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INTRODUCTION: Depressive symptoms are among early behavioral changes in Alzheimer's disease (AD); however, the relationship between neurodegeneration and depressive symptoms remains inconclusive. To better understand this relationship in preclinical AD, we examined hippocampal volume and depressive symptoms in cognitively unimpaired carriers of the presenilin‐1 (PSEN1) E280A mutation for autosomal dominant AD. METHODS: A total of 27 PSEN1 mutation carriers and 26 non‐carrier family members were included. Linear regression was used to test the relationship between hippocampal volume and 15‐item Geriatric Depression Scale. RESULTS: Carriers and non‐carriers did not differ in depressive symptoms or hippocampal volume. Within carriers, lower hippocampal volume was associated with greater depressive symptoms, which remained significant after adjusting for age and cognition. This relationship was not significant in non‐carriers. DISCUSSION: Hippocampal neurodegeneration may underlie depressive symptoms in preclinical autosomal dominant AD. These findings provide support for the utility of targeting depressive symptoms in AD prevention. Highlights: We compared unimpaired autosomal dominant Alzheimer's disease (AD) mutation carriers and non‐carriers.Carriers and non‐carriers did not differ in severity of depressive symptoms.In carriers, hippocampal volume was inversely associated with depressive symptoms.Depressive symptoms may be a useful target in AD prevention. [ABSTRACT FROM AUTHOR]

Background: Mnemonic anosognosia (i.e., unawareness) is a behavioral condition characterized by a lack of self‐awareness of objective memory decline. In the context of Alzheimer's Disease (AD), unawareness may be a sign of predementia stages. It contributes to disease severity, symptomatology worsening, and caregiver burden and is a good predictor of clinical progression. Here, we use in‐vivo multi‐modal neuroimaging to profile the brain phenotype of individuals presenting altered self‐awareness of memory during aging. Methods: We used amyloid‐ and tau‐PET (N = 335) and resting‐state fMRI (N = 713) data of individuals from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4)/Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies (Table1A). The neurocognitive profile of unawareness was characterized using between‐groups comparisons (omnibus and post‐hoc analyses) of the objective (LM delayed memory, and FCSRT free and cued scores) and subjective (MACQ) memory measurements of individuals classified as unaware of their memory impairment, compared to aware, subjective‐complainers and control individuals. To characterize the cortical burden of amyloid and tau and their modulatory effect on functional connectivity networks, we applied whole‐brain voxel‐wise GLM analyses, region‐of‐interest associations, and graph‐theory metrics (e.g., degree centrality). Results: Unaware and aware individuals perform worse than the control group in objective memory tests, while unaware individuals differ from aware but not from controls in MACQ (Table1B). The unaware group presents elevated amyloid and tau burden in midline core regions of the default mode network (DMN) compared to aware, complainer or control individuals (p‐value<0.05) (Figure1AB). Tau spreading in controls showed significant connectivity toward DMN and lateral and medial occipito‐parietal regions (Figure1C). Unawareness is characterized by an altered network connectivity pattern modulated by tau accumulation in which hyperconnectivity is observed mainly in midline DMN and posterior occipito‐parietal regions (p‐value<0.05) (Figure2A). Degree centrality revealed the main connectivity hubs altered by tau deposits in unaware individuals (e.g., posterior regions) (Figure2B). Conclusions: Mnemonic anosognosia is an early behavioral biomarker of AD pathology. Unawareness of memory decline leads to distinct brain phenotype, characterized by increased amyloid and tau burden, along with functional network connectivity disruptions, in several areas of the self‐referential brain network, including the posterior cerebral cortex of the human brain. [ABSTRACT FROM AUTHOR]

Background: Personal and social factors have had a varied effect on older adults during the COVID‐19 pandemic. Psychosocial factors and underlying pathological changes may have influenced the mental health of these older adults. Understanding the drivers behind the mental health of older adults during the pandemic may help identify treatment targets. We aimed to understand this phenomenon by exploring the relationships between the psychosocial factors iand self‐reported experiences of psychological well‐being. Method: We included 149 participants (mean age: 75.6) from the Harvard Aging Brain Study and Instrumental Activities of Daily Living Study who took a survey conducted during the Summer of 2021, to assess stress (Perceived Stress Scale), loneliness (UCLA Loneliness Scale. 3‐item version), resilience (Connor Davidson Resilience Scale) and psychological well‐being (PROMIS‐Global Mental), encompassing self‐reported quality of life, mood and thinking, satisfaction with social relationships and anxiety and depressive symptoms. Pre‐assessed measures of cortical amyloid (PiB; mean time difference = 1.8 years) and medial temporal tau (Flortaucipir; mean time difference = 1.7 years) were also included. We performed a hierarchal regression analysis to understand the relationships among the psychosocial factors, controlling for demographics, amyloid, and tau as predictors of well‐being. Result: Demographic and survey responses are presented in Table 1. Significant negative associations were found among perceived well‐being and pathology (amyloid and tau), stress and loneliness, such that increased pathology, increased stress and increased feelings of loneliness were related to worse mental health (Figure 1). A positive association was found between resilience and well‐being, such that increased resilience was related to higher well‐being. (Figure 1). The hierarchical regression analysis results revealed that loneliness (β = −0.32, t = −5.81, p<.001), stress (β = −0.38, t = −5.48, p<.001), and resilience (β = 0.28, t = 4.34, p<.001) uniquely accounted for a significant proportion of variance in well‐being even after controlling for demographic characteristics (age, sex, education, race) and psychosocial characteristics (marital status, living alone) (Table 2). Conclusion: Our findings suggest that measuring and quantifying loneliness, stress, and resilience can help clinicians and researchers understand the potential detrimental effects of the COVID‐19 pandemic among older adults. These findings may extend to other prolonged exposures to stressful situations and uncover much needed targets for intervention. [ABSTRACT FROM AUTHOR]

Background: Loss of awareness of cognitive decline (a.k.a. anosognosia) is a common symptom of Alzheimer's disease (AD) dementia and has also been observed in its predementia stages. Anosognosia is thought to be related not only to functional changes in individual brain regions, but also to a disturbance in functional connectivity (FC) between or within networks. This study aimed to investigate how memory awareness relates to resting‐state fMRI segregation (within‐network connectivity) and integration (between‐network connectivity) maps across the AD spectrum. Method: We included 66 older adults divided in two groups: cognitively normal (CN, n = 49), and symptomatic (mild cognitive impairment or mild AD; n = 17). Memory awareness was measured as the discrepancy between the participant's and study partner's scores on the Cognitive Function Instrument. Positive values indicated heightened awareness and negative values indicated unawareness. We assessed whole‐brain connectivity with resting‐state fMRI and computed voxel‐level maps of segregation and integration. General linear models were used to relate the integration or segregation of each voxel to memory awareness (in the total sample and in the two groups separately), adjusted for age, sex, and education. Multiple comparison correction was performed using cluster‐wise Monte Carlo simulations. Result: Demographics are presented in Table 1. Segregation maps showed that lower awareness was associated with increased connectivity within the frontoparietal network (FPN) and with decreased connectivity within the medial visual, default mode (DMN), and sensory‐motor networks (Figure 1A(i); Table 2A(i)). The relationship with the FPN persisted in the CN and symptomatic groups separately, and an additional negative association between awareness and FC in the salience network was found in the CN group (Figure 1B‐C(i); Table 2B‐C(i)). In integration maps, lower awareness was associated with increased between‐network connectivity of the dorsal attention and DMN, and decreased connectivity of the salience and sensory‐motor networks (Figure 1A(ii); Table 2A(ii)). In the CN group, the sensory‐motor relationship persisted, while the DMN relationship reversed (Figure 1B‐C(ii); Table 2B‐C(ii)). Conclusion: Anosognosia is characterized by reduced FC patterns featuring disconnection between self‐referential networks (DMN and salience) to other networks and hyperconnectivity within the FPN. Future studies should investigate the pathological underpinnings for these functional changes. [ABSTRACT FROM AUTHOR]

Background: Depression is a neuropsychiatric symptom of Alzheimer's disease (AD) and has been linked to greater cortical amyloid burden in preclinical AD. We sought to examine whether amyloid accumulation in brain regions subserving emotional control and changes in cognitive performance may contribute to increased depressive symptomatology over time. Method: 155 cognitively unimpaired participants who were below the cortical amyloid (<0.86DVR) and clinical depression thresholds (<12 on Geriatric Depression Scale (GDS); mean age = 72.6) at baseline were included from the Harvard Aging Brain Study, with annual GDS and Preclinical Alzheimer Cognitive Composite (PACC) assessment and MRI/PiB‐PET every three years (mean years follow‐up = 7.06). PiB slopes were calculated for FreeSurfer‐defined bilateral regions of interest (ROI) implicated in emotional control: amygdala, medial and lateral orbitofrontal cortices (mOFC, lOFC), superior and middle frontal (MFC) cortices, anterior cingulate (ACC), posterior cingulate (PCC), and isthmus cingulate (IC). Linear mixed‐effects models assessed whether main‐effects of ROI PiB slope and PACC slope predicted longitudinal GDS scores for each ROI, covarying for age, sex, education, and random intercept/slope, adjusted for multiple comparisons. Post‐hoc linear regression models assessed relationships between PiB and PACC slopes. Result: Steeper PiB slopes in the mOFC, MFC, ACC, and IC were associated with increasing GDS scores over time, while a decreasing PACC slope was predictive of increasing GDS scores over time in all regions (Table 1). Post‐hoc analyses indicated that PiB slopes were not significantly correlated with PACC slope (Figure 1). Conclusion: In a cohort of cognitively unimpaired older adults with low cortical amyloid and no/subclinical depressive symptoms at baseline, increasing depressive symptoms over time were significantly associated with both amyloid accumulation in specific regions associated with emotional control (i.e., mOFC, MFC, ACC, and IC) and worsening cognitive performance. Furthermore, changes in cognition were not significantly associated with changes in amyloid accumulation in regions involved in emotional control, suggesting that different factors may be independently influencing trajectories in depression versus cognition over time. These results shed light on the neurobiology of depression in older individuals and underscore the importance of monitoring new and increasing neuropsychiatric symptoms in addition to cognitive symptoms when screening for AD. [ABSTRACT FROM AUTHOR]

Background: Patients with Alzheimer's disease (AD) often demonstrate anosognosia, which is reduced awareness of cognitive decline. Anosognosia has been associated with tau accumulation (d'Oleire Uquillas et al., 2020) and impaired resting‐state functional connectivity (FC) in self‐referential networks (Vannini et al., 2017, Valera‐Bermejo et al., 2022). The explicit links between AD pathological deposits and large‐scale functional networks associated with anosognosia have yet to be elucidated. Here, we sought to examine whether FC plays a modulatory role in the effect of tau on awareness in participants across the AD spectrum. Method: We included 58 participants from two observational cohorts—44 asymptomatic (Clinical Dementia Rating (CDR) global score = 0) and 14 symptomatic (CDR≥0.5) individuals (Table1). Awareness was measured as the participant‐study partner discrepancy on the Cognitive Function Index. Flortaucipir‐PET was used to quantify tau accumulation, and segregation analysis was applied to resting‐state fMRI data to asses within‐network connectivity. For both modalities, the mean value in each of the Yeo 7 networks was used. First, a linear regression model was performed to assess the association between awareness and group (i.e., symptomatic/asymptomatic). Linear regression models were also used to assess the relationship between awareness and tau in the 7 networks, separately. Finally, we examined the effect of the FC×tau interaction on awareness. All models were adjusted for age, sex, and education. Result: Holding age, sex, and education constant, mean awareness was 0.18 lower in symptomatic (vs. asymptomatic) participants (p<0.01). Lower awareness was associated with a higher tau burden in all 7 networks (Table2). Interaction effects between tau and FC were observed. Specifically, reduced awareness was associated with high tau burden when the salience network was less functionally connected (Figure1A; β = ‐0.23, p = 0.02) and when the dorsal attention network was more functionally connected (Figure1B; β = 0.70, p = 0.03). For all other networks, the relationship between awareness and tau was not modified by the FC of the same network (Table2). Conclusion: These findings provide new insights into the neuropathological correlates of anosognosia in AD. It suggests that anosognosia is not only due to local pathology in single brain areas but also to altered connectivity between them, especially within self‐referential networks. [ABSTRACT FROM AUTHOR]

Background: Both loss of awareness for cognitive decline (a.k.a. anosognosia) and neuropsychiatric symptoms (NPS) are common symptoms in Alzheimer's disease (AD) and have been associated with AD pathology. Recent studies have shown a co‐occurrence between these symptoms across the AD spectrum, suggesting shared underlying neurophysiological processes, especially within the default mode network (DMN). Here, we investigated the relationship between NPS and altered awareness and the structural integrity (as assessed with diffusion tensor imaging, DTI) of brain regions supporting the DMN in participants with and without amyloid pathology. Methods: Three‐hundred participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) underwent an amyloid positron emission tomography (PET), using 18F‐AV45 (florbetapir), and were classified into two groups: amyloid‐positive (A+) and negative (A‐). Individual mean fractional anisotropy (FA) was calculated from tracts overlapping the DMN regions. An awareness index was computed using the discrepancy between Everyday Cognition questionnaire scores from participants and informants. The Neuropsychiatric Inventory Total Score was used to assess the informant‐reported NPS. We compared amyloid groups on demographics and our different measures of interest. Pearson correlations were used to determine associations between measures of interest in each amyloid group. A multivariate multiple regression (MMR) model was performed to determine whether structural brain integrity predicts altered awareness and NPS jointly. Results: A+ participants were significantly older (74 ± 7 vs. 72 ± 7 for A‐), more impaired (CDR global), and showed lower awareness and diffusion, and greater NPS (all p<0.001, see Table 1). Significant correlations were found between the FA, NPS, and awareness measures in A+ participants, with decreased FA associated with decreased awareness and more NPS. The MMR confirmed these associations between FA, awareness and NPS (p<0.02, see Table 2). The Pillai test revealed that the DTI effect jointly contributed to both models. No significant relationships were observed in the A‐ group. Conclusion: Our results show that, in amyloid‐positive individuals across the AD spectrum, decreased awareness and increased NPS were related to decreased structural integrity of the DMN. This supports the hypothesis of common neurobiological mechanisms underlying anosognosia and NPS in AD. [ABSTRACT FROM AUTHOR]

Background: Both the loss of awareness for cognitive decline (a.k.a anosognosia) and neuropsychiatric symptoms (NPS) are commonly seen in patients with Alzheimer's disease (AD) dementia, even in the prodromal stages. Anosognosia and NPS may negatively affect caregiver burden and patient's activities of daily living. Despite the high impact of these symptoms on patients and their caregivers, our knowledge of how they develop across the AD spectrum is limited. Here, we explored the cross‐sectional and longitudinal associations between anosognosia and NPS in individuals with mild cognitive impairment (MCI). Method: We included 310 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with a baseline Clinical Dementia Rating global score of 0.5. Everyday Cognition (ECog) questionnaire scores were used to measure complaints from participants and study‐partners at baseline and annually over a mean of 4 years (SD = 3). Anosognosia was defined as the study‐partner having an ECog score ≥2.5/4 and the participant having an ECog score ≤2.5/4 on their baseline measure and their last observation and without having more than 2 consecutive deviating observations during the follow‐up period. The 12 study‐partner‐rated Neuropsychiatric Inventory items determined the presence or absence of specific NPS (see Table 1). The Mini‐Mental State Examination (MMSE), an assessment used to screen for cognitive impairment, was administered annually. Survival analyses were performed to analyze the rate of appearance of NPS over time in individuals with and without anosognosia. Result: Sixty participants displayed anosognosia, while 250 did not. At baseline, groups had similar lengths of follow‐up. Participants with anosognosia had lower MMSE scores and a higher proportion of amyloid positivity (see Table 1). At baseline, the frequency of agitation and disinhibition was higher in the anosognosia group. Survival analyses showed earlier onset of all NPS in the anosognosia group (see Figure 1). Specifically, aberrant motor behavior, irritability, disinhibition, apathy, agitation, and hallucinations were highly significant. Conclusion: Loss of awareness for cognitive decline is associated with greater frequency and faster onset of NPS over time in participants with MCI. These results support the hypothesis of a potential common underlying neurophysiological process, a finding that needs to be addressed further in future studies. [ABSTRACT FROM AUTHOR]

Background: Discrepancy in the dyadic relationship of subjective cognitive change has revealed both increased/heightened awareness and decreased awareness/unawareness in the predementia stages of Alzheimer's Disease (AD). The dyadic relationship is often calculated using the mean discrepancy between an individual and their study partner's scores on a memory complaints questionnaire. However, participants may display heightened awareness on some questions and unawareness on others, canceling out each other's effect and masking subtle changes in either direction. Here, we present a new item‐level methodological approach allowing us to examine individual subtle changes in these two awareness dimensions separately. Moreover, we compared them to AD pathology and investigated their ability to predict clinical progression. Method: A total of 503 ADNI participants (Table.1) with baseline clinical dementia rating (CDR) = 0 and baseline CSF (Aβ1‐42 and t‐tau) were included. A subset (N = 329) had at least two follow‐up CDR time points to compute clinical progression. A traditional score was calculated as the average discrepancy between the partner and participant's responses on the Everyday Cognition questionnaire, with positive scores indicating heightened awareness and negative scores indicating unawareness. An unawareness (resp., heightened awareness) sub‐score was computed by applying a ceiling (resp., floor) at zero to item‐level differences before averaging. Each measure was compared by AD pathology, adjusted for age and sex. Survival analyses examined the relationship of the new scores with clinical progression. Result: CSF t‐tau, but not Aβ1‐42, was a significant independent predictor of the traditional and unawareness scores in models adjusting for each other. There was no significant interaction between the two (Table.2). Survival analyses showed a one‐point improvement on the unawareness sub‐score associated with an 84% reduction in progression hazard (HR = 0.16, p<0.001), or equivalently. A one‐point decline and 525% increase in progression hazard, with no significant effect for the heightened awareness score. Conclusion: Decomposing the traditional awareness score into two sub‐scores, allowed the investigation of the relationship between AD and awareness with more specific, sensitive measures. Of these, the unawareness sub‐score was associated with t‐tau and a strong predictor of clinical progression, providing further support that discordant self‐ and informant‐reported cognitive decline may provide important clinical information. [ABSTRACT FROM AUTHOR]

Background: Better predicting depression following a stressor like COVID‐19 would help identify vulnerable individuals who might benefit the most from early intervention. We examined change in depressive symptoms relative to the onset of COVID‐19 and longitudinal trajectories of depressive symptoms post‐pandemic‐onset. As a secondary objective, we examined associations of these changes with stress, resilience, and in vivo AD biomarkers. Method: Data were analyzed from 101 older adults (cognitively unimpaired at baseline) from the Harvard Aging Brain Study, a longitudinal observational cohort study. Depressive symptoms are assessed annually with the 30‐item Geriatric Depression Scale (GDS), and for these analyses, participants had no/mild self‐reported depression (GDS<11) at the last pre‐COVID examination. GDS‐delta scores were computed using the mean of the post‐COVID‐onset scores subtracted by the last pre‐COVID examination for participants. Levels of resilience (Connor‐Davidson Resilience scale) and stress (Perceived Stress Scale) were assessed within a year after pandemic onset. Cortical amyloid (PiB) and entorhinal (EC) and inferior temporal (IT) tau (FTP) were analyzed using pre‐pandemic acquisition (mean 1.6 years to pandemic onset). We used linear models to predict GDS‐delta and linear mixed effects models to predict GDS trajectory post‐COVID onset from resilience, stress, and the interaction of each with AD biomarkers (PiB and FTP). Results: GDS‐delta was predicted by resilience (t = ‐4.69, p<0.001) and stress (t = 3.51, p<0.001) such that those with lower resilience and higher stress experienced higher GDS‐delta. EC tau, but not IT tau or cortical amyloid, interacted with stress to predict GDS‐deltas (EC tau*stress: t = 2.04; p = 0.04) indicating that those with higher levels of EC tau and stress experienced higher GDS‐delta. For post‐pandemic‐onset GDS trajectory, no significant longitudinal associations were observed, but there was a marginal interaction between EC‐tau*stress in predicting greater GDS trajectories (t = ‐1.79, p = 0.08). Conclusion: Results suggest that change in depressive symptoms in elders following a societal stressor is associated with lower resilience and higher stress; this may be exacerbated by concurrent EC tau pathology. Moreover, elevated depressive symptoms in the years following onset of a societal stressor can be partially predicted by increased EC tau and stress, highlighting a vulnerable population who may benefit from preventive interventions throughout a major stressor. [ABSTRACT FROM AUTHOR]

Background: Depressive 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. Method: Longitudinal 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. Result: Higher 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. Conclusion: Findings 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. [ABSTRACT FROM AUTHOR]

Background: Awareness of memory was previously found to be reduced in the pre‐dementia stages, reaching unawareness/anosognosia 6‐years before dementia onset in individuals who carry the PSEN1 E280A mutation for autosomal dominant Alzheimer's disease (Vannini et al.,2021). Whether there are potential differences in awareness for specific types of situations involving memory as well as their association with molecular markers of AD disease progression in preclinical AD is unknown. Here, we investigated memory awareness on an item‐level basis as well as its relationship to neocortical amyloid and regional tau levels in non‐demented mutation carriers and non‐carrier family members. Method: A total of 119 Colombian kindred members, 56 carriers (7 mildly impaired) and 63 non‐carriers were included (Table.1). Awareness indexes were calculated using participant and study‐partner discrepancy scores for each of the 15 questions of the Memory Complaint Scale (Spanish version). A score of ≥0 indicates that the participant is aware and <0 unaware. A subset of 67 kindred members (N = 31 carriers, 1 impaired) underwent amyloid (PiB) and tau (FTP) scans. For each question, odds ratio and Fisher's exact test were used to evaluate prevalence of awareness/unawareness in carriers and non‐carriers. Pearson correlations, corrected for multiple comparisons, were used to assess the associations between awareness and pathology in the mutation carriers. Result: Mutation carriers had significantly decreased overall awareness (p = 0.03), increased mean cortical amyloid (p<0.001) and inferior temporal tau (p = 0.001), compared to non‐carriers. Two questions (items 10 and 15), showed significantly lower awareness in the carriers than non‐carriers (both p = 0.002, Table.2). These results remained significant after removing impaired carriers. In carriers, decreased awareness was related to increased tau for 5/15 (33%) questions (Table.3 and Figure.1). No significant associations were found between awareness and amyloid. Conclusion: Our results support previous findings that awareness is decreased in pre‐dementia stages of AD and related to tau, and not to amyloid pathology (Gagliardi et al.,2021). Importantly, we found that loss of awareness of specific memory items could differentiate carriers from non‐carriers. These findings support the usefulness of study‐partner‐reported cognitive decline. Individuals who become unaware of cognitive changes may represent a specific risk group to harbor pathology and develop AD dementia. [ABSTRACT FROM AUTHOR]

Background: Non‐invasive diffusion‐weighted imaging (DWI) to assess brain microstructural changes via cortical mean diffusivity (cMD) was recently shown to be cross‐sectionally associated with tau in cognitively‐normal older adults (Rodriguez‐Vieitez et al., Mol. Psych. 2021), suggesting that it might be an early marker of neuronal injury. However, the impact of cMD on longitudinal accumulation of tau pathology is currently unknown. Moreover, APOE‐e4 — the strongest genetic risk factor for sporadic AD — has been shown to be related to tau aggregation (Therriault et al.,JAMA Network 2019) and cognitive impairment in older adults. Here, we investigated whether cMD at baseline can predict longitudinal accumulation of tau as well as cognitive decline in cognitively‐normal adults with and without an APOE‐e4. Methods: 122 cognitively‐normal participants from the Harvard Aging Brain Study (71.0±9.7 years; 79 women[64.8%]), 30.3% APOE‐e4‐carriers, 16.0±2.9 years of education; Table 1) underwent DWI, T1w‐MRI, 18F‐flortaucipir(FTP)‐PET imaging and cognitive assessments at baseline. All participants had at least one longitudinal follow‐up FTP‐PET scan (average follow‐up time of 2.4±0.55 years). PET data were normalized to cerebellar grey‐matter. FTP‐PET was quantified using PVC‐corrected SUVR. Longitudinal measures of Preclinical Alzheimer Cognitive Composite (PACC5) were available for all individuals over a 7.2±2.4 years follow‐up interval. We assessed whether the interaction of APOE‐e4 and cMD (in entorhinal and inferior‐temporal cortices) was associated with longitudinal local tau accumulation and with longitudinal PACC5 using separate linear mixed‐effects models. Models were corrected for demographics and baseline tau or PACC5 as appropriate. Results: The APOE‐e4 carriers and non‐carriers had similar baseline demographics and imaging characteristics (Table 1). We found significant interaction effects of APOE‐e4 status and cMD in predicting longitudinal tau (entorhinal p=0.008 and inferior‐temporal p=0.032) and longitudinal PACC5 (both entorhinal and inferior‐temporal p<0.001), such that baseline cMD predicted the accumulation of tau and cognitive decline in APOE‐e4‐carriers only (Figures 1 and 2). Conclusions: Our results demonstrate that the cortical microstructual changes measured by cMD are related to accumulation of longitudinal local tau and cognitive decline in at‐risk individuals. The combination of APOE‐e4 and elevated cMD may help identify individuals at short‐term risk of tau accumulation and AD‐related cognitive decline, suggesting utility in therapeutic trials. [ABSTRACT FROM AUTHOR]

Background: Non‐invasive biomarkers of neuronal injury may be useful to detect cognitively‐normal individuals at risk of developing AD. A recent diffusion‐weighted imaging (DWI) method has allowed to assess microstructural properties of the brain's grey matter by means of cortical mean diffusivity (cMD) (Montal et al. Alz&Dem 14(3):340, 2018). Increased cMD is thought to reflect early neuronal injury that may precede macrostructural neurodegeneration. Here, we aimed to investigate the association of cMD with in vivo amyloid‐β and tau pathology in cognitively‐normal individuals, and to determine whether cMD can predict cognitive decline and clinical progression. Method: 196 cognitively‐normal participants from the Harvard Aging Brain Study (72.5±9.4 years; Table 1) underwent concurrent DWI, T1w‐MRI, 11C‐PIB‐PET, 18F‐flortaucipir (FTP)‐PET imaging and cognitive assessments at baseline. PIB‐PET was quantified using non‐PVC‐corrected Logan‐DVR, and FTP‐PET using PVC‐corrected SUVr; PET data were normalized to cerebellar grey‐matter. Longitudinal measures of Preclinical Alzheimer Cognitive Composite (PACC5) were available for n=186 individuals over a 3.72±1.96 yr follow‐up interval. Surface‐based image analysis (FreeSurfer 6.0) was performed to investigate vertex‐wise relationships between cMD and global amyloid‐β (PIB‐FLR), as well as tau (entorhinal, inferior‐temporal FTP). We assessed whether regional cMD predicted longitudinal PACC5 using linear mixed‐effects models, and progression to MCI using Cox proportional‐hazards regression. Result: Entorhinal and inferior‐temporal tau, but not amyloid‐β, were associated with increases in surface‐based cMD in AD‐signature clusters (Fig. 1A); illustrated for middle‐temporal gyrus cMD (Fig. 1B). Correcting for demographics and baseline PACC5, increased cMD within AD‐signature regions‐of‐interest predicted the rate of subsequent cognitive decline, which remained significant after correcting for PIB‐FLR and regional cortical thickness; there was a synergistic interaction between cMD and PIB‐FLR on the slope of PACC5 decline (Fig. 2). From n=163 participants with clinical follow‐up data, 11/163 (6.7%) converted to MCI within 3.3±1.5 years. Dichotomized regional cMD (top‐tertile group being "high cMD") predicted conversion to MCI, illustrated for the middle‐temporal gyrus, hazard ratio HR[95% CI] = 5.21 [1.14‐23.75], p=0.03, corrected by age, sex and education (Fig. 3). Conclusion: cMD is a promising technique to quantify cortical microstructural changes possibly related to tau‐induced neuronal injury. Its ability to predict short‐term cognitive decline and clinical progression suggests utility in clinical trials. [ABSTRACT FROM AUTHOR]

Background: Lower self‐ratings of performance on single timepoint neuropsychological measures have been previously associated with elevated AD biomarkers, aligned with the notion of a period of heightened awareness of cognitive decline in preclinical AD. With the rise of digital tools, cognitive assessments can now be collected over multiple days to examine learning over repeated exposures, thought to be diminished in preclinical AD. However, it is unknown whether daily self‐appraisal of performance would mimic reduced learning observed in individuals with elevated biomarkers. In this study, we used the Boston Remote Assessment for Neurocognitive Health (BRANCH) platform to capture multi‐day learning curves and to analyze whether self‐evaluation of performance was associated with amyloid and tau PET in a sample of cognitively unimpaired older individuals. Method: Our sample consisted of 193 cognitively unimpaired individuals (mean age = 74.1, 64.8% female, 85.5% Caucasian) already enrolled in a longitudinal observational study who underwent PiB‐ and Flortaucipir‐PET. Using the BRANCH platform remotely, participants completed two paired associative learning tests with repeated stimuli on their own digital devices for 7 consecutive days. A self‐evaluation was prompted at the end of each assessment, asking participants to rate their performance from 0‐100. Multi‐day learning curve metrics for objective performance (obj‐MDLC) and self‐appraisal (subj‐MDLC) were calculated for each participant. We examined correlations between obj‐MDLC and subj‐MDLC and using linear mixed‐effects models investigated the relationship between MDLCs, global β‐amyloid (Aβ) and tau burden in entorhinal (ET) cortex. Result: Obj‐MDLC was moderately correlated with the subj‐MDLC (r = 0.61, p < 0.001) and showed that, on average, participants under‐estimated their performance on the tasks. Both higher Aβ and higher ET tau were associated with a decreased obj‐MDLC (Day*Aβ = ‐0.08, p = 0.015; Day*ET = ‐0.06, p = 0.020) and subj‐MDLC (Day*Aβ = ‐0.09, p = 0.021; Day*ET = ‐0.09, p = 0.003). Conclusion: Participant's self‐appraisal of their performance on the BRANCH tasks across days showed significant associations with tau and amyloid that were consistent with those seen with actual performance on the BRANCH tasks. These findings demonstrate that utilizing daily self‐appraisals, in addition to objective assessment, provides complementary information in early preclinical AD. [ABSTRACT FROM AUTHOR]

Background: Self‐report of cognitive decline is an early behavioral manifestation of Alzheimer's disease at the preclinical stage, often thought to precede study partner‐report. Prior work has shown associations between subjective cognitive decline and amyloid, but less is known about tau deposition, particularly once tau has spread to neocortex. Using a multi‐cohort study of cognitively unimpaired individuals, we examined associations between self‐ and study partner‐report, amyloid and regional tau. Specifically, we hypothesized that greater self‐ and study partner‐report of cognitive decline would be observed with tau in the medial temporal lobe (MTL), whereas study partner‐report would be more strongly associated with neocortical (NEO) tau compared to self‐report. Method: 698 cognitively unimpaired individuals (55% elevated‐amyloid, mean age = 72.5, 58% female) came from the A4, LEARN, HABS, and SCD/IADL Studies. All participants underwent Flortaucipir‐PET quantified by SUVr. A MTL tau composite and a NEO tau composite were derived. An internally derived amyloid cut‐off was used for each study. Participants and their study partners completed the Cognitive Function Index (CFI), a 15‐item questionnaire asking about cognitive functioning over the last year. A series of linear regression models using tau (MTL vs. NEO) to predict CFI (self vs. study partner) were conducted, adjusting for age, sex, education, amyloid status and cohort. Result: We first examined amyloid status and CFI and found elevated‐amyloid was associated with higher self‐report (t = 2.8, p = 0.017), but not study partner‐report (t = 1.5, p = 0.12). Building on this model, greater MTL tau was associated with greater self‐report (t = 3.30, p<0.001) and study partner‐report (t = 3.4, p<0.001), but not amyloid status. Greater NEO tau was associated with greater self‐report (t = 3.2, p = 0.002) and study partner‐report (t = 4.1, p<0.00001), but not amyloid status. Conclusion: In this multi‐cohort study of cognitively unimpaired individuals, elevated‐amyloid was associated with greater self‐report CFI, but not study partner‐report. When accounting for amyloid status, both MTL and NEO tau were significantly associated with both self and study‐partner report, but effects were numerically stronger for study partner for NEO tau. These findings suggest that CFI report both from the participants and their study partners is valuable at the preclinical stage, but may evolve with increasing tau spread. [ABSTRACT FROM AUTHOR]

Background: Emerging difficulty performing cognitively complex everyday tasks, or 'instrumental activities of daily living' (IADL) may be an early clinical sign of Alzheimer's disease (AD). We aimed to investigate how changes over time in everyday functioning relate to tau across the AD clinical spectrum. Method: We included 581 participants (73.9±7.6 years old; 52% female) from the Alzheimer's Disease Neuroimaging Initiative who underwent tau positron emission tomography (PET) and completed at least two assessments of the Functional Activities Questionnaire (FAQ). FAQ total scores range 0‐30, with higher scores representing more functional impairment. Participants were classified as cognitively normal (n = 334) or symptomatic (n = 247), having either mild cognitive impairment or AD dementia. Using mixed‐effects models, we analyzed the association between longitudinal FAQ scores and baseline tau in six temporal, parietal, and frontal brain regions. The main effect of interest was the interaction term of tau by time. We covaried for age, sex, and baseline performance on tests for memory, executive function and premorbid cognition, and corrected for multiple testing. Models were run in the entire sample, as well as stratified by diagnostic group (cognitively normal or symptomatic). Baseline amyloid PET was additionally available for a subset (n = 363), and we investigated interactions between amyloid and tau in this subset. Result: Greater tau burden in several frontal, temporal, and parietal regions was associated with steeper decline over time in everyday functioning (Table 1, Figure 1). These findings remained when adjusting for baseline global cortical amyloid; amyloid itself was only associated with change over time in FAQ scores when tau was not included (unstandardized b = 1.18, 95%CI = [0.39,1.97], t = 2.94, p =.01). When stratifying by diagnostic group, these effects were present only in the symptomatic group. Conclusion: The rate of change in everyday functioning is related to baseline tau burden in various brain regions, more strongly so than global cortical amyloid. This aligns with previous findings that cognitive function relates more closely to tau pathology. Change in everyday functioning was only observed on the FAQ in symptomatic individuals. Longitudinal studies in incident dementia populations are needed to better understand functional changes in response to AD pathology across the disease spectrum. [ABSTRACT FROM AUTHOR]

Background: Subclinical depressive symptoms in older adults have been linked to AD pathology and cognitive decline. However, it's unclear how these findings translate to the spectrum of clinically significant late life depressive symptoms. To explore this, we examined cross‐sectional associations between depressive symptoms and neuroimaging biomarkers of AD (ATN) in a pilot cohort of older adults with moderate‐to‐severe depressive symptoms and compared these participants to non‐depressed older adults. Method: Seventeen community‐dwelling clinically‐normal (CN) older adults meeting DSM5 criteria for major depression (73.4±4.7 y.o., 58.8% female) underwent MRI, amyloid‐(C11‐PiB)‐PET, and tau‐(F18‐FTP)‐PET and completed a clinical battery including the 30‐item Geriatric Depression Scale (GDS) and Preclinical Alzheimer's Cognitive Composite (PACC). A comparison group of non‐depressed older adults (no history of depression, GDS≤5; 73.0±5.5 y.o., 63.2% female) derived from existing observational studies at our site with similar clinical‐neuroimaging batteries were matched using nearest neighbor propensity score to depressed participants by age, sex, and APOE‐ε4 carrier status in a 4:1 ratio (Table 1). We examined cortical amyloid and regional tau and atrophy in a priori regions of interest (ROI) previously implicated in AD and mood (medial temporal lobe, amygdala, frontal cortex). We utilized t‐tests to explore group differences and linear regressions adjusted for age to investigate associations between depressive symptoms and ATN biomarkers. Result: In the depressed group, depressive symptoms were significantly associated with elevated FTP in all ROI and with lower hippocampal volume, but not with cortical PiB (Table 2, Fig. 1). There were no significant group differences compared to non‐depressed controls in cortical PiB, regional FTP, or volume measures; however, participants with depression had worse cognitive performance on the PACC than non‐depressed participants (t=‐2.04, p=0.050). Conclusion: Preliminary findings in this pilot sample suggest that moderate‐to‐severe depressive symptoms in older adults may be more closely associated cross‐sectionally with tau and hippocampal volume than cortical amyloid. Future work in a larger depressed cohort and with longitudinal follow‐up is needed to characterize risk in older adults with depression and consider opportunities for AD prevention. [ABSTRACT FROM AUTHOR]

Background: Subjective perception of cognitive decline is identified as an important marker related to the risk of progression to Alzheimer's disease. However, loss of awareness has also been observed in predementia stages, potentially reducing the validity of the subjective experience. The aim of this study was to characterize the trajectories of complaints in cognitively normal (CN) individuals who later developed cognitive decline, as well as investigate differences in demographics, brain pathology and clinical progression between individuals aware and unaware of these changes. Method: We included participants (CN at baseline) from the Harvard Aging Brain Study. Linear Mixed effect models were used to compute individual longitudinal changes of memory complaints (7 questions questionnaire) and cognition (Preclinical Alzheimer's Cognitive Composite, PACC5). Participants who demonstrated a statistically significant PACC5 decline over time were divided into two groups: an Unaware (N=36) group defined as individuals with statistically significantly decreasing or displaying low (<2.5/7) complaints, and a Heightened (N=14) group defined as individuals with significantly increasing or displaying high (>2.5/7) complaints (Fig 1). Participants who did not decline in memory were assigned to the Stable group (N=248). Kaplan‐Meier survival analysis was performed to determine the rate of progression from CN to clinically impaired (MCI or dementia diagnosis) across groups. Result: No group differences were found for gender, education, depressive symptoms or Apolipoprotein E4‐carrier status (Tab 1). Unaware participants were significantly older than the Stable group (p<0.001). The Heightened and Unaware groups demonstrated equivalent amyloid burden, which was significantly greater than the Stable group (p<0.01). The survival analysis revealed significant differences between all groups (p<0.001,Fig 2). Heightened participants had the fastest rate of clinical progression, followed by the Unaware group. Conclusion: Participants with heightened awareness demonstrated the fastest rate of progression from cognitively normal to MCI or dementia. Importantly, among the individuals with a subsequent cognitive decline, a number of individuals (72%) were unaware of their decline. These individuals had the same demographic profile and amyloid burden as the individuals with heightened awareness. Future research will investigate the mechanisms of self‐awareness and potential dysfunction of systems underlying the loss of awareness, as it can be essential for the preservation of individual autonomy. [ABSTRACT FROM AUTHOR]

Background: AD clinical trials are increasingly looking towards intervention at the earliest stage of preclinical AD, when beta‐amyloid (Aβ) is emerging and tau pathology remains restricted to the MTL. While some evidence suggests subtle cognitive changes start at this early stage, it is unclear what cognitive measures may be most sensitive to emerging pathology and whether they reflect Aβ, tau or both. Method: 143 clinically‐normal adults with longitudinal PIB‐PET, FTP‐PET and cognitive data (median follow‐up: 7.68(1.17) years) were included from the Harvard Aging Brain Study (HABS). Analyses focused first on those initially PIB‐ (

Background: Heightened awareness and unawareness of memory decline are known to manifest at different stages in AD, and both have been shown to predict clinical progression. Awareness is often measured by the discrepancy between the informant's and participant's mean scores on a memory complaints questionnaire. A major limitation of this approach is that a participant may display heightened awareness on some items and unawareness on others, averaging out each's effect. Here, we present a new item‐level methodological approach, allowing us to examine these two dimensions of awareness (heightened/unawareness). We aimed to compare all these measures and investigate their ability to predict clinical progression. Method: This study included 438 ADNI participants with CDR global = 0 at the time of their baseline Everyday Cognition (ECog) measurement and at least two follow‐up CDR assessments (Tab.1). Disease progression was defined as the first instance of two consecutive CDR global≥0.5. A traditional awareness score was calculated by subtracting the mean average ECog score between the informant and participant complaints (Fig.1A). An unawareness score was generated by capping item‐level positive differences at zero and then averaging (Fig.1B). Its complementary heightened awareness score was generated by capping negative differences at zero (Fig.1C). For all three measures, baseline group differences were analyzed using Wilcoxon rank‐sum tests. Robust Cox regression models were run to test the association between each baseline measure and progression, adjusted for age, gender, and education. Result: The progressing (N = 91) and stable (N = 347) groups demonstrated similar scores for traditional (p =.11) and heightened awareness (p =.72). A significant difference was found for unawareness, with progressors displaying more unawareness than stable participants (p<.001;Tab.1,Fig.1). Robust Cox regression models showed a significant association between greater risk of progression and unawareness (p<.001) and a marginal association with lower traditional scores (p =.06). There was not a significant association with heightened awareness (p =.75). Conclusion: By separating its two dimensions, our novel approach allows us to refine the analysis of awareness and to determine each dimension's respective contributions to future clinical progression. These findings provide evidence that unawareness rather than heightened awareness is associated with clinical progression and supports the utility of informant report of decline. [ABSTRACT FROM AUTHOR]

Background: While loss of insight of cognitive deficits, anosognosia, is a common symptom in Alzheimer's disease (AD) dementia, there is a lack of consensus regarding the presence of altered awareness of memory function in the pre‐dementia stages of the disease. Here, we investigated the evolution of memory awareness in the AD‐course in a large cohort of individuals who carry mutations for autosomal dominant AD (ADAD; a population that are genetically determined to develop early‐onset dementia, and have a well‐characterized disease trajectory from pre‐symptomatic to clinical stages) and compared it with family members who do not carry the mutation. Methods: Pseudo‐longitudinal analyses using linear mixed‐effect models was used to predict self‐awareness (assessed using an awareness index based on the discrepancy score between participant and study‐partner report on the Memory Complaint Scale (Spanish version),in a total of 2,379 members of a Colombian kindred including 396 ADAD (14.9% impaired) and 1,983 non‐carrier family members (Table 1). Age was entered as a fixed and random factor in the models. Results: The mutation carriers complained significantly more than their study‐partner until the mean age of 35, and complained significantly less (unawareness/anosognosia) than their study‐partner around the age of 43 (Figure 1A), approximately 6 years prior to their estimated median age of dementia onset (49yo). Cognitively‐unimpaired non‐carriers complained significantly more than their study‐partners (heightened awareness/hypernosognosia) between ages 20‐60 (Figure 1B). Using the awareness index (Figure 2) we observed a decrease with age (est.=‐0.04 discrepant‐points/year,se=0.02,t=‐2.2,p=0.03) in the non‐carriers and an even steeper decline in the mutation carriers (est.=‐0.21 discrepant‐points/year,se=0.04,t=‐5.1,p=2.8*e‐7). The awareness index was significantly different between groups from age 22.5, indicating less awareness of memory in the mutation carriers as compared to the non‐carriers. Conclusion: Hypernosognosia was observed in both groups, indicating that heightened awareness of memory function is common and non‐specific in this cohort. In mutation‐carriers, awareness of memory decreased in the pre‐dementia stages, reaching anosognosia 6 years before dementia onset. These findings provide further support for the usefulness of informant‐reported cognitive decline and add to the sporadic AD literature suggesting that individuals who become unaware of cognitive change in preclinical stages may represent a specific risk group to develop AD dementia. [ABSTRACT FROM AUTHOR]

Background: Depressive symptoms are thought to be among the earliest behavioral changes in preclinical Alzheimer's disease (AD). However, the association between AD pathology and depressive symptoms in preclinical AD remains poorly understood. In the current study we examined the impact of pathology burden (amyloid and tau) on longitudinal change in depressive symptoms in cognitively unimpaired adults. Method: 252 adults (age: 70.8 ±8.2; 61% females) from the Harvard Aging Brain Study completed annual assessment with the 30‐item Geriatric Depression Scale (GDS) (average follow‐up=5.87 annual visits). All were cognitively normal, without clinically significant depression at study entry (mean GDS=3.19±3.12; range: (0‐16)). All underwent tau (18F‐Flortaucipir) and amyloid‐β(11C‐Pittburgh Compound B) PET at study year 3 or 4 to derive measures of inferior temporal (IT) and entorhinal cortex (EC) tau and cortical amyloid. A mixed model was employed with dependent variable GDS (for each annual study visit), a random intercept and slope for each participant, and fixed predictors: tau (IT or EC, at study year 3/4), cortical amyloid (at year closest to tau), time (time of tau PET), covariates: age, sex, education; and the interaction of predictors with time. Result: Baseline tau burden was associated with increasing GDS over time. In the model with predictor EC tau, EC tau X time was a significant predictor of GDS (β=0.48; t=3.80; 95% CI (0.23, 0.73); p=0.0002). Findings were similar for IT tau:(β = 0.71; t=3.67; 95% CI (0.33, 1.1); p=0.0002). By contrast, amyloid was not a significant predictor of longitudinal GDS in tau models: (β=‐0.14; t=‐1.58; 95% CI(‐0.23, ‐0.08); p=0.11). Conclusion: Baseline tau, but not amyloid, is independently associated with increasing depressive symptoms over time. Future research incorporating longitudinal tau PET and individuals with more severe depressive symptoms is needed to delineate the temporal sequence of rising depressive symptoms and increasing tauopathy in preclinical AD. [ABSTRACT FROM AUTHOR]

Background: A novel technique for the analysis of diffusion‐weighted imaging (DWI) has allowed quantifying brain microstructural properties by means of cortical mean diffusivity (cMD) in the grey matter. Using this approach a biphasic trajectory of the cMD signal has been revealed, characterized by an early decline followed by an increase across preclinical stages of Alzheimer's disease (AD), primarily in temporo‐parietal brain regions (Montal et al.,Alz&Dem,2018). The initial cMD reduction has been hypothesized to be due to glial activation (Vilaplana et al.,Neurology,2020), while increased cMD in later stages is thought to reflect breakdown of cortical tissue microstructure and neurodegeneration. However, the pathological underpinnings of the cMD signal, specifically its relationship to in vivo amyloid‐β and tau, remain unknown. Methods: 84 cognitively‐normal participants from the Harvard Aging Brain Study underwent cross‐sectional DWI, T1‐weighted‐MRI, 11C‐PiB‐PET, and 18F‐Flortaucipir (FTP)‐PET imaging (Table 1). 11C‐PiB‐PET was quantified using non‐PVC‐corrected Logan DVR, and individual amyloid‐β burden was extracted from a cortical composite including frontal‐lateral‐retrosplenial (FLR) regions. 18F‐FTP‐PET was quantified using PVC‐corrected SUVR and individual tau burden was extracted from the entorhinal cortex. All PET data were normalized to cerebellar grey matter. First, a whole‐brain surface‐based approach was used to investigate the linear and quadratic (correcting for the linear term) vertex‐wise relationships of cMD to amyloid‐β and tau. Second, cMD signal was extracted from significant regions‐of‐interest to visualize its relationships with amyloid‐β and tau. Results: Cortical MD was not significantly associated to amyloid‐β using either the linear or quadratic term. The relationship between cMD and tau was best described by a quadratic model across the whole cohort, as seen vertex‐wise (Fig.1) and regionally (Fig.2). Specifically, cMD signal decreased and then increased as both amyloid‐β and tau accumulated. Conclusions: The novel imaging technique of cMD is a promising approach to measure cortical microstructural changes. Our findings of a non‐linear trajectory of cortical mean diffusivity, particularly in the temporal regions, may indicate an initial phase of reduced cMD due to glial activation followed by increased cMD signal due to breakdown of cortical tissue microstructure as amyloid‐β and tau accumulate. Ongoing longitudinal studies will help elucidate the temporal dynamics of cortical microstructure and protein accumulation. [ABSTRACT FROM AUTHOR]

Background: Depressive symptoms are commonly observed early in Alzheimer's disease (AD), but their temporal association with progression along the AD continuum is less clear. We sought to determine if initial measurements of regional tau were predictive of increasing depressive symptoms, and if changes in depressive symptoms predicted later tau levels. We examined these relationships in a region of early tau accumulation (i.e., entorhinal cortex (EC)), and in regions of later neocortical tau spread commonly involved in affective regulation (amygdala and medial and lateral orbitofrontal cortex (mOFC, lOFC)). Method: Participants (n = 257; mean age = 70.7; 61% female) came from the Harvard Aging Brain Study, a longitudinal observational cohort of cognitively unimpaired adults with no/low depression at baseline (mean years of follow‐up = 7.2). All participants completed the self‐reported 30‐item Geriatric Depression Scale (GDS) annually and tau PET imaging (Flortaucipir‐FTP) every 3 years. On average, initial tau PET scans occurred 2.3 years after enrollment and the latest available scan occurred 5.1 years after enrollment. Separate linear mixed effects models investigated relationships between longitudinal GDS and cross‐sectional regional tau (FTP PET SUVr), at initial scan and at the latest scan available, in the following regions of interest: EC, amygdala, mOFC, and lOFC. Covariates included age, sex, and education. Result: Higher initial FTP levels were associated with significant increases in GDS score over time in temporal cortex (amygdala: b = 0.29,p = 0.0002; EC: b = 0.21,p = 0.0006) and mOFC (b = 0.30,p = 0.004), with marginal significance in lOFC (b = 0.21,p = 0.07). However, the reverse temporal sequence was only observed between GDS scores over all time points and later measurement of amygdala FTP, such that increasing depressive symptoms over time preceded higher final amygdala tau levels (b = 0.15,p = 0.02). Conclusion: Higher tau in EC, amygdala and OFC regions predicted increasing depressive symptoms over time in older adults. Only for the amygdala did we also observe the converse relationship: increasing depressive symptoms predicting higher final tau. These results suggest early tau proliferation in affective regions is associated with increased depressive symptoms, though the question of causality is still unclear. Further work is needed to dissect possible temporal relationships across whole brain voxels to better understand depressive symptoms in AD progression. [ABSTRACT FROM AUTHOR]

Background: Awareness of memory impairment has been shown to vary across the AD spectrum with an initial heightened awareness at the preclinical stage, and a subsequent loss of awareness with AD progression (Hanseeuw et al.,2020). Whether there are potential differences in the evolution of awareness for cognitive domains other than memory is unknown. In this study, we investigated the evolution of awareness in visuospatial, language, planning, divided attention and organization in cognitively older adults that later progressed versus those who remained stable. Methods: Our study included 621 cognitively normal (CN) ADNI participants (Tab1). Individuals were considered Stable or Progressors (n = 147) on the basis on the Clinical Dementia Rating scale global score (stable: scores at first and last observation both 0, progression:last score≥0.5). Cognitive complaints were recorded using the Everyday Cognition (ECog) questionnaire, using both participant's and informant's average complaints in each of the six subscales: divided attention, language, memory, organization, planning and visuo‐spatial. Generalized linear mixed‐effect models were run to predict complaints within each subscale, using time, the source of complaint (informant vs participant), and their interaction as independent variables, adjusting for age, gender and education. Jonhson‐Neyman Points (JNP) were computed for significant interactions, and simple slopes analyses were performed. Results: Stable participants displayed a similar evolution of both informant and participant complaints (Fig1, left panels). Among progressors, all models showed significant interactions with participants expressing greater, and subsequent lower complaints than informants (Fig1, right panels). JNP analyses revealed that, while on some subscales this transition occurred only after/close to progression (i.e., divided attention, language, memory and organization), it could be observed years before progression in others (i.e., planning and visuo‐spatial). Conclusions: Progressive participants expressed greater, and then lower complaints as compared to their informant, demonstrating a transition from heightened to reduced awareness over time. Our results attest that, while most studies are focusing on memory awareness, other domains might also show early changes in awareness. This advocates for including the informant's appraisal in the examination process, as well as to expand the focus to other cognitive abilities. [ABSTRACT FROM AUTHOR]

Background: Psychological resilience, a construct representing a person's ability to return to their baseline when difficulties occur, can play an important role in determining outcomes in the face of stressors. Resilience is a crucial component to consider during times of prolonged stress, such as experienced during the coronavirus disease (COVID‐19) pandemic, given that chronic stress has been associated with cognitive decline and dementia. Here, we investigated whether psychological resilience modified levels of perceived stress (assessed over 7 months), as well as examined the influence of demographic variables and Alzheimer's disease biomarkers on this relationship. Method: In May‐November 2020 of the COVID‐19 pandemic, 39 cognitively normal participants (mean age=78.38; 53.85% female) in the Harvard Aging Brain Study (HABS) completed questionnaires assessing stress (Perceived Stress Scale, PSS) and resilience (only at baseline; Connor‐Davidson Resilience Scale), higher scores on each measure indicating greater stress and increased resilience, respectively. We used previously collected data to better characterize the cohort, with the Preclinical Alzheimer Cognitive Composite (PACC;mean=0.46, SD=0.79) to assess cognition, and PET imaging data to assess Aß burden. A hierarchical regression model was used to assess whether resilience could predict baseline perceived stress. A separate linear mixed effect model (LME) was used to explore how resilience, time, and their interaction may affect stress. Both models also included age, sex, education, cognition, and Aß status (SUVR>1.324). Result: Perceived stress levels were generally low (mean=13.54, SD=8.65, range=0‐35), and did not significantly vary over the study period (p>0.5; mean number of timepoints=3.13). Both models demonstrated a main effect of resilience, such that higher resilience was associated with lower stress levels (p<0.001;Figure 1). Perceived stress was not influenced by demographic factors, cognition or Aß status. No significant interaction was found between resilience and time in predicting stress levels longitudinally. Conclusion: Our findings confirm that resilience is critical for coping with stress during the COVID‐19 pandemic, suggesting that resilience could be an important target for potential interventions in the future. Efforts at increasing resilience could not only help support older adults navigating stressful situations, but may also mitigate negative effects of stress on neurocognitive and mental health. [ABSTRACT FROM AUTHOR]

Background: The outbreak of the 2019 novel coronavirus SARS‐CoV‐2, causing the COVID‐19 pandemic, along with the global measures used to control the spread of the disease, have been particularly stressful for older individuals. Robust evidence suggests that stress‐related physiological processes may play a significant role in the onset of age‐related cognitive decline and dementia, such as Alzheimer's disease (AD). For example, previous animal and human research have shown that stress exacerbates tau pathology and subsequent cognitive impairment. One important factor determining a person's level of stress is psychological resilience, which refers to a person's ability to return to equilibrium when difficulties occur. As such, resilience may buffer and protect individuals against the deleterious effects of stress. The objectives of this study were to examine the relationship between psychological resilience and tau burden in cognitively unimpaired individuals, and to evaluate whether amyloid (Aß) pathology modifies this relationship. Method: A total of 114 older adults (mean age=74.5;66 females (57.9%)) enrolled in the Harvard Aging Brain Study or the Instrumental Activities of Daily Living study completed an electronic survey online including measures of psychological resilience (Connor‐Davidson Resilience Scale‐10, where a higher score indicates greater resilience) during the COVID‐19 pandemic period (May 2020). We used previously collected (mean time from survey=1.75 year) PET imaging data to assess Aß and tau burden. Results: Overall, participants demonstrated high levels of resilience (mean=29.5,range=9‐40). Multiple regression analyses (correcting for age, gender and time difference between survey and PET) demonstrated an interaction between resilience and amyloid on tau pathology (ß=‐0.01,p=0.015, Figure1). Specifically, in Aß+ individuals (SUVR>1.324), those with higher psychological resilience also had lower tau pathology. No relationship was seen in Aß‐ individuals. Conclusion: Our findings suggest that greater resilience during the pandemic is associated with lower tau burden in individuals at higher risk of cognitive decline (i.e. preclinical AD). Future studies are needed to determine the impact of stress and psychological resilience on prospective pathological brain changes and subsequent cognitive decline. Furthermore, resilience may be an important target for interventions to support older adults navigating stressful situations and to lessen the influence of stressors on AD pathological processes. [ABSTRACT FROM AUTHOR]

Background: Previous work has shown discordance between participant‐ and study‐partner‐reported cognitive concerns across symptomatic stages of Alzheimer's Disease (AD). Longitudinal trajectories of participant and study‐partner report in preclinical AD have not been fully elucidated. This study sought to capture longitudinal trajectories of participant‐ and study‐partner‐reported concerns along with potential modifying factors: participant amyloid‐biomarker burden and depressive symptoms Method: Participants came from the Harvard Aging Brain Study, a longitudinal observational cohort of cognitively unimpaired individuals at baseline who received PIB‐PET imaging (high‐amyloid>1.185DVR;all participants and study‐partners blinded to amyloid status). In this sub‐study (n=74,mean age=77.29,56% female), every 3 months participants and study‐partners completed a modified Cognitive Function Index (CFI) measuring current concerns (median sessions completed=6) and participants also completed the Geriatric Depression Scale (GDS). Additionally, participants and study‐partners were asked about any change in cognitive functioning over the last year during an in‐clinic visit (median months=10). Linear mixed effects models were used to investigate the interaction between in‐clinic CFI and amyloid burden on longitudinal remote‐CFI, for both study‐partners and participants. Remote‐CFI slopes for participant and study‐partner were extracted from ordinary least‐squares regression models and compared to remote GDS slopes (stratified by participant amyloid status) using linear regression models. All models controlled for age, sex, and education. Result: Participant remote‐CFI did not change over time (slope=0.94,SE=0.66,p=0.15), unlike the modestly‐increasing study‐partner remote‐CFI (slope=1.52,SE=0.66,p=0.02). Participant remote‐CFI slope was not significantly related to in‐clinic CFI. A significant interaction was seen with participant amyloid burden in study‐partners, whereby increasing study‐partner remote‐CFI was associated with higher in‐clinic CFI for participants with greater amyloid burden (estimate=‐1.21(0.6),p=0.04). In participants with high‐amyloid, however, concurrent change was seen in participant‐rated remote‐CFI and GDS, but not with study‐partner‐rated remote‐CFI. Conclusion: Increasing concerns over months are associated with an overall perception of change over the last year from study‐partners of higher‐amyloid participants. Conversely, in high‐amyloid participants, increasing cognitive concerns were associated with increasing depressive symptoms suggesting greater alignment between cognitive complaints and mood symptoms among those with high‐amyloid. These data suggest that frequent assessment offers rapid insight into emerging divergent patterns of cognitive concerns between participant and study‐partner during preclinical AD. [ABSTRACT FROM AUTHOR]

Background: With the advent of prevention trials in preclinical Alzheimer’s disease (AD), evaluating novel and sensitive methods to measure instrumental activities of daily living (IADL) is becoming increasingly important in order to detect these clinically meaningful changes at the earliest stages of disease. The objective of the current exploratory study was to examine the cross‐sectional relationship between a phone performance‐based IADL test, the Harvard Automated Phone Task (APT), and regional cerebral tau and cortical amyloid burden in clinically normal (CN) older adults. Method: Thirty‐one CN participants (mean age 70.0 (SD 4.8), 70% female) underwent flortaucipir (FTP) tau and Pittsburgh Compound B (PiB) amyloid positron emission tomography (PET). IADL were assessed using the 3 Harvard APT tasks: refilling a prescription (APT‐Script), calling the health insurance company to select a new primary care physician (APT‐PCP), and making a bank account transfer and payment (APT‐Bank). Linear regression models were used in the primary analyses to determine the associations between each APT task rate (correct responses/time) as the dependent variable and cortical amyloid aggregate, entorhinal cortex, inferior temporal, or precuneus tau as predictors of interest in separate analyses. In secondary analyses, models were repeated with an interaction between cortical amyloid and regional tau. Analyses included age, sex, and education as covariates. Result: A significant association was found between the APT‐Script rate and entorhinal cortex tau (β=‐0.08, 95% CI=‐0.14, ‐0.21, t value=‐2.78, p=0.01). No significant associations were found between other APT tasks and amyloid and tau regions. Additionally, no significant associations were found with the interaction between amyloid and tau regions. Conclusion: Our preliminary findings suggest an association between a region of early tau accumulation in CN adults, the entorhinal cortex, and a real‐life IADL test. Moreover, APT‐Script task was more normally distributed, and had overall larger variability compared to the other two tasks, suggesting that it may be a more sensitive IADL measurement in CN individuals. Further analyses should explore this relationship in larger samples and longitudinally in order to determine whether the Harvard APT can serve as a reliable IADL outcome measure for preclinical AD prevention trials and ultimately in the clinic setting. [ABSTRACT FROM AUTHOR]