number of biological pathways they regulate. This study explored associations between brain expression of VEGF genes with cognitive performance and AD pathology. Genetic, cognitive, and neuropathology data were acquired from the Religious Orders Study and Rush Memory and Aging Project. Expression of ten VEGF ligand and receptor genes was quantified using RNA sequencing of prefrontal cortex tissue. Global cognitive composite scores were calculated from 17 neuropsychological tests. β-amyloid and tau burden were measured at autopsy. Participants (n = 531) included individuals with normal cognition (n = 180), mild cognitive impairment (n = 148), or AD dementia (n = 203). Mean age at death was 89 years and 37% were male. Higher prefrontal cortex expression of VEGFB, FLT4, FLT1, and PGF was associated with worse cognitive trajectories (p ≤ 0.01). Increased expression of VEGFB and FLT4 was also associated with lower cognition scores at the last visit before death (p ≤ 0.01). VEGFB, FLT4, and FLT1 were upregulated among AD dementia compared with normal cognition participants (p ≤ 0.03). All four genes associated with cognition related to elevated β-amyloid (p ≤ 0.01) and/or tau burden (p ≤ 0.03). VEGF ligand and receptor genes, specifically genes relevant to FLT4 and FLT1 receptor signaling, are associated with cognition, longitudinal cognitive decline, and AD neuropathology. Future work should confirm these observations at the protein level to better understand how changes in VEGF transcription and translation relate to neurodegenerative disease.

Influence of tau PET, amyloid PET, and hippocampal volume on cognition in Alzheimer disease.

To examine the independent and interactive influences of neuroimaging biomarkers on retrospective cognitive decline. A total of 152 middle-aged and older adult participants with at least 2 clinical and cognitive assessments, a Clinical Dementia Rating score of 0 or 0.5, and a flortaucipir (18F-AV-1451) tau PET scan, a florbetapir (18F-AV-45) amyloid PET scan, and a structural MRI scan were recruited from the Knight Alzheimer Disease Research Center at Washington University in St. Louis. Cognition was assessed with standard measures reflecting episodic memory, executive functioning, semantic fluency, and processing speed. Results from retrospective longitudinal analyses showed that each biomarker had a univariate association with the global cognitive composite; however, when each marker was analyzed in a single statistical model, only tau was a significant predictor of global cognitive decline. There was an interaction between tau and amyloid such that tau-related cognitive decline was worse in individuals with high amyloid. There was also an interaction with hippocampal volume indicating that individuals with high levels of all 3 pathologies exhibited the greatest declines in cognition. Additional analyses within each cognitive domain indicated that tau had the largest negative influence on tests of episodic memory and executive functioning. Together, these results suggest that increasing levels of tau most consistently relate to declines in cognition preceding biomarker collection. These findings support models of Alzheimer disease (AD) staging that suggest that elevated β-amyloid alone may be insufficient to produce cognitive change in individuals at risk for AD and support the use of multiple biomarkers to stage AD progression.

Multi-scale modeling of altered synaptic plasticity related to Amyloid [formula omitted] effects

As suggested by Palop and Mucke (2010) pathologically elevated β-amyloid (Aβ) impairs long term potentiation (LTP) and enhances long term depression (LTD) possible underlying mechanisms in Alzheimer’s Disease (AD). In the present paper we adopt and further elaborate a phenomenological computational model of bidirectional plasticity based on the calcium control hypothesis of Shouval et al. (2002). First, to account for Aβ effects the activation function Ω was modified assuming competition between LTP and LTD, and parameter sets were identified that well describe both normal and pathological synaptic plasticity processes. Second, a biophysically plausible kinetic model of bidirectional synaptic plasticity by D’Alcantara et al. (2003) was used to support findings of the phenomenological model and to further explain underlying kinetic processes. Model fitting pointed out molecular contributors, particularly calcineurin and type 1 protein phosphatase that might contribute to observed physiological disturbances in AD.

Cued memory decline in biomarker-defined preclinical Alzheimer disease.

To determine whether a decline in cued recall is observable in the preclinical stage of Alzheimer disease (AD) in clinically normal older adults with elevated β-amyloid (Aβ) burden on PET imaging. Clinically normal older adults underwent baseline neuroimaging (PET to assess Aβ+/- status and MRI) and annual neuropsychological testing. Cox proportional hazards models were used to assess the relative risk of cued memory decline (drop of 1, 2, 3, or 4 points on the total score of the Free and Cued Selective Reminding Test) in relation to neuroimaging measures, functional status, age, sex, and education. A total of 276 older adults (Clinical Dementia Rating = 0, mean Mini-Mental State Examination score = 29 ± 1.06) were followed up for a mean of 3.6 ± 1.2 years. Despite the infrequency of cued memory decline (only 19% of participants scored ≤46/48 in total recall by year 3), Aβ+ participants were 3.55 times (95% confidence interval = 1.77-7.12) more likely to exhibit decline in total recall (≤46/48) compared with their Aβ- peers. Furthermore, Aβ+ participants who scored ≤46/48 had smaller hippocampal volumes (t = 3.37, p = 0.001) and evidence of early functional decline, i.e., greater risk of progression to global Clinical Dementia Rating of 0.5 (χ2 = 14.30, p < 0.001), compared with their Aβ+ peers with intact total recall. Cued memory decline in healthy older adults may be particularly indicative of Aβ-related decline during the preclinical stage of AD and useful for identifying Aβ+ clinically normal individuals at greatest risk of short-term clinical progression.

Evolution of neurodegeneration-imaging biomarkers from clinically normal to dementia in the Alzheimer disease spectrum

The availability of antemortem biomarkers for Alzheimer's disease (AD) enables monitoring the evolution of neurodegenerative processes in real time. Pittsburgh compound B (PIB) positron emission tomography (PET) was used to select participants in the Mayo Clinic Study of Aging and the Mayo Alzheimer's Disease Research Center with elevated β-amyloid, designated as “A+,” and hippocampal volume and 18fluorodeoxyglucose (FDG) positron emission tomography were used to characterize participants as having evidence of neurodegeneration (“N+”) at the baseline evaluation. There were 145 clinically normal (CN) A+ individuals, 62 persons with mild cognitive impairment (MCI) who were A+ and 20 with A+ AD dementia. Over a period of 1–6 years, MCI A+N+ individuals showed declines in medial temporal, lateral temporal, lateral parietal, and to a lesser extent, medial parietal regions for both FDG standardized uptake value ratio and gray matter volume that exceeded declines seen in the CN A+N+ group. The AD dementia group showed declines in the same regions on FDG standardized uptake value ratio and gray matter volume with rates that exceeded that in MCI A+N+. Expansion of regional involvement and faster rate of neurodegeneration characterizes progression in the AD pathway.

β-amyloid, hippocampal atrophy and their relation to longitudinal brain change in cognitively normal individuals

Recent literature has examined baseline hippocampal volume and extent of brain amyloidosis to test potential synergistic effects on worsening cognition and extent of brain atrophy. Use of hippocampal volume in prior studies was based on the notion that limbic circuit degeneration is an early manifestation of the Alzheimer's Disease (AD) pathophysiology. To clarify these interactions early in the AD process, we tested the effects of amyloid and baseline normalized hippocampal volume on longitudinal brain atrophy rates in a group of cognitively normal individuals. Results showed that the combination of elevated β-amyloid and baseline hippocampal atrophy is associated with increased rates specific to the limbic circuit and splenium. Importantly, this atrophy pattern emerged from a voxelwise analysis, corroborated by regression models over region of interests in native space. The results are broadly consistent with previous studies of the effects of amyloid and baseline hippocampal atrophy in normals, while pointing to accelerated atrophy of AD-vulnerable regions detectable at the preclinical stage.

Deficits in hippocampal-dependent transfer generalization learning accompany synaptic dysfunction in a mouse model of amyloidosis.

Elevated β-amyloid and impaired synaptic function in hippocampus are among the earliest manifestations of Alzheimer's disease (AD). Most cognitive assessments employed in both humans and animal models, however, are insensitive to this early disease pathology. One critical aspect of hippocampal function is its role in episodic memory, which involves the binding of temporally coincident sensory information (e.g., sights, smells, and sounds) to create a representation of a specific learning epoch. Flexible associations can be formed among these distinct sensory stimuli that enable the "transfer" of new learning across a wide variety of contexts. The current studies employed a mouse analog of an associative "transfer learning" task that has previously been used to identify risk for prodromal AD in humans. The rodent version of the task assesses the transfer of learning about stimulus features relevant to a food reward across a series of compound discrimination problems. The relevant feature that predicts the food reward is unchanged across problems, but an irrelevant feature (i.e., the context) is altered. Experiment 1 demonstrated that C57BL6/J mice with bilateral ibotenic acid lesions of hippocampus were able to discriminate between two stimuli on par with control mice; however, lesioned mice were unable to transfer or apply this learning to new problem configurations. Experiment 2 used the APPswe PS1 mouse model of amyloidosis to show that robust impairments in transfer learning are evident in mice with subtle β-amyloid-induced synaptic deficits in the hippocampus. Finally, Experiment 3 confirmed that the same transfer learning impairments observed in APPswePS1 mice were also evident in the Tg-SwDI mouse, a second model of amyloidosis. Together, these data show that the ability to generalize learned associations to new contexts is disrupted even in the presence of subtle hippocampal dysfunction and suggest that, across species, this aspect of hippocampal-dependent learning may be useful for early identification of AD-like pathology.