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EVERYDAY FUNCTIONING AND ENTORHINAL AND INFERIOR TEMPORAL TAU BURDEN IN COGNITIVELY NORMAL OLDER ADULTS

 

M.A. Dubbelman1, J. Sanchez2,3, A.P. Schultz2, D.M. Rentz2,4, R.E. Amariglio2,4, S.A.M. Sikkes1,5, R.A. Sperling2,4, K.A. Johnson2,3,4, G.A. Marshall2,4, on behalf of the A4 Study team, full listing of team and site personnel available at A4STUDY.org

 

1. Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands; 2. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; 3. Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; 4. Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; 5. Faculty of Behavioural and Movement Sciences, Clinical Developmental Psychology & Clinical Neuropsychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

Corresponding Author: Gad A. Marshall, MD, Center for Alzheimer Research and Treatment, Brigham and Women’s Hospital, 60 Fenwood Road, 9016P, Boston, MA 02115, P: 617-732-8085, F: 617-264-6831, E: gamarshall@partners.org

J Prev Alz Dis 2022;
Published online June 16, 2022, http://dx.doi.org/10.14283/jpad.2022.58

 


Abstract

Background: Performance of cognitively complex “instrumental activities of daily living” (IADL) has previously been related to amyloid deposition in preclinical Alzheimer’s disease.
Objectives: We aimed to investigate the relationship between IADL performance and cerebral tau accumulation in cognitively normal older adults.
Design: Cross-sectional.
Setting: Data was collected in the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies.
Participants: Participants (n = 447, age 71.9±4.9 years, 57.5% female) who underwent tau positron emission tomography were selected from the A4 and LEARN studies.
Measurements: IADL performance was measured using the self- and study partner-reported versions of the Alzheimer’s Disease Cooperative Study Activities of Daily Living – Prevention Instrument (ADCS ADL-PI). We also investigated discordance between participants and their study partners. Cross-sectional associations between entorhinal and inferior temporal tau (independent variables) and ADCS ADL-PI total scores, item-level scores and discordance (dependent variables) were investigated in linear and logistic regressions. Analyses were adjusted for age, sex and education and a tau by amyloid interaction was also included.
Results: Participants and their study partners reported high levels of IADL performance. Entorhinal and inferior temporal tau were related to study partner but not to self-reported total ADCS ADL-PI scores. The association was not retained after adjustment for global cerebral amyloid burden. At the item level, greater entorhinal tau was associated with study partner-reported difficulties remembering important dates (odds ratio (OR) = 1.24, 95% confidence interval (95%CI) = [1.06, 1.45], p = 0.008) and difficulties remembering the details of TV programs and movies (OR = 1.32, 95%CI = [1.08, 1.61], p = 0.007). Greater inferior temporal tau was associated with self-reported difficulties managing to find personal belongings (OR = 1.23, 95%CI = [1.04, 1.46], p = 0.018) and study partner-reported difficulties remembering the details of TV programs and movies (OR = 1.39, 95%CI = [1.11, 1.75], p = 0.005). Discordance between participant and study partner-report was more likely with greater entorhinal (OR = 1.18, 95%CI = [1.05, 1.33], p = 0.005) and inferior temporal tau burden (OR = 1.29, 95%CI = [1.10, 1.51], p = 0.002).
Discussion: We found a cross-sectional relationship between study partner-reported everyday functioning and tau in cognitively normal older adults. Participants were more likely to self-report difficulties differently from their study partners when tau burden was higher. This may hint at an altered early-disease awareness of functional changes and underscores the importance of self-report of IADL functioning in addition to collateral report by a study partner.

Key words: Alzheimer’s disease, tau, cognitively normal, flortaucipir, instrumental activities of daily living, positron emission tomography.


 

Introduction

In prodromal stages of Alzheimer’s disease (AD), difficulties with everyday activities that require higher-order cognitive functioning have been shown to increase over time (1-5). These activities, referred to as ‘instrumental activities of daily living’ (IADL) (6), reflect cognition in daily life and are related to autonomy and quality of life. As such, IADL comprise an inherently clinically meaningful outcome. IADL performance in the prodromal stage has been related to both amyloid (7, 8) and tau (9) accumulation, which form the two key components of the biological definition of AD (10).
Before AD enters the prodromal stage, there exists a period of amyloid and tau accumulation in the absence of apparent clinical signs: the preclinical stage. Studies have shown that in this stage, higher amyloid burden seems to be associated with poorer IADL performance (8, 11, 12). However, to our knowledge, only one study investigated the relationship between IADL performance and tau in the preclinical stage of AD; that study did not show a direct association between regional tau deposition and IADL in cognitively normal older adults. However, in individuals with elevated amyloid, greater regional tau burden was associated with greater IADL difficulties (13).
IADL performance is usually rated by a study partner, but self-report in the preclinical stage may also be of value. There is evidence arguing for the utility of both self- and study partner-report, as both have been shown to be related to subjective memory concerns (14), objective cognitive performance (15, 16), and future cognitive decline (17, 18). As such, both sources may provide valuable information and the combination of the two may be greater than the sum of its parts.
A previous investigation of IADL performance in cognitively normal older adults who participated in the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) (19, 20) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Studies in relation to amyloid showed that worse IADL performance was associated with a higher amyloid burden (12). In the present study, we aimed to investigate the association between IADL and cerebral tau. IADL performance was measured using the Alzheimer’s Disease Cooperative Study Activities of Daily Living Prevention Instrument (ADCS ADL-PI) and tau burden was measured using flortaucipir positron emission tomography (PET). We hypothesized that difficulties with IADL performance would be associated with greater tau burden when assessed independently of amyloid, as well as in conjunction with amyloid.

 

Methods

Participants

We included participants from the A4 Study and its companion study, LEARN. The A4 Study cohort is described in more detail elsewhere (20). Participants in A4 were selected for high cortical amyloid burden, while participants in LEARN had low amyloid. In brief, all participants were cognitively normal older adults between the ages of 65 and 85, who had a study partner who could provide collateral information about the participant’s IADL performance. In addition to the A4 and LEARN inclusion criteria, to be included in the present study, participants also had to have undergone flortaucipir (tau) PET. We used only data from the baseline visit.

Assessments

IADL performance

Both participants and their study partners completed the Alzheimer’s Disease Cooperative Study Activities of Daily Living Prevention Instrument (ADCS ADL-PI) (21) to assess IADL performance. The ADCS ADL-PI was previously found to have adequate reliability (21). Each item was scored on a 4-point scale with response options of the participant “did not do the activity” (0), the participant did the activity “with a lot of difficulty” (1), “with a little difficulty” (2) or “as well as usual, with no difficulty” (3). Total (sum) scores for the 15-item version ranged from 0 to 45, with higher scores indicating better IADL performance. For the present study, item responses were dichotomized as the participant did the activity “with no difficulty” (0) or “with a little/a lot of difficulty” (1) because very few participants endorsed “a lot of difficulty”. When the participant did not do the activity, or when the informant did not know whether the participant did the activity, the item was considered missing. Missing item scores were prorated based on the individual’s mean response on the non-missing items. This was done for a total of 152 items across all self-reported ADCS ADL-PI (2.3%) and 286 items across all study partner-reported ADCS ADL-PI (4.3%). Additionally, total scores were dichotomized as “without difficulty” (total score = 45, coded 0) or “with difficulty” (total score < 45, coded 1) because of a highly skewed distribution.
Based on a previous investigation in the larger A4/LEARN screening sample of 4,486 participants (12), we focused on four items from the ADCS ADL-PI that showed a relatively high endorsement in the difficulty range: (a) remembering important dates and times, (b) managing to find personal belongings at home, (c) following TV programs or movies and remembering the details, and (d) talking about and remembering current events.
Finally, we investigated discordance between participant and study partner by subtracting the study partner total score from the participant total score. The resulting discordance score potentially ranges from -45 (self-report < study partner-report) to +45 (self-report > study partner-report). We divided the discordance score into two groups: (1) in concordance (i.e., participant and study partner report the same score) and (2) in discordance (i.e., participant and study partner report different scores). We further distinguished between participants who self-reported less IADL difficulty (i.e., participant self-reported score is higher than the study partner-reported score, “participant underreport”) and participants who self-reported more IADL difficulty (i.e., participant self-reported score is lower than the study partner-reported score, “participant overreport”).

PET imaging

Tau burden was visualized in vivo with 18F-flortaucipir PET using the A4 PET scanning protocol. Our analyses focused on two regions of interest: the entorhinal and inferior temporal cortices. These regions were selected based on prior findings with other IADL instruments (13, 22). For our primary analyses, we used non-partial volume corrected (non-PVC) standard uptake volume ratios (SUVr) with cerebellar gray matter as reference region. To facilitate interpretation of analyses, SUVr were multiplied by 10 so that a one-unit increase in tau burden represents a 0.1 SUVr increase.
A global composite of cortical amyloid was obtained from 18F-florbetapir PET SUVr, which used the whole cerebellum as the reference region, as previously described (20). Global cortical amyloid was used as a continuous measure. Additionally, we dichotomized amyloid using a threshold SUVr of ≥1.15 to distinguish elevated from non-elevated amyloid.

Statistical analyses

R version 4.1.2 was used for all analyses (23). Group differences were tested using t-tests or chi-squared tests, as appropriate. The Tukey Honest Significant Difference (HSD) correction for multiple comparisons was applied as necessary. Linear regressions were fitted with the ADCS ADL-PI total scores for participant and study partner as the dependent variables, and continuous tau in entorhinal and inferior temporal cortices separately as the main independent variables. Subsequently, we employed logistic regressions to analyze the associations between tau and the dichotomized total and item ADCS ADL-PI scores. We additionally explored the interaction between tau and amyloid.
We analyzed agreement between participants and study partners in ADCS ADL-PI total scores using the intraclass correlation coefficient (ICC), focusing on differences in the raters’ mean ratings. An ICC < 0.5 has been suggested to show poor agreement, an ICC between 0.5 and 0.75 shows moderate and an ICC > 0.75 shows good agreement (24).
In logistic regressions, we first analyzed the relationship between cerebral tau burden and rater discordance, with the concordant group as the reference group. Then, in multinomial logistic regressions we further analyzed the discordance, distinguishing between participant under and overreport, again using the concordant group as the reference.
For all linear and logistic regressions, we report betas or odds ratios (ORs), as appropriate, 95% confidence intervals (95%CIs) and p-values. All models were adjusted for age, sex, and education.

 

Results

A total of 447 participants (71.9±4.9 years old; 58% female) were included in the present study, n = 392 from A4 and n = 55 from LEARN, based on availability of tau PET. Approximately one third of participants (N = 151, 34%) self-reported any IADL difficulties (ADCS ADL-PI self-reported total score median 45, range 37–45). Somewhat less than a third of study partners (N = 127, 28%) reported any IADL difficulties (ADCS ADL-PI study partner-reported total score median 45, range 35–45). Most participants (n = 346; 77.4%) had elevated global cortical amyloid. Those who self-reported difficulties were more likely to be male (p = 0.004), more likely to be of Asian descent (p = 0.02) and had a greater global composite amyloid SUVr (p = 0.009), compared to participants who self-reported to have no difficulties. Table 1 shows the characteristics of the sample.

Table 1. Sample characteristics

1. Shown here are the total scores based on the first 15 items of the ADCS ADL-PI; Abbreviations: ADCS ADL-PI, Alzheimer’s Disease Cooperative Study – Activities of Daily Living – Prevention Instrument; IQR, interquartile range; M, median; PET, positron emission tomography; SUVr, standard uptake value ratio.

 

Total scores

In the entire sample, study partner-reported ADCS ADL-PI total scores were significantly associated with both entorhinal tau (B = -1.13, 95% confidence interval (95%CI) = [-1.89, -0.37], p = 0.004) and inferior temporal tau (B = -1.72, 95%CI = [-2.68, -0.76], p < 0.001). Self-reported ADCS ADL-PI total scores were not related to tau in either region (both p > 0.05, Table 2). The associations are visualized in Supplementary Figure 1. The relationship between entorhinal and inferior temporal tau and study partner-reported ADCS ADL-PI total scores was not retained when correcting for global cerebral amyloid burden. There was no interaction between tau and amyloid, nor was amyloid associated with ADCS ADL-PI total scores in this sample when adjusting for tau. Table 2 shows the associations between tau and ADCS ADL-PI total scores, both with and without covarying for continuous amyloid. Results with dichotomized amyloid were largely similar (see Supplemental Table 1). Results from the models with dichotomized ADCS ADL-PI total scores showed no associations with either entorhinal or inferior temporal tau (see Supplemental Table 2).

Table 2. Coefficients and 95% confidence intervals from models with continuous ADCS ADL-PI scores

Model 1 includes only tau, model 2 includes tau, amyloid and a tau–amyloid interaction. Both models are adjusted for age, sex and education; Abbreviations: B, estimate; 95%CI, 95% confidence interval

 

Item-level analysis

Greater entorhinal tau burden was associated with greater odds for study partner-reported difficulties remembering important dates and times (OR = 1.24, 95%CI = [1.06, 1.45], p = 0.008), as well as greater odds for study partner-reported difficulties following TV programs or movies and remembering the details (OR = 1.32, 95%CI = [1.08, 1.61], p = 0.007). Entorhinal tau was not associated with self-reported difficulties. A greater inferior temporal tau burden was associated with greater odds for study partner-reported difficulties following TV programs or movies and remembering the details (OR = 1.39, 95%CI = [1.11, 1.75], p = 0.005). Greater inferior temporal tau burden was associated with greater odds for self-reported difficulties managing to find personal belongings (OR = 1.23, 95%CI = [1.04, 1.46], p = 0.018). All odds ratios are shown in Table 3. The distributions of tau for no and some level of difficulty with performing each of the four activities are shown in Figure 1, for both entorhinal tau (panel A) and inferior temporal tau (panel B) and both participant self-report (gold) and study partner-report (blue).

Figure 1. Distributions and individual data points of entorhinal tau burden (panel A) and inferior temporal tau burden (panel B) set against the four ADCS ADL-PI items, as self-reported by the participant (gold) and the study partner (blue)

 

Participant and study partner discordance

There was a low intraclass correlation coefficient of 0.21 (95%CI = [0.12, 0.30]) for the concordance between participants and study partners in the total ADCS ADL-PI scores. Two hundred and fifty-four participants (56.8%) had the same score as their study partners, while 112 participants (25.1%) had lower scores (indicating more IADL difficulty) and 81 (18.1%) had higher scores than their study partners (indicating less IADL difficulty). Participants who self-reported less IADL difficulty than their study partner were more likely to be male (χ2(1) = 12.52, p < 0.001) and had a higher inferior temporal tau burden than participants who reported the same amount of difficulty as their study partner (Tukey HSD-adjusted p = 0.019).
Participants and their study partners were more likely to be in discordance when the participant had a greater entorhinal tau (OR = 1.18, 95%CI = [1.05, 1.33], p = 0.005) or inferior temporal tau burden (OR = 1.29, 95%CI = [1.10, 1.51], p = 0.002). This was not found for amyloid alone (OR = 1.71, 95%CI = [0.62, 4.70], p = 0.296). The discordance between dyads was significant in both the direction where the participant reported more IADL difficulty than their study partner and where the participant reported less IADL difficulty than their study partner. An overview of all model results can be found in the Supplementary Material. Figure 2 shows the distributions of entorhinal and inferior temporal tau for the three groups.

Figure 2. Entorhinal (left) and inferior temporal (right) tau distributions, stratified by rater difference (no difference [blue], participant self-reported more IADL difficulties than their study partner [red] or participant self-reported less IADL difficulties than their study partner [brown])

Table 3. Odds ratios from item-level models

All models are adjusted for age, sex and education; Abbreviations: OR, odds ratio; 95%CI, 95% confidence interval.

 

Discussion

In this study, we investigated the cross-sectional relationship between cerebral tau burden and the performance of higher-order cognitive everyday activities. We observed a relationship with overall IADL performance, as reported by the study partners but not the participants themselves. We also found that difficulty performing specific activities may be increased when there is a greater regional cerebral tau burden. Furthermore, we observed that participants reported difficulties differently from their study partners when tau burden was greater.
First, as previously reported in a larger sample of cognitively normal older adults from the same cohort (12), relatively few participants reported having difficulties carrying out the various tasks included in the ADCS ADL-PI. While a third of our sample reported at least some difficulty with one or more of the activities, the range in total scores was restricted and the ADCS ADL-PI showed a ceiling effect. Impairments in everyday functioning are uncommon in cognitively normal individuals, but more subtle difficulties carrying out activities do occur and have been reported in other cohorts as well (14). Because changes in daily functioning may be considered an early marker of cognitive decline, it is relevant to investigate these subtle difficulties even in early stages of AD. As ceiling effects compromise analysis of effects, outcome measures that have a broader range in total scores among individuals who have no to very mild impairments are needed.
We observed a relationship between global IADL functioning as reported by a study partner and cerebral tau in the entorhinal and inferior temporal lobe. This relationship was not found with participant self-reported IADL functioning, nor with dichotomized self or study partner-reported total scores. A previous study showed that tau in the medial temporal and medial frontal regions was associated with IADL functioning in cognitively impaired individuals with elevated amyloid (9), and it has been previously established that tau in various brain regions is related to clinical outcomes such as cognition (25). Most individuals in our sample had elevated amyloid, yet we found inconsistent associations between tau burden and global IADL functioning, which were not retained after adjusting for amyloid. We also did not observe an interaction between tau and amyloid in the associations with IADL functioning. One possible explanation for these null findings, is that difficulties with daily functioning in this sample may have been too subtle to detect, or that the instrument used, the ADCS ADL-PI, is not sensitive enough.
When looking at individual activities, we found more consistent associations. Both inferior temporal and entorhinal tau were related to a slightly increased odds of study partner-reported difficulties following a TV show or movie and remembering the details. Entorhinal tau was also related to study partner-reported difficulties remembering important dates and times, while inferior temporal tau was associated with self-reported difficulties managing to find personal belongings at home. These same items showed an association with amyloid in the larger A4/LEARN screening sample (12). Unfortunately, we were unable to investigate the interplay of tau and amyloid in the association with the performance of these activities due to infrequent endorsement of difficulty.
At the group level, participants and study partners reported overall similar levels of daily functioning, yet there was a low level of agreement between participants and their study partners. We divided our sample into participant–study partner dyads who were in concordance (reported the same level of daily functioning) and dyads who were not in concordance (reported different levels of daily functioning). We then further distinguished between dyads where the participant self-reported more difficulty and dyads where the participant self-reported less difficulty in daily functioning than their study partner. Slightly more than half the dyads were in concordance, while approximately a quarter of participants self-reported more difficulty and approximately a fifth of participants self-reported less difficulty than their study partners. Another study previously found a similar proportion of cognitively normal participants who reported more difficulties than their study partners (14).
Employing the above concordance groups, we found an association between inferior temporal tau and discordance between participants and their study partners. Participants with a greater tau burden in both regions of interest were more likely to report IADL difficulties differently from their study partner. Interestingly, it seemed that both under and overreport by the participant were more likely with greater tau burden. The finding of participant overreport may hint at an early-stage increase in awareness of functional impairments among those with more AD pathology: those with a greater tau burden report having more overall difficulties than their study partners, albeit only slightly more difficulties. Conversely, the finding of participant underreport might reflect a decrease in awareness. Our findings add to a growing body of literature indicating that participants and study partners report differently on the participants’ cognitive and functional performance, even when participants are cognitively normal (14, 26-29). As both self-reported and study partner-reported IADL functioning has been related to objective cognitive performance and future cognitive decline (15, 17), including both assessments in early disease stages may have added value and be beneficial for identifying those at risk for disease progression.
This study had a few limitations. The restricted range on the outcome measure, the ADCS ADL-PI, potentially reduced our power to detect associations, and the ceiling effect might have inflated correlation coefficients. While we checked the assumptions for linear regression and found that they were sufficiently met, we additionally dichotomized the ADCS ADL-PI total scores. We could not replicate the findings from the linear models in the dichotomized models, suggesting that our results should be interpreted with caution. Finding a way to optimally assess the first, subtle changes in daily functioning is an important challenge for future work. Further, our sample was predominantly non-Hispanic White and was highly educated, limiting the generalizability of our findings to individuals who do not match this profile. Recruitment of participants who represent the entirety of the population at-risk for AD should be a priority in the future. Future studies will also investigate the longitudinal association between AD biomarkers and daily functioning in the earliest stages of the disease. On the other hand, an important strength of our study was the large sample of cognitively normal older adults who underwent tau PET scans, combined with assessment of daily functioning as provided by the participant and a study partner.
In conclusion, we found evidence of a cross-sectional relationship between cerebral tau and study-partner reported difficulties with overall IADL functioning, as well as both participant self and study partner-reported difficulties performing specific cognitively complex activities among cognitively normal older adults. Moreover, participants were more likely to self-report their difficulties differently from their study partners when tau burden was greater. These findings may hint at an altered awareness of functional changes among those with underlying AD pathology but who are still cognitively normal, and underscore the importance of using assessments of IADL from multiple sources.

 

Funding: The A4 Study is a secondary prevention trial in preclinical Alzheimer’s disease, aiming to slow cognitive decline associated with brain amyloid accumulation in clinically normal older individuals. The A4 Study is funded by a public-private-philanthropic partnership, including funding from the National Institutes of Health-National Institute on Aging (U19AG010483; R01AG063689), Eli Lilly and Company, Alzheimer’s Association, Accelerating Medicines Partnership, GHR Foundation, an anonymous foundation and additional private donors, with in-kind support from Avid, Cogstate, Albert Einstein College of Medicine, US Against Alzheimer’s disease, and Foundation for Neurologic Diseases. The companion observational Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study is funded by the Alzheimer’s Association and GHR Foundation. MAD is supported by grants from Alzheimer Nederland and the Amsterdam UMC Young Talent Fund. SAMS was funded by public-private funding from Health&Holland, Topsector Life Sciences & Health (PPPallowance; LSHM20084-SGF, project DEFEAT-AD, LSHM19051, project OTAPA), and the National Institutes of Health. The sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of data; in the preparation of the manuscript; or in the review or approval of the manuscript.

Acknowledgments: The A4 and LEARN Studies are led by Dr. Reisa Sperling at Brigham and Women’s Hospital, Harvard Medical School and Dr. Paul Aisen at the Alzheimer’s Therapeutic Research Institute (ATRI), University of Southern California. The A4 and LEARN Studies are coordinated by ATRI at the University of Southern California, and the data are made available through the Laboratory for Neuro Imaging at the University of Southern California. The participants screening for the A4 Study provided permission to share their de-identified data to advance the quest to find a successful treatment for Alzheimer’s disease. We would like to acknowledge the dedication of all the participants, the site personnel, and all of the partnership team members who continue to make the A4 and LEARN Studies possible. The complete A4 Study Team list is available at a4study.org/a4-studyteam.

Conflicts of interest/Disclosures: MAD and JSS have nothing to disclose. APS has consulted for Janssen, Biogen, Qynapse, and NervGen. DMR has served as a consultant for Eli Lilly, Biogen Idec, Digital Cognition Technologies, and serves as a member of the Scientific Advisory Board for Neurotrack. REA has nothing to disclose. SAMS has provided consultancy services in the past 2 years for Nutricia and Takeda, and has received license fees from Green Valley, VtV Therapeutics, Alzheon, Vivoryon and Roche, as well as honoraria from Boehringer and Toyama. All funds were paid to her institution. RAS has served as a paid consultant for AC Immune, Alynlam, Cytox, Genentech, Janssen, Neurocentria, Prothena, and Roche. She has received research support as an investigator for Eli Lilly, Janssen and Eisai Alzheimer disease clinical trials. KAJ has served as paid consultant for Bayer, GE Healthcare, Janssen Alzheimer’s Immunotherapy, Siemens Medical Solutions, Genzyme, Novartis, Biogen, Roche, ISIS Pharma, AZTherapy, GEHC, Lundberg, and Abbvie. He is a site coinvestigator for Eli Lilly/Avid, Pfizer, Janssen Immunotherapy, and Navidea. He has spoken at symposia sponsored by Janssen Alzheimer’s Immunotherapy and Pfizer. GAM has received research salary support for serving as site principal investigator for clinical trials funded by Eisai Inc., Eli Lilly and Company, and Genentech. These relationships are not related to the content in the manuscript.

Ethical standards: The study protocol was approved by the local institutional review board (IRB) of each site. Study procedures were completed only after participants signed an IRB approved informed consent form.

 

SUPPLEMENTARY MATERIAL

 

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