Preclinical Stage Of Alzheimer's Disease Research Articles

Altered EEG Theta and Alpha Band Functional Connectivity in Mild Cognitive Impairment During Working Memory Coding.

Individuals with mild cognitive impairment (MCI), the preclinical stage of Alzheimer disease (AD), suffer decline in their visual working memory (WM) functions. Using large-scale network analysis of electroencephalography (EEG), the current study intended to investigate if there are differences in functional connectivity properties extracted during visual WM coding stages between MCI patients and normal controls (NC). A total of 21 MCI patients and 20 NC performed visual memory tasks of load four, while 32-channel EEG recordings were acquired. The functional connectivity properties were extracted from the acquired EEGs by the directed transform function (DTF) via spectral Granger causal analysis. Brain network analyses revealed distinctive brain network patterns between the two groups during the WM coding stage. Compared with the NC, MCI patients exhibited a reduced visual network connectivity of the frontal-temporal in θ (4-7Hz) band. A likely compensation mechanism was observed in MCI patients, with a strong brain functional connectivity of the frontal-occipital and parietal-occipital in both θ and α (8-13Hz) band. Further analyses of the network core node properties based on the differential brain network showed that, in θ band, there was a significant difference in the out-degree of the frontal lobe and parietal lobe between the two groups, while in α band, such difference was located only in the parietal lobe. The current study found that, in MCI patients, dysconnectivity is found from the prefrontal lobe to bilateral temporal lobes, leading to increased recruitment of functional connectivity in the frontal-occipital and parietal-occipital direction. The dysconnectivity pattern of MCI is more complex and primarily driven by core nodes Pz and Fz. These results significantly expanded previous knowledge of MCI patients' EEG dynamics during WM tasks and provide new insights into the underpinning neural mechanism MCI. It further provided a potential therapeutic target for clinical interventions of the condition.

Aging and Alzheimer’s Disease Have Dissociable Effects on Local and Regional Medial Temporal Lobe Connectivity

AbstractBackgroundThe extent to which pathological processes in aging and Alzheimer’s disease (AD) relate to functional disruption of the medial temporal lobe (MTL)‐dependent brain networks is poorly understood. To address this knowledge gap, we examined functional connectivity (FC) alterations between anterior and posterior regions of the MTL and in MTL‐associated functional communities – the Anterior‐Temporal (AT) and Posterior‐Medial (PM) networks – in normal agers, individuals with preclinical AD, and patients with Mild Cognitive Impairment or mild dementia due to AD.MethodIn this cross‐sectional study, we analyzed data from 179 individuals from the Aging Brain Cohort study of the Penn ADRC. Detailed information about participants is provided in Table 1. For intra‐MTL FC comparisons, the MTL subregions were segmented using the automated segmentation of hippocampal subfields‐T1 (ASHS‐T1) pipeline (Fig. 1a). When modeling the MTL’s interactions with the rest of the cortex, we employed four MTL ROIs (left/right × anterior/posterior) derived from an ex vivo atlas of tau accumulation in the MTL. Our functional datasets were preprocessed using a customized fMRIprep pipeline. Sparse network estimations and modularity‐based consensus clustering were used to reconstruct the AT and PM network systems (Fig. 1b). Age effect analyses and group comparisons along the AD continuum were performed using the General Linear Model within the network‐based statistical framework.ResultsThe preclinical stage of AD was characterized by increased FC between the perirhinal cortex and other regions of the MTL, as well as between the anterior MTL and its direct neighbors in the AT network (Fig. 1c‐d). This effect was not present in symptomatic AD. Instead, symptomatic patients displayed reduced hippocampal and intra‐PM connectivity. For normal aging, our results led to three main conclusions (for visuals, see Fig. 2). First, intra‐network connectivity of both the AT and PM networks decreases with age. Second, FC between the anterior and posterior segments of the MTL declines with age. Finally, within the MTL, we observed greater vulnerability of the posterior MTL subregions, particularly the parahippocampal cortex, to age‐associated FC decline.ConclusionTogether, the current results provide evidence for aberrant connectivity in the preclinical stage of AD that may have implications for early AD pathophysiology.

Aging and Alzheimer’s Disease Have Dissociable Effects on Local and Regional Medial Temporal Lobe Connectivity

AbstractBackgroundThe extent to which pathological processes in aging and Alzheimer’s disease (AD) relate to functional disruption of the medial temporal lobe (MTL)‐dependent brain networks is poorly understood. To address this knowledge gap, we examined functional connectivity (FC) alterations between anterior and posterior regions of the MTL and in MTL‐associated functional communities – the Anterior‐Temporal (AT) and Posterior‐Medial (PM) networks – in normal agers, individuals with preclinical AD, and patients with Mild Cognitive Impairment or mild dementia due to AD.MethodIn this cross‐sectional study, we analyzed data from 179 individuals from the Aging Brain Cohort study of the Penn ADRC. Detailed information about participants is provided in Table 1. For intra‐MTL FC comparisons, the MTL subregions were segmented using the automated segmentation of hippocampal subfields‐T1 (ASHS‐T1) pipeline (Fig. 1a). When modeling the MTL’s interactions with the rest of the cortex, we employed four MTL ROIs (left/right × anterior/posterior) derived from an ex vivo atlas of tau accumulation in the MTL. Our functional datasets were preprocessed using a customized fMRIprep pipeline. Sparse network estimations and modularity‐based consensus clustering were used to reconstruct the AT and PM network systems (Fig. 1b). Age effect analyses and group comparisons along the AD continuum were performed using the General Linear Model within the network‐based statistical framework.ResultThe preclinical stage of AD was characterized by increased FC between the perirhinal cortex and other regions of the MTL, as well as between the anterior MTL and its direct neighbors in the AT network (Fig. 1c‐d). This effect was not present in symptomatic AD. Instead, symptomatic patients displayed reduced hippocampal and intra‐PM connectivity. For normal aging, our results led to three main conclusions (for visuals, see Fig. 2). First, intra‐network connectivity of both the AT and PM networks decreases with age. Second, FC between the anterior and posterior segments of the MTL declines with age. Finally, within the MTL, we observed greater vulnerability of the posterior MTL subregions, particularly the parahippocampal cortex, to age‐associated FC decline.ConclusionTogether, the current results provide evidence for aberrant connectivity in the preclinical stage of AD that may have implications for early AD pathophysiology.

Clinical Manifestations.

Episodic memory impairment is a widely known core clinical symptom of Alzheimer's disease (AD). However, it is still uncertain if it is possible to detect meaningful signs or changes in memory in the preclinical stage of AD due to their within-normal-range performance. In the current study, we investigated both verbal and visuospatial memory as markers to track the disease progression in the preclinical AD. We selected cognitively normal (CN) participants from the Gwangju Alzheimer's Disease and Related Dementia Cohort in Korea. We included a group of CN individuals who showed a significant amyloid-beta (aß) deposition, defined by amyloid PET, at baseline and completed at least two follow-up evaluations. In the final analysis, we included 130 individuals in the preclinical stage of AD. Episodic memory measures were delayed recall scores from the Rey Complex Figure Test (RCFT_delayed) and Seoul Verbal Learning test (SVLT_delayed). We performed logistic regression analysis with stepwise selection to examine associations between memory tests and progression. The mean follow-up month was 36.21. Twenty-one (16.2%) participants were converted to MCI (n = 19) or AD dementia (n = 2), while the rest stayed as CN. When both RCFT_delayed and SVLT_delayed at baseline were entered in the logistic regression model, only the RCFT_delayed was significantly associated with the progression (OR = 0.288; 95% CI, 0.138-0.602; p = 0.001). When change scores were added to the model, RCFT_delayed at baseline (OR = 0.223; 95% CI, 0.101-0.496; p < 0.001), RCFT_delayed change score (OR = 0.470; 95% CI, 0.258-0.857; p = 0.014), and SVLT_delayed change score (OR = 0.523; 95% CI, 0.290-0.942; p = 0.031), were significant. Our results suggest that visuospatial, not verbal, memory measures may play an important role in sensitively detecting the relevant sign of future progression in asymptomatic individuals. In terms of verbal memory, the longitudinal decline was associated with progression. Our study suggests that the inclusion of a visuospatial memory test and repeated evaluation can help to detect the earliest decline in the preclinical stages of AD.

Depressive symptoms in relation to markers of neurodegeneration, cerebrovascular injury and Alzheimer’s Disease (AD) in community‐dwelling older adults: a plasma and multimodal neuroimaging study

AbstractBackgroundDepressive symptoms are common with aging and Alzheimer’s Disease (AD). Both neurodegenerative and cerebrovascular diseases have been postulated as underlying mechanisms, but it’s unclear if they contribute to depressive symptom pathogenesis in preclinical stages of AD. Probing these mechanisms using both central (neuroimaging) and peripheral (plasma) biomarkers is critical to gain insight into the neurobiology of depression and provide opportunities for clinical translation.MethodLongitudinal data were analyzed from 350 Harvard Aging Brain Study participants, an observational cohort study of older adults who are cognitively unimpaired and have no/minimal depressive symptoms at baseline. Depressive symptoms were assessed annually with the 30‐item Geriatric Depression Scale (GDS) (average follow up = 7.2+/‐3.4yrs). At baseline, all participants underwent blood sampling for a plasma marker of general neurodegeneration, neurofilament light (NfL) and 11 cerebrovascular markers in plasma. Participants also underwent baseline amyloid (PiB) PET‐ wherein a cortical amyloid composite was derived‐ and baseline and subsequent MRI scans every three years‐ to derive slopes of regional cortical thickness and global white matter hyperintensities (WMH). Linear mixed effects models examined relationships between longitudinal GDS scores and predictors: (NfL or cerebrovascular markers)*time, and covariates: age, sex, education. Secondary model examined plasma markers and amyloid as interactive predictors of GDS, and repeated analyses using predictors: regional cortical thickness (neurodegeneration) or global WMH (cerebrovascular injury) slopes.ResultHigher baseline levels of NfL and of ICAM1, a marker of cerebrovascular injury, predicted increasing GDS scores over time (NfL: β = 0.03+/‐0.01, t = 2.7, p = 0.007; ICAM1: β = 0.02+/‐0.01, t = 2.2, p = 0.03). Each also interacted with amyloid in predicting GDS scores: (NfL X PiB: β = ‐0.03+/‐0.01, t = ‐2.42, p = 0.02; ICAM1 X PiB: β = 0.023+/‐0.01, t = 2.44, p = 0.02). Regarding neuroimaging correlates, medialorbitofrontal cortical thickness slope (β = ‐0.03+/‐0.01, t = ‐2.94, p = 0.004), but not global WMH slope, predicted increasing GDS over time. None of the other cerebrovascular markers interacted with amyloid in predicting GDS.ConclusionFindings suggest that cerebrovascular injury, and peripheral and central biomarkers of regional neurodegeneration, alone and in synergy with amyloid burden, are associated with depressive symptoms in cognitively unimpaired older adults. Future studies incorporating additional measures of peripheral and central neurodegeneration, tauopathy, and cerebrovascular injury are needed to guide AD prevention efforts targeting depressive symptoms.

Specific damages to olfactory‐related structures and their relation to episodic memory in Individuals at Risk of Alzheimer’s Disease.

AbstractBackgroundOne of the major challenges in the diagnosis of Alzheimer’s disease (AD) is to increase the specificity of the early diagnosis. While episodic memory impairment is a sensitive marker of AD, other markers are needed to improve diagnostic specificity. A promising biomarker might be a cerebral atrophy of the central olfactory processing areas in the early stages of the disease since an impairment of olfactory identification is present at early clinical stages of AD. Our goal was to evaluate whether reduced grey matter volume (GMV) in the central olfactory processing regions could be observed in early and preclinical stages of AD. We also aimed to verify if GMV of central olfactory processing regions is associated with episodic memory performance.Method166 participants from the Consortium for the Early Identification of Alzheimer’s Disease‐Quebec (CIMA‐Q) (92 with subjective cognitive decline ‐ SCD, 40 with mild cognitive impairment ‐ MCI and 34 cognitively healthy controls) were included. We performed regions of interest (ROI) analysis using a mask of the regions that are activated during olfactory stimulation. We also extracted GMV outside ROIs, representing non‐olfactory areas of these regions, i.e., regions which do not respond to olfactory stimulation. Verbal episodic memory was assessed using a free word recall task from Memoria Word Recall test.ResultCompared to controls (p = .019) and participants with SCD (p = .003), participants with MCI exhibited a smaller total GMV of central olfactory processing regions, with a significant interaction effect between region and group (p = .004). Specifically, the piriform cortex, amygdala, entorhinal cortex, and left hippocampus were significantly smaller in individuals with MCI (p≤.05, corrected). In contrast, when comparing GMV outside ROIs between the three groups, there was no such interaction between region and group (p = .428). Additionally, GMV in the olfactory areas of the piriform cortex, amygdala, and left hippocampal gyrus was correlated with episodic memory performance, while GMV in the non‐olfactory areas of the left hippocampus and left parahippocampal gyrus was correlated with episodic memory performance (p≤.05, corrected).ConclusionThere is a specific neurodegeneration of limbic and medial‐temporal olfactory‐structures in MCI, GMV of these regions being related to cognitive performance.

Naturalistic Assessment of Reaction Time Variability in Older Adults at Risk for Alzheimer’s Disease

AbstractBackgroundBreakdowns in attentional control may underscore cognitive changes seen in the earliest stages of Alzheimer’s disease (AD). One way to measure these changes is to assess variability in cognitive performance. Variability in cognition may be most evident when repeatedly sampled over hours or days and in different environmental contexts or at different times of day. We analyzed data from an ongoing smartphone‐based study of cognition in AD which utilizes extremely brief cognitive tests taken remotely over several days in natural environments.MethodOlder adults (N = 319, aged 75 +/‐ 5 years) completed repeated cognitive testing on the Ambulatory Research in Cognition (ARC) platform and had CSF or PET amyloid biomarkers and APOE genotype available. RTSD was assessed in a brief processing speed task by taking the SD of correct RTs. All models adjusted for baseline age, education, and gender.ResultAveraging across sessions, symptomatic participants (indicated by Clinical Dementia Rating® (CDR®) &gt; 0) showed more variability than asymptomatic (CDR 0) participants (p = 0.009). APOE ε4 carriers showed more variability than non‐carriers, although this was not significant (p = 0.067). More fine‐grained models considered RTSD within each session (e.g. from trial‐to‐trial) using mixed effects models. Symptomatic participants exhibited greater trial‐to‐trial RTSD compared to asymptomatic participants (p = 0.001). APOE ε4 carriers also exhibited greater trial‐to‐trial RTSD compared to non‐carriers (p = 0.004). When limiting the sample to asymptomatic participants to determine if there were changes in the preclinical stage of AD, there remained a strong APOE ε4 effect, with carriers exhibiting greater trial‐to‐trial RTSD than non‐carriers (p = 0.005). Interestingly, amyloid was not significant in any models.ConclusionOlder adults at risk for AD show increased RTSD even in brief assessments. These subtle fluctuations in attention were most evident in APOE e4 carriers at very short time intervals, and less so when averaged across trials and sessions. Overall, these findings suggest that fluctuations in attention in preclinical AD are most evident from moment to moment, highlighting the need for fine‐grained and repeated assessment of attentional control.

Specific damages to olfactory‐related structures and their relation to episodic memory in Individuals at Risk of Alzheimer’s Disease

AbstractBackgroundOne of the major challenges in the diagnosis of Alzheimer’s disease (AD) is to increase the specificity of the early diagnosis. While episodic memory impairment is a sensitive marker of AD, other markers are needed to improve diagnostic specificity. A promising biomarker might be a cerebral atrophy of the central olfactory processing areas in the early stages of the disease since an impairment of olfactory identification is present at early clinical stages of AD. Our goal was to evaluate whether reduced grey matter volume (GMV) in the central olfactory processing regions could be observed in early and preclinical stages of AD. We also aimed to verify if GMV of central olfactory processing regions is associated with episodic memory performance.Method166 participants from the Consortium for the Early Identification of Alzheimer’s Disease‐Quebec (CIMA‐Q) (92 with subjective cognitive decline ‐ SCD, 40 with mild cognitive impairment ‐ MCI and 34 cognitively healthy controls) were included. We performed regions of interest (ROI) analysis using a mask of the regions that are activated during olfactory stimulation. We also extracted GMV outside ROIs, representing non‐olfactory areas of these regions, i.e., regions which do not respond to olfactory stimulation. Verbal episodic memory was assessed using a free word recall task from Memoria Word Recall test.ResultCompared to controls (p = .019) and participants with SCD (p = .003), participants with MCI exhibited a smaller total GMV of central olfactory processing regions, with a significant interaction effect between region and group (p = .004). Specifically, the piriform cortex, amygdala, entorhinal cortex, and left hippocampus were significantly smaller in individuals with MCI (p = .05, corrected). In contrast, when comparing GMV outside ROIs between the three groups, there was no such interaction between region and group (p = .428). Additionally, GMV in the olfactory areas of the piriform cortex, amygdala, and left hippocampal gyrus was correlated with episodic memory performance, while GMV in the non‐olfactory areas of the left hippocampus and left parahippocampal gyrus was correlated with episodic memory performance (p = .05, corrected).ConclusionThere is a specific neurodegeneration of limbic and medial‐temporal olfactory‐structures in MCI, GMV of these regions being related to cognitive performance.

Sex/gender differences in subjective cognitive decline’s association to cognition and depression

AbstractBackgroundDespite the fact that women are more likely to develop Alzheimer’s disease (AD) than men, and develop pathological changes at an earlier age, women often receive diagnoses later. This disparity is possibly due to women’s verbal memory advantage, and the fact that verbal memory tests are often the gold‐standard for diagnostics. Further, a recent meta‐analysis found that female sex/gender was associated with greater depression which is often a differential diagnosis for dementia (Eikelboom 2022). Understanding sex/gender differences in Subjective Cognitive Decline (SCD) is critical to closing the care gap, as SCD is thought to be a preclinical stage of AD where intervention may be most effective. Integration of challenging cognitive testing, including non‐verbal memory tests, along with measurement of depression, is key for defining this preclinical stage. In this study, we compare SCD’s associations with non‐verbal and verbal list‐learning and depression as a function of sex/gender.Method97 cognitively unimpaired older adults were recruited for this study. Participants completed surveys regarding SCD and depression (Geriatric Depression Scale [GDS]) and cognitive testing. Non‐verbal memory was assessed with the Biber Figure Learning Test – Extended (BFLT‐E), a challenging non‐verbal figure‐learning test. Verbal memory was assessed with the Loewenstein‐Acevedo Scales for Semantic Interference and Learning (LASSI‐L). Both tests are associated with early AD changes. Linear regressions were conducted and stratified by sex/gender to assess the relationships of cognition and mood with SCD. Models of cognitive performance included age and education as covariates.ResultVerbal list‐learning (LASSI‐L) predicted SCD in men (R2= .416, β = ‐.390, p = .017), but not in women (R2 = .217, β = ‐.173, p = .167). Non‐verbal figure‐learning, as measured by the BFLT‐E, predicted SCD in women (R2 = .267, β = ‐.342, p = .006), but not in men (R2 = .175, β = ‐.334, p = .078). Similarly, depression predicted SCD in women (R2 = .109, β = .330, p = .007), but not in men (R2 = .003, β = .055, p = .763).ConclusionResults demonstrate that in AD risk states such as SCD, cognitive dysfunction may manifest differently for women than men. Clinical care settings should consider integration of non‐verbal memory tests such as BFLT‐E along with regular screening of depression in order to address the inequities in diagnostics for women.

Sleep fragmentation is associated with lower cerebral structural integrity in females

AbstractBackgroundSex is a risk factor for Alzheimer’s disease (AD), with females accounting for two‐thirds of all cases. Epidemiological evidence showcases that sleep disturbances also increase AD risk, with females reporting more disrupted sleep in ageing compared to males. However, little is understood about how objective measures of sleep are associated with brain structural integrity, especially regarding the role of sex. We explored associations between actigraphy‐measured sleep and regional cortical thickness in middle‐aged cognitively unimpaired (CU) adults at risk of AD.MethodsWe included 151 CU adults from the ALFASleep project (mean age 64.6 years, 64.2% females) (Table 1). Correlates of sleep quality were measured using actigraphy (Actiwatch2®, Philips Respironics) for two weeks. The cortical thickness (CTh) of the “Alzheimer’s disease (AD) signature” composite region of interest (ROI) was calculated using FreeSurfer v6.0. We performed separate general linear models with CTh as the dependent variable, and actigraphy‐derived sleep parameters [total sleep time (TST), sleep efficiency, sleep latency, wake after sleep onset (WASO) and sleep fragmentation] as the predictors of interest. All models were corrected for age, sex, APOE‐ε4 status, sleep medication use and the time difference between MRI and actigraphy data acquisition. To investigate whether sex modified these associations we performed interactions between each actigraphy measure and sex. Finally, we performed stratified analyses to understand which group was driving any significant effects.ResultsHigher sleep fragmentation was associated with lower CTh (p = 0.006) in the whole group (Figure 1). Results remained significant after correction for sleep medication use. Significant interactions were found between sex and sleep efficiency, WASO and sleep fragmentation (Table 2, Figure 2). Stratified analyses showed that, among females, lower sleep efficiency (p = 0.003), higher WASO and higher fragmentation were significantly associated with lower CTh (p&lt;0.001), without any significant associations among males.ConclusionsIn CU, higher sleep fragmentation is associated with reduced cortical thickness in areas vulnerable to early AD‐related neurodegeneration. Importantly, in females, lower sleep efficiency, as well as higher WASO and sleep fragmentation are associated with lower integrity in AD‐vulnerable regions. These results suggest that females in the preclinical stages of AD are more vulnerable to the effects of sleep fragmentation.

Hub brain regions for the remote spatial association between tau and Amyloid‐β proteins

AbstractBackgroundThe pathology of Alzheimer’s disease (AD) is characterized by two types of proteins: intracellular neurofibrillary tau tangles and extracellular β‐amyloid (Aβ) plaques. In the present observational studies, spatial discrepancies between these two proteins across the brain regions are well‐documented. However, the association between these two proteins remains elusive in different stages of depositions.MethodsWe aimed to investigate the remote association between tau and Aβ uptakes by using 572 elderlies 67.11 ± 6.08 (476 healthy control (HC) and 96 mild cognitive impairments (MCI)) Aβ and tau positron emission tomography (PET) scans. We leveraged 47 tau‐PET and 97 Aβ‐PET scans of healthy young individuals (aged 20‐40) to find the regional cut‐points for 68 cortical regions in the brain. Then by using these cut‐points and tau PET scans of all elderly individuals, we identified four groups of individuals (no tau phase, pre‐acceleration phase, acceleration phase, and post‐acceleration phase) (Table 1). Finally, a regional multiple linear regression model is performed for each group to detect the hubs region based on the remote association between each target region of tau and all other regions Aβ in the different phases of tau accumulations (controlling for gender, age, intracranial volume, and each target region Aβ).ResultsFirst, we show that the left and right entorhinal cortex, and right parahippocampal tau are the hubs of remote association with Aβ in several cortical regions (especially temporal regions) in the early stage of aggregation (Figure 1). Second, we identify tau in the same regions, continuing to demonstrate the highest remote associations with cortical Aβ (Figure 2) in the acceleration phase.ConclusionThe remote association appears in medial temporal lobe (MTL) tau during the early stage, as well as the later stage of tau accumulation (pre‐acceleration and acceleration phases). While the cellular mechanism of remote association is still elusive, in vivo studies have demonstrated that the Aβ triggers tau deposition indirectly in distal regions. Understanding the association between tau and Aβ at the preclinical stage of AD is critically important for a better consideration of tau spreading, especially in disease‐related brain regions.

Increased neural activity relates to greater neuropsychiatric symptoms and beta‐amyloid plaque load in cognitively normal older adults

AbstractBackgroundEpidemiological studies have shown that individuals predisposed to experiencing psychological stress, and those affected with diseases associated with chronic stress such as depression and anxiety have an increased risk of developing Alzheimer’s disease (AD). These findings may imply that poor resilience to psychological stress is not simply a characteristic of dementia, but may reflect mechanisms involved in disease etiology. In this study, we examined the level of neural activity as a potential mechanism of linking individual susceptibility to psychological stress and AD‐related neuropathology across the spectrum of AD.MethodsA total of 166 participants (mean age = 74.21; 90 Females) spanning diagnostic spectrums along cognitively normal (CN) individuals and AD patients was selected for analysis from the ADNI2 database based on the availability of resting state fMRI and AV45 PET data. Neural activity was quantified by applying the amplitude of low frequency fluctuations (ALFF) method to time series of fMRI blood oxygenation‐level‐dependent signals (in the frequency range of 0.01‐0.08 Hz) obtained during resting‐state fMRI (rsfMRI) scan. Amyloid pathology was quantified by AV45‐SUVR measures that were normalized to the cerebellum. Mini‐Mental State Exam (MMSE) and the total Neuropsychiatric Inventory Questionnaire (NPI‐Q) scores were used as cognitive and stress susceptibility measures.ResultsBehavioral measures of stress were significantly associated with brain Aβ indices and neural activity across the entire cohort, spanning from CN older adults to AD patients (ps&lt;0.05). Relationships between the neural activity, stress responses, and Aβ deposition, however, differ by diagnostic groups. As stress indicators increased, CN subjects exhibited increased activity in several brain regions including the regions within the default mode network (DMN), while AD participants exhibited decreased activity across the brain. Moreover, as brain Aβ load increased, CN participants experienced DMN hyperactivity, while AD participants experienced hypoactivity.ConclusionThese results indicate a potential link between heightened stress responses and increased susceptibility to the development of AD pathologies through neuronal hyperactivity, especially in the preclinical stage of AD. Alleviating stress and regulating stress responses may be important modifiable factors and intervention strategies that could help prevent and intervene the development of AD pathology.

Clinical Manifestations.

The preclinical stage of Alzheimer disease (AD) is a clinically silent period that is detectable through neuroimaging and biofluid biomarkers of amyloid, tau, and neurodegeneration. We evaluated whether performance on cognitively-focused complex daily tasks is associated with cerebrospinal fluid (CSF) biomarkers of brain amyloidosis or tau pathology in cognitively normal (CN) older adults. In this cross-sectional analysis of an ongoing longitudinal cohort study, CN older adults performed three cognitively-focused complex tasks of daily living (shopping, checkbook balancing, and medication management) from the Performance Assessment of Self-Care Skills (PASS) in their home. PASS tasks were scored for independence (cues required to complete task) and adequacy of performance (quality and process, efficiency, redundant actions). Participants also had a CSF sample obtained within two years of completing the PASS. CSF amyloid (Aβ42, Aβ40) and CSF tau phosphorylated at position 181 (p-tau181) were measured with Lumipulse immunoassays. Nonparametric partial correlations were used to examine the associations between task performance and biomarkers of AD (CSF Aβ42/Aβ40 and CSF p-tau181), controlling for age, gender, and level of education. 122 CN participants (mean age 74.4 years, 53% female, 88% white) were included. After controlling for age, gender, and years of education, worse performance on complex daily tasks was associated with lower CSF Aβ42/Aβ40 (more cues required: Spearman rho = -0.213, p = 0.03), and there was a trend towards lower adequacy (rho = 0.161, p = 0.08). There were no significant associations with CSF p-tau181. This study suggests that worse performance on complex daily tasks in CN older adults may be associated with greater amyloid burden. These findings could lead to a better understanding of functional changes that may be associated with amyloidosis prior to the onset of noticeable memory symptoms in AD or related dementias.

Two‐year longitudinal outcomes of subjective cognitive decline in Hispanics compared to non‐Hispanic Whites

AbstractBackgroundHispanics are at higher risk for Alzheimer disease (AD) than non‐Hispanic Whites (NHW), motivating further study of differences and risk factors at the preclinical level. Subjective cognitive decline (SCD) is considered a preclinical AD stage, but its features and outcomes in Hispanics are less studied. We investigated the differences in longitudinal change in SCD phenotype, cognition, and function among Hispanics compared to NHW.MethodLongitudinal analyses were performed on consecutive participants with SCD who were evaluated at the NYU Alzheimer’s Disease Research Center. Inclusion criteria were self‐identification as Hispanic (n = 23) or NWH (n = 165) and a 2‐year follow‐up visit. Demographics, conversion rate to mild cognitive impairment (MCI), SCD characteristics, and psychometric performance were analyzed by t‐test, multiple linear regression models, or Cox models as appropriate. Models were adjusted for age, sex, education, depression, and baseline values.ResultHispanics were at higher risk for conversion to MCI (HR: 6.57, 95% CI 1.25‐34.47, p = 0.02596). Hispanic ethnicity was associated with increased SCD severity in time as measured via the total Brief Cognitive Rating Scale (BCRS) score (OR: 4.28, 95% CI 1.42‐12.83, p = 0.0094), and in specific BCRS domains: mood and behavior (OR: 0.18, 95% CI 0.03‐0.89, p = 0.0355) and calculation (OR: 29.68, 95% CI 4.02‐219.18, p = 0.0009). Global cognitive function by Mini‐Mental State Examination had a higher risk of declining in time in Hispanics (HR: 2.83, CI 1.09‐7.35, p = 0.0320). Likelihood of decline in domain‐specific tests associated with Hispanic ethnicity for Trails A (HR: 4.05, 95% CI 1.93‐8.47, p = 0.0002), Trails B (HR: 3.16, 95% CI 1.62‐6.14, p = 0.0007), and delayed paragraph recall (HR: 2.08, 95% CI 1.01‐4.24, p = 0.0444).ConclusionHispanics present a higher risk of conversion from SCD to MCI than NHW. Apart from stage conversion, subjective and objective measure of cognition worsen more in Hispanics, but in a domain‐specific manner. These findings suggests that Hispanics not only decline at a faster rate, but that this decline is expressed with a different phenotype. This should be considered when studying this population in preclinical investigations.

Identifying the optimal age to intervene in Alzheimer’s disease prevention trials: Validation of Emax modelling in sporadic Alzheimer’s disease

AbstractBackgroundMany clinical trials of disease‐modifying therapies which seek to delay or prevent Alzheimer’s disease (AD) currently exist. However, a limitation of these trials is the absence of considering the earliest age groups at which decline in cognition can be detected to guide optimal participant recruitment.Previous work has shown that in people with Down syndrome, Emax modelling can be used to identify the trajectory of cognitive decline in the preclinical and prodromal stages of AD. We aimed to validate Emaxmodelling to identify the earliest age of change in cognition in people who developed sporadic AD and compare these individuals to healthy controls without AD.MethodOur sample consisted of participants aged 65 years old from the Enquête Sante ́ Psychologique – Risques, Incidence et Traitement (ESPRIT) study. Participants were categorised into two groups based on whether they were ever diagnosed with possible and probable AD while enrolled in the study (n = 101) or did not receive a diagnosis of any subtype of dementia (n = 1392, our healthy control group). We included measures of general cognitive functioning (Mini Mental State Examination; MMSE), verbal fluency, visual memory (Benton Visual Retention Test) and executive functioning (Trail Making Test).ResultIn people with AD, the earliest decline in general cognitive functioning could be detected in the 67‐71 age band while verbal fluency appears to decline from the 41‐45 age band and visual memory in the 82‐86 age band according to our model. In healthy controls, general cognitive functioning shows early change in the 87‐91 age band while verbal fluency starts to decline in the 43‐47 age band and executive functioning in the 85‐89 age band. Models for Trail Making Models for people with AD and visual memory for controls were not well fitted to the data.ConclusionWe have shown that sensitivity to change depend on the primary outcome so authors designing trials need to ensure the research question, population and primary outcome are consistent. This has implications particularly for trials targeting the stages of disease before dementia diagnosis.

Functional and structural changes of cholinergic basal forebrain in asymptomatic PSEN1 E280A mutation carriers compared with non‐mutation carriers from the API ADAD Colombia cohort

AbstractBackgroundImaging studies showed early atrophy of the cholinergic basal forebrain in prodromal sporadic Alzheimer’s disease (AD) and alterations of the posterior basal forebrain functional connectivity in amyloid positive, but cognitively normal people. Similar investigations in familial cases of AD are still lacking. Here we investigated whether basal forebrain volume, metabolism, and posterior connectivity were already reduced in preclinical stages of autosomal dominant AD.MethodWe analyzed baseline data from 242 cognitively unimpaired subjects (69% PSEN1 E280A mutation carriers; mean age = 38 years; 62% female; mean education = 9 years) enrolled in the API ADAD Colombia Trial including available MRI, FDG‐PET and cognitive measures. We determined volume and metabolism of the basal forebrain, and of the hippocampus as a comparison region. In addition, we created connectivity maps from resting state fMRI data using anterior and posterior BF seed regions. We carried out Bayesian ANCOVA to determine evidence in favor or against an effect of carriers’ status on volumes, metabolism, functional connectivity and cognitive scores.ResultWe found inconclusive to moderate evidence in favor of no effect of carrier status on basal forebrain (BF10 = 0.884) and hippocampal volumes (BF10 = 0.964) or metabolism (BF10 = 0.187) (see Figure) in preclinical (CDR = 0) and prodromal (CDR = 0.5) subjects. However, we found extreme evidence that delayed memory was decreased already in preclinical mutation carriers (BF10 = 4066.73). Yet, we found no conclusive evidence that this subtle memory impairment was associated with basal forebrain (BF10 = 0.582) or hippocampal (BF10 = 0.906) atrophy.ConclusionOur findings indicate absence of basal forebrain and hippocampus atrophy or metabolic impairment in preclinical mutation carriers. Interestingly, memory impairment was already present in preclinical mutation carriers. This is consistent with results of the Dominantly Inherited Alzheimer Network (DIAN) cohort showing early cognitive impairment in mutation carriers, but no significant group differences in hippocampal volume until later stages of the disease. These previous and our findings may suggest that different brain regions and networks are affected in preclinical stages of familial AD than in preclinical sporadic AD, which should be investigated in future studies.

Genome‐wide association meta‐analysis identifies a novel LRBA locus for brain age acceleration in two independent Korean Cohorts

AbstractBackgroundAging is a key risk factor for Alzheimer’s disease (AD) and has a significant structural impact on the brain. Machine learning approaches have been developed to estimate the biological age of the brain from MRI scans. Here, we performed genome‐wide association (GWA) analysis of accelerated brain aging in two independent Korean AD cohorts.MethodParticipants included 1,738 Korean older adults from two independent cohorts that consisted of preclinical and clinical stages of AD (n = 1,209 from the K‐ROAD cohort (Korea‐Registries to Overcome and Accelerate Dementia Research Project) and n = 529 from the KBASE cohort (Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease)). Brain age was estimated from structural MRI scans using brainageR. Brain age acceleration (predicted brain age ‐ chronological age) was calculated for each participant. Genetic variants associated with brain age acceleration were assessed after accounting for age, sex, APOE e4 carrier status, and diagnosis. Meta‐analysis was performed using METAL, followed by transcriptomic analysis. Polygenic risk scores for brain age acceleration were calculated with PRS‐CS using GWAS meta‐analysis summary statistics, followed by molecular imaging analysis.ResultGWA meta‐analysis identified six intronic SNPs in the LRBA (Lipopolysaccharide responsive Beige‐like Anchor) locus on chromosome 4 as significantly associated with brain age acceleration with the most significant signal at rs7699001 (Fig. 1; p&lt;5´10−8). LRBA is highly expressed in the brain, especially in microglia. The LRBA gene is differentially expressed in AD compared to cognitively normal older adults. rs7699001 was associated with expression levels of the LRBA gene in tissue from several organs including brain. rs7690001 has been reported to be associated with inferior parietal cortical thickness in non‐Hispanic whites (p = 5´10−3). Polygenic risk scores of brain age acceleration in the K‐ROAD cohort were significantly associated with amyloid‐β deposition measured from amyloid PET scans (Fig. 2; p = 2.7´10−4).Conclusion LRBA is a novel genetic risk factor for brain aging in the Korean population with relevance for AD. The microglial LRBA protein may be involved in phagocytosis, which has been implicated in aging processes and AD progression. Replication in other populations and mechanistic follow‐up studies are warranted.This work was supported by U01AG072177.

SPDGFRβ and neuroinflammation are associated with AD biomarkers and differ by race: The ASCEND Study.

There remains an urgent need to identify preclinical pathophysiological mechanisms of Alzheimer's disease (AD) development in high-risk, racially diverse populations. We explored the relationship between cerebrospinal fluid (CSF) markers of vascular injury and neuroinflammation with AD biomarkers in middle-aged Black/African American (B/AA) and non-Hispanic White (NHW) participants. Adults (45-65 years) with a parental history of AD were enrolled (n=82). CSF and blood biomarkers were collected at baseline and year 2. CSF total tau (t-tau), phosphorylated tau (p-tau), and amyloid beta (Aβ)40 were elevated at year 2 compared to baseline. CSF soluble platelet-derived growth factor receptor β (sPDGFRβ) levels, a marker of pericyte injury, correlated positively with t-tau, p-tau, Aβ40 markers of vascular injury, and cytokines at baseline and year 2. CSF sPDGFRβ and tau were significantly lower in B/AA than NHW. Vascular dysfunction and neuroinflammation may precede cognitive decline and disease pathology in the very early preclinical stages of AD, and there are race-related differences in these relationships. Cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers changed over 2 years in high-risk middle-aged adults. Markers of vascular dysfunction were associated with the CSF biomarkers amyloid beta and tau. AD biomarkers were lower in Black compared to non-Hispanic White individuals. Markers of vascular dysfunction were lower among Black individuals.

29 Smoking as a Risk Factor: Altered Brain Activity in Areas Associated with Preclinical Alzheimer's Disease

Objective:Those at genetic risk for Alzheimer's Disease (AD) because of the ApoE ε4 allele show differences in activation during olfactory information processing and memory in areas such as MTL structures, entorhinal cortex, posterior cingulate, precuneus, and inferior parietal lobule, suggesting preclinical AD neuropathology and olfactory impairment as a biomarker for predicting later AD onset (Murphy, 2019). The effects of smoking on AD have varied, with early studies suggesting either no effect or protective effects, and recent studies suggesting smoking as a risk factor for AD but with the need for further investigation in preclinical stages. Therefore, this study focused on olfaction and smoking as risk factors for preclinical AD neuropathology by studying differences in fMRI BOLD signal changes in smokers and nonsmokers during olfactory tasks.Participants and Methods:Archival data from 25 non-demented older adults recruited from the UCSD Alzheimer's Disease Research Center who completed an Assessment Scale-Cognitive Subscale (ADAS-Cog) and functional MRI scans at 3T, acquired during performance of an odor identification task. Odor Identification (OI) measured correct (hits) or incorrect (misses) identification of odors presented by an olfactometer to deliver the odor stimuli in short, controlled durations during fMRI scanning.Results:fMRI data were preprocessed using fMRIprep, smoothed at 4mm, scaled, and first level analyses were conducted using 3dDeconvolve in AFNI with time points corresponding to hits and misses as regressors. Differences between smokers and nonsmokers revealed smokers show a larger difference in BOLD signal change from hits minus misses at five significant clusters (p = 0.01 with the minimum cluster size [voxels] at 42). Peak areas of significant clusters included the right precuneus, right calcarine gyrus, left inferior parietal lobule, left superior parietal lobule, and left middle occipital gyrus. Analyses suggested a greater difference in activity between hits and misses in smokers compared to nonsmokers, with more activity during hits.Conclusions:Differences in activation between smokers and nonsmokers during an olfactory identification task, with greater activity in smokers during hits, suggests greater effort to correctly identify an odor. These findings of hyperactivation in areas (such as the precuneus and inferior parietal lobule) are similar to findings of hyperactivation during odor memory observed in studies of ε4 carriers during preclinical stages. Results provide further insight into smoking as a risk factor for AD. Moreover, results suggest the risk of smoking could potentially be reflected in altered activity in olfactory information processing networks in preclinical stages of AD. The study highlights the need for research to further understand the role smoking plays in the development of AD and the use of olfaction as a biomarker to aid in disease detection, prevention, and stage-associated treatments.

Serotonin Degeneration and Amyloid-β Deposition in Mild Cognitive Impairment: Relationship to Cognitive Deficits.

Neuropathological and neuroimaging studies have demonstrated degeneration of the serotonin system in Alzheimer's disease (AD). Neuroimaging studies have extended these observations to the preclinical stages of AD, mild cognitive impairment (MCI). Serotonin degeneration has been observed also in transgenic amyloid mouse models, prior to widespread cortical distribution of amyloid-β (Aβ). The present study evaluated the regional distribution of the serotonin transporter (5-HTT) and of Aβ in individuals with MCI and healthy older controls, as well as the contribution of 5-HTT and Aβ to cognitive deficits. Forty-nine MCI participants and 45 healthy older controls underwent positron emission tomography (PET) imaging of 5-HTT and Aβ, structural magnetic resonance imaging and neuropsychological assessments. Lower cortical, striatal, and limbic 5-HTT and higher cortical Aβ was observed in MCIs relative to healthy controls. Lower 5-HTT, mainly in limbic regions, was correlated with greater deficits in auditory-verbal and visual-spatial memory and semantic, not phonemic fluency. Higher cortical A β was associated with greater deficits in auditory-verbal and visual-spatial memory and in semantic, not phonemic fluency. When modeling the association between cognition, gray matter volumes and Aβ, inclusion of 5-HTT in limbic and in select cortical regions significantly improved model fit for auditory-verbal and visual-spatial memory and semantic, but not phonemic fluency. These results support the role of serotonin degeneration in the memory and semantic fluency deficits observed in MCI.