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Background: Detecting clinically meaningful changes in instrumental activities of daily living (IADL) at the earliest stages of Alzheimer’s disease (AD) is critical. Objective: The objective of this exploratory study was to examine the cross-sectional relationship between a performance-based IADL test, the Harvard Automated Phone Task (APT), and cerebral tau and amyloid burden in cognitively normal (CN) older adults. Methods: Seventy-seven CN participants underwent flortaucipir tau and Pittsburgh Compound B amyloid PET. IADL were assessed using the three Harvard APT tasks: prescription refill (APT-Script), health insurance company call (APT-PCP), and bank transaction (APT-Bank). Linear regression models were used to determine associations between each APT task and entorhinal cortex, inferior temporal, or precuneus tau with or without an interaction with amyloid. Results: Significant associations were found between APT-Bank task rate and interaction between amyloid and entorhinal cortex tau, and APT-PCP task and interactions between amyloid and inferior temporal and precuneus tau. No significant associations were found between the APT tasks and tau or amyloid alone. Conclusion: Our preliminary findings suggest an association between a simulated real-life IADL test and interactions of amyloid and several regions of early tau accumulation in CN older adults. However, some analyses were underpowered due to the small number of participants with elevated amyloid, and findings should be interpreted with caution. Future studies will further explore these associations cross-sectionally 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.

Background: Associations between epigenetic aging with cognitive aging and neuropsychiatric measures are not well-understood. Objective: 1) To assess cross-sectional correlations between second-generation DNA methylation (DNAm)-based clocks of healthspan and lifespan (i.e., GrimAge, PhenoAge, and DNAm-based estimator of telomere length [DNAmTL]) and cognitive and neuropsychiatric measures; 2) To examine longitudinal associations between change in DNAm markers and change in cognition over 2 years. Methods: Participants were members of VITAL-DEP (VITamin D and OmegA-3 TriaL- Depression Endpoint Prevention) study. From previously ascertained cognitive groups (i.e., cognitively normal and mild cognitive impairment), we randomly selected 45 participants, aged≥60 years, who completed in-person neuropsychiatric assessments at baseline and 2 years. The primary outcome was global cognitive score (averaging z-scores of 9 tests). Neuropsychiatric Inventory severity scores were mapped from neuropsychiatric symptoms (NPS) from psychological scales and structured diagnostic interviews. DNAm was assayed using Illumina MethylationEPIC 850K BeadChip at baseline and 2 years. We calculated baseline partial Spearman\hfilneg correlations between DNAm markers and cognitive and NPS measures. We constructed multivariable linear regression models to examine longitudinal relations between DNAm markers and cognition. Results: At baseline, we observed a suggestive negative correlation between GrimAge clock markers and global cognition but no signal between DNAm markers and NPS measures. Over 2 years: each 1-year increase in DNAmGrimAge was significantly associated with faster declines in global cognition; each 100-base pair increase in DNAmTL was significantly associated with better global cognition. Conclusion: We found preliminary evidence of cross-sectional and longitudinal associations between DNAm markers and global cognition.

Background: Greater neuroticism has been associated with higher risk for Alzheimer’s disease (AD) dementia. However, the directionality of this association is unclear. We examined whether personality traits differ between cognitively-unimpaired carriers of autosomal-dominant AD (ADAD) and non-carriers, and are associated with in vivo AD pathology. Objective: To determine whether personality traits differ between cognitively unimpaired ADAD mutation carriers and non-carriers, and whether the traits are related to age and AD biomarkers. Methods: A total of 33 cognitively-unimpaired Presenilin-1 E280A mutation carriers and 41 non-carriers (ages 27–46) completed neuropsychological testing and the NEO Five-Factor Personality Inventory. A subsample (n = 46; 20 carriers) also underwent tau and amyloid PET imaging. Results: Carriers reported higher neuroticism relative to non-carriers, although this difference was not significant after controlling for sex. Neuroticism was positively correlated with entorhinal tau levels only in carriers, but not with amyloid levels. Conclusion: The finding of higher neuroticism in carriers and the association of this trait with tau pathology in preclinical stages of AD highlights the importance of including personality measures in the evaluation of individuals at increased risk for cognitive impairment and dementia. Further research is needed to characterize the mechanisms of these relationships.

Psychotic phenomena are among the most severe and disruptive symptoms of dementias and appear in 30% to 50% of patients. They are associated with a worse evolution and great suffering to patients and caregivers. Their current treatments obtain limited results and are not free of adverse effects, which are sometimes serious. It is therefore crucial to develop new treatments that can improve this situation. We review available data that could enlighten the future design of clinical trials with psychosis in dementia as main target. Along with an explanation of its prevalence in the common diseases that cause dementia, we present proposals aimed at improving the definition of symptoms and what should be included and excluded in clinical trials. A review of the available information regarding the neurobiological basis of symptoms, in terms of pathology, neuroimaging, and genomics, is provided as a guide towards new therapeutic targets. The correct evaluation of symptoms is transcendental in any therapeutic trial and these aspects are extensively addressed. Finally, a critical overview of existing pharmacological and non-pharmacological treatments is made, revealing the unmet needs, in terms of efficacy and safety. Our work emphasizes the need for better definition and measurement of psychotic symptoms in dementias in order to highlight their differences with symptoms that appear in non-dementing diseases such as schizophrenia. Advances in neurobiology should illuminate the development of new, more effective and safer molecules for which this review can serve as a roadmap in the design of future clinical trials This manuscriptwas facilitated by the Alzheimer’s Association International Society to Advance Alzheimer’s Research and Treatment (ISTAART), through the Neuropsychiatric Syndromes professional interest area (PIA). The views and opinions expressed by authors in this publication represent those of the authors and do not necessarily reflect those of the PIA membership, ISTAART or the Alzheimer’s Association. Ganesh M. Babulal receives research support from the BrightFocus Foundation (A2021142S), and NIH/NIA (R01AG074302 AG068183, AG067428, AG056466). Marie-Andr´ee Bruneau has received support from Optimizing Practices, Use, Care and Services - Antipsychotics (OPUS-AP) in Quebec, Canadian Foundation for Healthcare Improvement and Quebec Ministry of Health and Social services. Jennifer Gatchel has received research support from the BrightFocus Foundation, Alzheimer’s Association, and NIH/NIA. Zahinoor Ismail has received support from Brain Canada, Canadian Institutes of Health Research, and Canadian Consortium on Neurodegeneration in Dementia. Sanjeev Kumar has received support from Academic Scholars Award from the Department of Psychiatry, University of Toronto, Brain and Behavior Foundation, National institute on Ageing, BrightFocus Foundation, Brain Canada, Canadian Institute of Health Research, Canadian Consortium on Neurodegeneration in Aging, Centre for Ageing and Brain Health Innovation, Centre for Addiction and Mental Health, University of Toronto. Equipment support from Soterix Medical. Krista L. Lanctˆot has received support from the Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation, National Institute on Ageing, Canadian Institutes of Health Research,Weston Brain Institute and the Canadian Consortium on Neurodegeneration in Aging. Moyra E. Mortby has received support from the Australian National Health and Medical Research Council (NHMRC) and Australian Research Council (ARC) Dementia Research Development Fellowship #1102028. Nicolas A. Nu˜nez has received support from the National Institute of General Medical Sciences of the National Institutes of Health under award number T32 GM008685. Fabricio Oliveira has received support from FAPESP – The State of S˜ao Paulo Research Foundation (grant #2015/10109-5). Authors’ disclosures available online (https:// www.j-alz.com/manuscript-disclosures/21-5483r2) SI

Background Neurofilament light (NfL) is a promising biomarker of early neurodegeneration in Alzheimer's disease (AD). We examined whether plasma NfL was associated with in vivo amyloid beta and tau, and cognitive performance in non-demented presenilin-1 (PSEN1) E280A mutation carriers. Methods Twenty-five mutation carriers and 19 non-carriers (age range: 28 to 49 years) were included in this study. Participants underwent 11C Pittsburgh compound B (PiB)-PET (positron emission tomography), flortaucipir-PET, blood sampling, and cognitive testing. Results Mutation carriers exhibited higher plasma NfL levels than non-carriers. In carriers, higher NfL levels were related to greater regional tau burden and worse cognition, but not amyloid beta load. When we adjusted for age, a proxy of disease progression, elevated plasma NfL levels were only correlated with worse memory recall. Conclusions Findings support an association between plasma NfL, cognition, and tau pathology in non-demented individuals at genetic risk for developing AD dementia. Plasma NfL may be useful for selecting individuals at increased risk and tracking disease progression in AD.

In the present study, we tested the hypothesis that higher amyloid-beta (Aβ) burden at baseline is associated with greater longitudinal decline in body mass index (BMI) in clinically normal adults. Participants from the Harvard Aging Brain Study (n = 312) and the Alzheimer's Disease Neuroimaging Initiative (n = 336) underwent Aβ positron emission tomography at baseline. BMI was assessed longitudinally over a median of >4 years. Linear mixed models showed that higher baseline Aβ burden was significantly associated with greater decline in BMI in both the Harvard Aging Brain Study (t = −1.93; p = 0.05) and Alzheimer's Disease Neuroimaging Initiative cohorts (t = −2.54; p = 0.01), after adjusting for covariates, including cognitive performance and depressive symptoms. In addition, the association of Aβ burden with longitudinal decline in BMI persisted in both cohorts after excluding participants with diabetes/endocrine disturbances and participants classified as underweight or obese (BMI 30). These findings suggest that decline in BMI in clinically normal adults may be an early manifestation related to cerebral amyloidosis that precedes objective cognitive impairment. Therefore, unintentional BMI decline in otherwise healthy individuals might alert clinicians to increased risk of Alzheimer's disease.

Objective:Subjective Cognitive Decline (SCD) may be an early indicator of risk for Alzheimer’s disease (AD). Findings regarding sex differences in SCD are inconsistent. Studying sex differences in SCD within cognitively unimpaired individuals with autosomal-dominant AD (ADAD), who will develop dementia, may inform sex-related SCD variations in preclinical AD. We examined sex differences in SCD within cognitively unimpaired mutation carriers from the world’s largest ADAD kindred and sex differences in the relationship between SCD and memory performance.Methods:We included 310 cognitively unimpaired Presenilin-1 (PSEN-1) E280A mutation carriers (51% females) and 1998 noncarrier family members (56% females) in the study. Subjects and their study partners completed SCD questionnaires and the CERAD word list delayed recall test. ANCOVAs were conducted to examine group differences in SCD, sex, and memory performance. In carriers, partial correlations were used to examine associations between SCD and memory performance covarying for education.Results:Females in both groups had greater self-reported and study partner-reported SCD than males (allp< 0.001). In female mutation carriers, greater self-reported (p= 0.02) and study partner-reported SCD (p< 0.001) were associated with worse verbal memory. In male mutation carriers, greater self-reported (p= 0.03), but not study partner-reported SCD (p= 0.11) was associated with worse verbal memory.Conclusions:Study partner-reported SCD may be a stronger indicator of memory decline in femalesversusmales in individuals at risk for developing dementia. Future studies with independent samples and preclinical trials should consider sex differences when recruiting based on SCD criteria.

Background: Greater subjective cognitive changes on the Cognitive Function Index (CFI) was previously found to be associated with elevated amyloid (Aß) status in participants screening for the A4 Study, reported by study partners and the participants themselves. While the total score on the CFI related to amyloid for both sources respectively, potential differences in the specific types of cognitive changes reported by either participants or their study partners was not investigated. Objectives: To determine the specific types of subjective cognitive changes endorsed by participants and their study partners that are associated with amyloid status in individuals screening for an AD prevention trial. Design, Setting, Participants: Four thousand four hundred and eighty-six cognitively unimpaired (CDR=0; MMSE 25-30) participants (ages 65-85) screening for the A4 Study completed florbetapir (Aß) Positron Emission Tomography (PET) imaging. Participants were classified as elevated amyloid (Aß+; n=1323) or non-elevated amyloid (Aß-; n=3163). Measurements: Prior to amyloid PET imaging, subjective report of changes in cognitive functioning were measured using the CFI (15 item questionnaire; Yes/Maybe/No response options) and administered separately to both participants and their study partners (i.e., a family member or friend in regular contact with the participant). The impact of demographic factors on CFI report was investigated. For each item of the CFI, the relationship between Aß and CFI response was investigated using an ordinal mixed effects model for participant and study partner report. Results: Independent of Aß status, participants were more likely to report ‘Yes’ or ‘Maybe’ compared to the study partners for nearly all CFI items. Older age (r= 0.06, p

INTRODUCTION: There has been considerable progress in identifying early cognitive and biomarker predictors of Alzheimer’s disease (AD). Neuropsychiatric symptoms (NPS) are common in AD and appear to predict progression after the onset of mild cognitive impairment or dementia. OBJECTIVES: The objective of the study is to examine the relationship between NPS in clinically normal older adults and subsequent cognitive decline in a population-based sample. METHODS: The Cache County Study on Memory in Aging consists of a population-based sample of 5,092 older adults. We identified 470 clinically normal adults who were followed for an average period of 5.73 years. NPS were evaluated at the baseline clinical assessment using the Neuropsychiatric Inventory (NPI). NPI domains scores were quantified as the product of frequency X severity in individual NPI domains, and then summed for the NPI-Total. Neuropsychological measures were collected at baseline and at each subsequent follow-up wave. Linear mixed effects models assessed the association of NPI-Total, NPI-Depression, and NPI-Anxiety scores (obtained at baseline) on longitudinal change in neuropsychological performance, controlling for age, sex, and education. RESULTS: Baseline Neuropsychiatric Inventory (NPI)-Total score was associated with a more rapid rate of decline in word list memory, praxis recall, and animal fluency. Baseline NPI-Depression was not associated with later decline on any of the cognitive tests, while baseline NPI-Anxiety was associated with decline in Symbol Digit Modality. CONCLUSION: In conclusion, among clinically normal older adults derived from this population-based study, total burden of NPS was associated with longitudinal cognitive decline. These results add to the evidence that NPS are risk factors for or clinical indicators of preclinical dementia syndrome. Our study was an exploratory study and we did not control for multiple comparisons.

BACKGROUND: Brain proteins, including Insulin-like Growth Factor Binding Protein 5 (IGFBP-5), have been associated with cognitive dysfunction in aging. Mechanisms linking depression with cognition are poorly understood. We hypothesize that the association of depressive symptoms with cognition is mediated or modified by brain proteins. METHODS: IGFBP-5, HSPB2, AK4, ITPK1 and PLXNB1 were measured in dorsolateral prefrontal cortex in 1057 deceased participants, who underwent annual assessments of depressive symptoms and cognition for a mean of 8.9 years. The average number of depressive symptoms per year before a dementia diagnosis was calculated for each person. RESULTS: A one standard deviation above the mean IGFBP-5 was associated with a 14% higher odds of having more depressive symptoms (p0.070). LIMITATIONS: Participants were volunteers and self-selection bias limits the generalizability of our findings. In addition, we used self-reported data on depressive symptoms. However, we also used data on depression medications as sensitivity analyses to confirm findings. CONCLUSIONS: In old age, brain IGFBP-5 is associated with depressive symptoms and cognition. The association of depressive symptoms with cognitive decline is conditional on IGFBP-5.

Background Autosomal dominant Alzheimer’s disease (ADAD) is distinguished from late-onset AD by early striatal amyloid-β deposition. To determine whether striatal Pittsburgh compound B (PiB)-PET measurements of amyloid-β can help predict disease severity in ADAD, we compared relationships of striatal and neocortical PiB-PET to age, tau-PET, and memory performance in the Colombian Presenilin 1 E280A kindred. Methods Fourteen carriers (age = 28–42, Mini-Mental State Examination = 26–30) and 20 age-matched non-carriers were evaluated using PiB, flortaucipir (FTP; tau), and memory testing (CERAD Word List Learning). PiB-PET signal was measured in neocortical and striatal aggregates. FTP-PET signal was measured in entorhinal cortex. Results Compared to non-carriers, mutation carriers had age-related elevations in both neocortical and striatal PiB binding. The PiB elevation in carriers was significantly greater in the striatum than in the neocortex. In mutation carriers, PiB binding in both the neocortex and the striatum is related to entorhinal FTP; however, the association was stronger with the striatum. Only striatal PiB was associated with worse memory. Remarkably, PiB binding in the striatum, but not in the neocortex, predicted entorhinal FTP and lower memory scores after adjusting for age, indicating that striatal PiB identified the carriers with the most severe disease. Conclusions Based on these preliminary cross-sectional findings, striatal PiB-PET measurements may offer particular value in the detection and tracking of preclinical ADAD, informing a mutation carrier’s prognosis and evaluating amyloid-β-modifying ADAD treatments.

Background Instrumental activities of daily living (IADL) impairment and apathy occur in early-stage Alzheimer's disease (AD) and are associated with regional atrophy and hypometabolism in vivo and greater tau burden at autopsy. Objective To explore the association between IADL impairment, apathy, and in vivo regional tau in mild cognitive impairment (MCI) and AD dementia. Methods Forty participants (24 MCI, 16 AD dementia) underwent assessments of IADL (Functional Activities Questionnaire, FAQ) and apathy (Apathy Evaluation Scale Informant report, AES-I). Regional tau was assessed using flortaucipir positron emission tomography (PET) and amyloid using Pittsburgh Compound B PET. Regions with unadjusted associations of p≤0.01 were entered into regression models assessing the relationship between tau and FAQ or AES-I, adjusting for age, sex, and cognition, with/without a tau by amyloid interaction. Results Unadjusted IADL impairment but not apathy was associated with greater tau in multiple regions. After adjusting for covariates, for medial orbitofrontal and entorhinal cortex the interaction between tau and amyloid was associated with IADL impairment and for anterior cingulate it was not but independent associations with both tau and amyloid were retained. With whole brain analyses, similar results were seen for IADL, while for apathy tau in small clusters within the right anterior cingulate and dorsolateral prefrontal cortices were seen, which were more pronounced in individuals with greater amyloid. Conclusions This exploratory study suggests that IADL impairment in AD is associated with medial temporal and frontal tau, especially in individuals with elevated amyloid, while apathy may be associated with right frontal tau.

OBJECTIVE: Neuropathological studies have demonstrated that cerebrovascular disease and Alzheimer disease (AD) pathology frequently co-occur in older adults. The extent to which cerebrovascular disease influences the progression of AD pathology remains unclear. Leveraging newly available positron emission tomography (PET) imaging, we examined whether a well-validated measure of systemic vascular risk and β-amyloid (Aβ) burden have an interactive association with regional tau burden. METHODS: Vascular risk was quantified at baseline in 152 clinically normal older adults (mean age = 73.5 ± 6.1 years) with the office-based Framingham Heart Study cardiovascular disease risk algorithm (FHS-CVD). We acquired Aβ (11 C-Pittsburgh compound B) and tau (18 F-flortaucipir) PET imaging on the same participants. Aβ PET was performed at baseline; tau PET was acquired on average 2.98 ± 1.1 years later. Tau was measured in the entorhinal cortex (EC), an early site of tau deposition, and in the inferior temporal cortex (ITC), an early site of neocortical tau accumulation associated with AD. Linear regression models examined FHS-CVD and Aβ as interactive predictors of tau deposition, adjusting for age, sex, APOE e4 status, and the time interval between baseline and the tau PET scan. RESULTS: We observed a significant interaction between FHS-CVD and Aβ burden on subsequently measured ITC tau (p < 0.001), whereby combined higher FHS-CVD and elevated Aβ burden was associated with increased tau. The interaction was not significant for EC tau (p = 0.16). INTERPRETATION: Elevated vascular risk may influence tau burden when coupled with high Aβ burden. These results suggest a potential link between vascular risk and tau pathology in preclinical AD. Ann Neurol 2019; 1-8 ANN NEUROL 2019;85:272-279.

Background A decline in instrumental activities of daily living (IADL) correlates with the progression from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) dementia and has been associated with frontal and parietal hypometabolism, lower cerebrospinal fluid amyloid β 1–42, and inferior temporal cortical thinning. Identifying the underlying biomarkers of functional decline will allow for the early identification of individuals at risk of disease progression. Objective To investigate the association between IADL impairment and in vivo regional cerebral tau and cortical amyloid deposition across clinically normal (CN) elderly, MCI, and AD dementia. Methods Fifty-one CN elderly, 30 MCI, and 9 AD dementia participants of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) underwent assessment of regional tau deposition with flortaucipir (FTP) positron emission tomography (PET). An aggregate of cortical amyloid burden was assessed by florbetapir PET. IADL were assessed using the Functional Activities Questionnaire (FAQ). Tau regions with unadjusted correlations of p ≤ 0.006 (Bonferroni correction) with FAQ were used to evaluate the cross-sectional association between FAQ (dependent variable) and regional cerebral tau deposition, amyloid burden, and tau-amyloid interaction in separate general linear regression models with backward elimination. Covariates included age, American National Adult Reading Test (AMNART) intelligence quotient (IQ), and Rey Auditory Verbal Learning Test (RAVLT) total learning. Results Unadjusted correlations between FAQ and tau in the entorhinal cortex (EC) and inferior temporal cortex (IT) survived Bonferroni correction. FAQ was associated with the tau-amyloid interaction, such that in participants with greater amyloid burden, greater IADL impairment was associated with greater regional tau (EC tau × amyloid: partial r (pr) = 0.47, p

First used over eighty years ago, electroconvulsive therapy (ECT) is the oldest of the currently used biological treatments in psychiatry. ECT is indicated for severe depression, mania, treatment resistant schizophrenia psychosis, catatonia, and comorbid depression in dementia. ECT delivers a unilateral or bilateral electrical stimulus to the brain of an anesthetized patient to induce a generalized seizure. Response and remission rates of ECT in depression are high (73%-90% and 67%-73%, respectively) (1). In bipolar disorder (BD) the effectiveness of ECT has been shown for manic, depressive, and mixed episodes.

Objective Neuropsychiatric symptoms (NPS) are often present in individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia. NPS are associated with structural and functional changes in the brain such as atrophy, regional hypometabolism, and hypoperfusion, considered proxies of neurodegeneration. Our objective was to evaluate the association between NPS and regional cerebral tau burden, a more direct representation of neurodegeneration, in cognitively normal (CN), MCI, and AD dementia individuals. Methods Cross-sectional NPS were assessed using the Neuropsychiatric Inventory (NPI) in 410 CN, 199 MCI, and 61 AD dementia participants who underwent flortaucipir tau positron emission tomography as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). Total NPI score and two factors of NPS (Affective and Hyperactive) were used in analyses. Linear regression models with backward elimination were employed with NPI as dependent variable and regional tau or tau-amyloid interaction as predictor of interest. Covariates included education, age, sex, Rey Auditory Verbal Learning Test Total Learning, and Trail Making Test B. Results There were significant associations (p Conclusions Increased tau burden in the entorhinal and precuneus cortices was modestly associated with greater NPS in MCI and AD dementia. Further evaluation of NPS and their effect on early-stage AD could aid in finding new interventions and slowing disease progression. This article is protected by copyright. All rights reserved. Key points Neuropsychiatric symptoms (NPS) are common manifestations of early-stage Alzheimer's disease (AD). In the current study, we found that increased tau burden in the entorhinal and precuneus cortices was modestly associated with greater NPS in mild cognitive impairment (MCI) and AD dementia. These associations were noted with affective symptoms in particular. These associations were seen in participants with greater amyloid burden in particular.

BackgroundNeuroimaging studies of autosomal dominant Alzheimer’s disease (ADAD) enable characterization of the trajectories of cerebral amyloid-β (Aβ) and tau accumulation in the decades prior to clinical symptom onset. Longitudinal rates of regional tau accumulation measured with positron emission tomography (PET) and their relationship with other biomarker and cognitive changes remain to be fully characterized in ADAD.MethodsFourteen ADAD mutation carriers (Presenilin-1E280A) and 15 age-matched non-carriers from the Colombian kindred underwent 2–3 sessions of Aβ (11C-Pittsburgh compound B) and tau (18F-flortaucipir) PET, structural magnetic resonance imaging, and neuropsychological evaluation over a 2–4-year follow-up period. Annualized rates of change for imaging and cognitive variables were compared between carriers and non-carriers, and relationships among baseline measurements and rates of change were assessed within carriers.ResultsLongitudinal measurements were consistent with a sequence of ADAD-related changes beginning with Aβ accumulation (16 years prior to expected symptom onset, EYO), followed by entorhinal cortex (EC) tau (9 EYO), neocortical tau (6 EYO), hippocampal atrophy (6 EYO), and cognitive decline (4 EYO). Rates of tau accumulation among carriers were most rapid in parietal neocortex (~ 9%/year). EC tau PET signal at baseline was a significant predictor of subsequent neocortical tau accumulation and cognitive decline within carriers.ConclusionsOur results are consistent with the sequence of biological changes in ADAD implied by cross-sectional studies and highlight the importance of EC tau as an early biomarker and a potential link between Aβ burden and neocortical tau accumulation in ADAD.

Key Points Question How does lack of awareness (anosognosia) of memory impairment evolve in the Alzheimer disease (AD) trajectory? Findings In this cohort study of 2379 members of the Alzheimer’s Prevention Initiative Registry with a presenilin (PSEN1 E280A) variant for autosomal dominant AD, awareness of memory function was increased in carriers and noncarriers approximately 14 years before their estimated median age of dementia onset (49 years). In variant carriers only, awareness of memory function was reduced in the predementia stages, reaching anosognosia 6 years before dementia onset. Meaning The findings suggest that alteration of awareness of memory function in predementia stages may inform practitioners about AD progression., Importance Recent studies have suggested that unawareness, or anosognosia, of memory decline is present in predementia stages of Alzheimer disease (AD) and may serve as an early symptomatic indicator of AD. Objective To investigate the evolution of anosognosia of memory decline in individuals who carry the PSEN1 E280A variant for autosomal dominant AD compared with family members who do not carry the variant. Design, Setting, and Participants This cohort study investigated a total of 2379 members of a Colombian kindred with autosomal dominant AD who were part of the Alzheimer’s Prevention Initiative Registry. Assessments were completed at the University of Antioquia, Colombia, with data collected between January 1, 2000, and July 31, 2019. Main Outcomes and Measures Awareness of memory function was operationalized using the discrepancy between self-report and study partner report on a memory complaint scale. Linear mixed effects models were used to assess memory self-awareness over age separately in variant carriers and noncarriers. Results This study included 396 variant carriers (mean [SD] age, 32.7 [11.9] years; 200 [50.5%] female), of whom 59 (14.9%) were cognitively impaired, and 1983 cognitively unimpaired noncarriers (mean [SD] age, 33.5 [12.5] years; 1129 [56.9%] female). The variant carriers demonstrated increased awareness until the mean (SD) age of 35.0 (2.0) years and had anosognosia at approximately 43 years of age, approximately 6 years before their estimated median age of dementia onset (49 years; 95% CI, 49-51 years). Cognitively unimpaired noncarriers reported more complaints than their study partners aged 20 and 60 years (10.1 points, P, This cohort study investigates the evolution of anosognosia of memory decline in individuals with the PSEN1 E280A variant for autosomal dominant Alzheimer disease compared with family members without the variant.

OBJECTIVE: Amyloid accumulation, the pathological hallmark of Alzheimer’s disease, may predispose some older adults to depression and cognitive decline. Deposition of amyloid may occur prior to the development of cognitive decline. It is unclear whether amyloid influences antidepressant outcomes in cognitively intact depressed elders. DESIGN: A pharmacoimaging trial utilizing florbetapir(18F) PET scanning followed by two sequential 8-week antidepressant medication trials. PARTICIPANTS: Twenty-seven depressed elders who were cognitively intact on screening. MEASUREMENTS AND INTERVENTIONS: After screening, diagnostic testing, assessment of depression severity and neuropsychological assessment, participants completed florbetapir(18F) PET scanning. They were then randomized to receive escitalopram or placebo for 8 weeks in a double-blinded two-to-one allocation rate. Individuals who did not respond to initial treatment transitioned to a second open-label trial of bupropion for another 8 weeks. RESULTS: Compared with 22 amyloid-negative participants, 5 amyloid-positive participants exhibited significantly less change in depression severity and a lower likelihood of remission. In the initial blinded trial, 4 of 5 amyloid-positive participants were non-remitters (80%), while only 18% (4 of 22) of amyloid-negative participants did not remit (p=0.017; Fisher’s Exact test). In separate models adjusting for key covariates, both positive amyloid status (t=3.07, 21 df, p=0.003) and higher cortical amyloid binding by standard uptake value ratio (t=2.62, 21 df, p=0.010) were associated with less improvement in depression severity. Similar findings were observed when examining change in depression status across both antidepressant trials. CONCLUSIONS: In this preliminary study, amyloid status predicted poor antidepressant response to sequential antidepressant treatment. Alternative treatment approaches may be needed for amyloid-positive depressed elders.