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Article ; Online: Tangles, not TANGO: targeting tau aggregates.

Stern, Andrew M / Sperling, Reisa A

Nature aging

2023 Volume 3, Issue 12, Page(s) 1472–1473

MeSH term(s)	Humans ; Alzheimer Disease ; tau Proteins
Chemical Substances	tau Proteins
Language	English
Publishing date	2023-11-28
Publishing country	United States
Document type	Journal Article
ISSN	2662-8465
ISSN (online)	2662-8465
DOI	10.1038/s43587-023-00526-7
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Article ; Online: What Should the Goals Be for Diverse Recruitment in Alzheimer Clinical Trials?

Grill, Joshua D / Sperling, Reisa A / Raman, Rema

JAMA neurology

2022 Volume 79, Issue 11, Page(s) 1097–1098

MeSH term(s)	Humans ; Alzheimer Disease/therapy ; Goals ; Minority Groups ; Ethnicity ; Patient Selection
Language	English
Publishing date	2022-08-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	2702023-X
ISSN	2168-6157 ; 2168-6149
ISSN (online)	2168-6157
ISSN	2168-6149
DOI	10.1001/jamaneurol.2022.2274
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Article ; Online: Association of Alcohol Consumption with Cognition in Older Population: The A4 Study.

Nallapu, Bhargav T / Petersen, Kellen K / Lipton, Richard B / Grober, Ellen / Sperling, Reisa A / Ezzati, Ali

Journal of Alzheimer's disease : JAD

2023 Volume 93, Issue 4, Page(s) 1381–1393

Abstract: Background: Alcohol use disorders have been categorized as a 'strongly modifiable' risk factor for dementia.: Objective: To investigate the cross-sectional association between alcohol consumption and cognition in older adults and if it is different ... ...

Abstract	Background: Alcohol use disorders have been categorized as a 'strongly modifiable' risk factor for dementia. Objective: To investigate the cross-sectional association between alcohol consumption and cognition in older adults and if it is different across sexes or depends on amyloid-β (Aβ) accumulation in the brain. Methods: Cognitively unimpaired older adults (N = 4387) with objective and subjective cognitive assessments and amyloid positron emission tomography (PET) imaging were classified into four categories based on their average daily alcohol use. Multivariable linear regression was then used to test the main effects and interactions with sex and Aβ levels. Results: Individuals who reported no alcohol consumption had lower scores on the Preclinical Alzheimer Cognitive Composite (PACC) compared to those consuming one or two drinks/day. In sex-stratified analysis, the association between alcohol consumption and cognition was more prominent in females. Female participants who consumed two drinks/day had better performance on PACC and Cognitive Function Index (CFI) than those who reported no alcohol consumption. In an Aβ-stratified sample, the association between alcohol consumption and cognition was present only in the Aβ- subgroup. The interaction between Aβ status and alcohol consumption on cognition was not significant. Conclusion: Low or moderate consumption of alcohol was associated with better objective cognitive performance and better subjective report of daily functioning in cognitively unimpaired individuals. The association was present only in Aβ- individuals, suggesting that the pathophysiologic mechanism underlying the effect of alcohol on cognition is independent of Aβ pathology. Further investigation is required with larger samples consuming three or more drinks/day.
MeSH term(s)	Humans ; Female ; Aged ; Alzheimer Disease/pathology ; Cognitive Dysfunction/pathology ; Alcoholism ; Cross-Sectional Studies ; Cognition/physiology ; Amyloid beta-Peptides/metabolism ; Brain/pathology ; Positron-Emission Tomography ; Amyloid/metabolism
Chemical Substances	Amyloid beta-Peptides ; Amyloid
Language	English
Publishing date	2023-05-12
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-221079
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Article ; Online: Predicting Amyloid Positivity in Cognitively Unimpaired Older Adults: A Machine Learning Approach Using A4 Data.

Petersen, Kellen K / Lipton, Richard B / Grober, Ellen / Davatzikos, Christos / Sperling, Reisa A / Ezzati, Ali

Neurology

2022 Volume 98, Issue 24, Page(s) e2425–e2435

Abstract: Background and objectives: To develop and test the performance of the Positive Aβ Risk Score (PARS) for prediction of β-amyloid (Aβ) positivity in cognitively unimpaired individuals for use in clinical research. Detecting Aβ positivity is essential for ... ...

Abstract	Background and objectives: To develop and test the performance of the Positive Aβ Risk Score (PARS) for prediction of β-amyloid (Aβ) positivity in cognitively unimpaired individuals for use in clinical research. Detecting Aβ positivity is essential for identifying at-risk individuals who are candidates for early intervention with amyloid targeted treatments. Methods: We used data from 4,134 cognitively normal individuals from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) Study. The sample was divided into training and test sets. A modified version of AutoScore, a machine learning-based software tool, was used to develop a scoring system using the training set. Three risk scores were developed using candidate predictors in various combinations from the following categories: demographics (age, sex, education, race, family history, body mass index, marital status, and ethnicity), subjective measures (Alzheimer's Disease Cooperative Study Activities of Daily Living-Prevention Instrument, Geriatric Depression Scale, and Memory Complaint Questionnaire), objective measures (free recall, Mini-Mental State Examination, immediate recall, digit symbol substitution, and delayed logical memory scores), and Results: PARS model 1 included age, body mass index (BMI), and family history and had an area under the curve (AUC) of 0.60 (95% CI 0.57-0.64). PARS model 2 included free recall in addition to the PARS model 1 variables and had an AUC of 0.61 (0.58-0.64). PARS model 3, which consisted of age, BMI, and Discussion: PARS models are a set of simple and practical risk scores that may improve our ability to identify individuals more likely to be amyloid positive. The models can potentially be used to enrich trials and serve as a screening step in research settings. This approach can be followed by the use of additional variables for the development of improved risk scores. Classification of evidence: This study provides Class II evidence that in cognitively unimpaired individuals PARS models predict Aβ positivity with moderate accuracy.
MeSH term(s)	Activities of Daily Living ; Aged ; Alzheimer Disease/diagnosis ; Amyloid ; Amyloid beta-Peptides ; Amyloidosis ; Apolipoprotein E4/genetics ; Cognitive Dysfunction/diagnosis ; Humans ; Machine Learning ; Positron-Emission Tomography
Chemical Substances	Amyloid ; Amyloid beta-Peptides ; Apolipoprotein E4
Language	English
Publishing date	2022-04-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0000000000200553
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Article ; Online: Increased intraindividual variability in reaction time performance is associated with emerging cognitive decline in cognitively unimpaired adults.

Jutten, Roos J / Amariglio, Rebecca E / Maruff, Paul / Properzi, Michael J / Rentz, Dorene M / Johnson, Keith A / Sperling, Reisa A / Papp, Kathryn V

Neuropsychology

2023 Volume 38, Issue 2, Page(s) 184–197

Abstract: Objective: To investigate whether intraindividual variability (IIV) in reaction time (RT) over monthly administered cognitive tasks is increased in cognitively unimpaired older adults who are at risk for cognitive decline, and whether this is ... ...

Abstract	Objective: To investigate whether intraindividual variability (IIV) in reaction time (RT) over monthly administered cognitive tasks is increased in cognitively unimpaired older adults who are at risk for cognitive decline, and whether this is independent of mean RT performance. Method: N Results: After adjusting for mean RT, increased IIV on complex RT tasks was independently associated with worse EF performance (β = -0.10, 95% CI [-.16, -0.03], Conclusions: Increased variability in monthly RT may reflect subtle EF deficits and provide unique information about short-term cognitive decline in preclinical Alzheimer's disease. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
MeSH term(s)	Humans ; Female ; Aged ; Male ; Cross-Sectional Studies ; Reaction Time ; Alzheimer Disease/psychology ; Amyloid beta-Peptides ; Cognitive Dysfunction/diagnostic imaging ; Cognitive Dysfunction/complications ; Positron-Emission Tomography ; tau Proteins
Chemical Substances	Amyloid beta-Peptides ; tau Proteins
Language	English
Publishing date	2023-11-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	1042412-x
ISSN	1931-1559 ; 0894-4105
ISSN (online)	1931-1559
ISSN	0894-4105
DOI	10.1037/neu0000928
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Article: Computerized cognitive practice effects in relation to amyloid and tau in preclinical Alzheimer's disease: Results from a multi-site cohort.

Young, Christina B / Mormino, Elizabeth C / Poston, Kathleen L / Johnson, Keith A / Rentz, Dorene M / Sperling, Reisa A / Papp, Kathryn V

Alzheimer's & dementia (Amsterdam, Netherlands)

2023 Volume 15, Issue 1, Page(s) e12414

Abstract: Scalable cognitive paradigms that provide metrics such as the Computerized Cognitive Composite (C3) may be sensitive enough to relate to Alzheimer's disease biomarkers in the preclinical clinically unimpaired (CU) stage. We examined CU older adults ( ...

Abstract	Scalable cognitive paradigms that provide metrics such as the Computerized Cognitive Composite (C3) may be sensitive enough to relate to Alzheimer's disease biomarkers in the preclinical clinically unimpaired (CU) stage. We examined CU older adults (
Language	English
Publishing date	2023-03-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2832898-X
ISSN	2352-8729
ISSN	2352-8729
DOI	10.1002/dad2.12414
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Article: Immediate Reactions to Alzheimer Biomarker Disclosure in Cognitively Unimpaired Individuals in a Global Truncated Randomized Trial.

Grill, Joshua D / Raman, Rema / Ernstrom, Karin / Wang, Shunran / Donohue, Michael C / Aisen, Paul S / Karlawish, Jason / Henley, David / Romano, Gary / Novak, Gerald / Brashear, H Robert / Sperling, Reisa A

Neurology. Clinical practice

2024 Volume 14, Issue 2, Page(s) e200265

Abstract: Background and objectives: Preclinical Alzheimer disease (AD) trials simultaneously test candidate treatments and the implications of disclosing biomarker information to cognitively unimpaired individuals.: Methods: The EARLY trial was a randomized, ... ...

Abstract	Background and objectives: Preclinical Alzheimer disease (AD) trials simultaneously test candidate treatments and the implications of disclosing biomarker information to cognitively unimpaired individuals. Methods: The EARLY trial was a randomized, double-blind, placebo-controlled, phase 2b/3 study conducted in 143 centers across 14 countries from November 2015 to December 2018 after being stopped prematurely because of treatment-related hepatotoxicity. Participants age 60-85 years deemed cognitively unimpaired were disclosed an elevated or not elevated brain amyloid result by a certified clinician. Among 3,686 participants, 2,066 underwent amyloid imaging, 1,394 underwent CSF biomarker assessment, and 226 underwent both. Among biomarker-tested participants with at least one change score on an outcome of interest, 680 with elevated and 2,698 with not elevated amyloid were included in this analysis. We compared the Geriatric Depression Scale (GDS), the State-Trait Anxiety Scale (STAI), and the Columbia Suicide Severity Rating Scale (CSSRS) before disclosure between amyloid groups. After disclosure, we assessed for differences in the Impact of Events Scale (IES, collected 24-72 hours after disclosure), a measure of intrusive thoughts. Additional scales included the Concerns for AD scale. Results: Among 3378 included participants, the mean (SD) age was 69.0 (5.3); most were female (60%) and White race (84%). No differences were observed before disclosure between participants with elevated and not elevated amyloid for the GDS, STAI, or CSSRS. Participants with elevated amyloid demonstrated higher Concerns for AD scores compared with participants with not elevated amyloid before disclosure. Participants with elevated amyloid demonstrated higher IES scores (9.6 [10.8] vs 5.1 [8.0]) after disclosure and increased Concerns about AD. Patterns of reactions (elevated vs not elevated) were similar for biomarker modalities, although scores were lower among those undergoing CSF compared with PET testing. Although score differences were apparent comparing geographical regions, patterns of group differences were similar. Discussion: Although sample bias must be considered, these results suggest that amyloid disclosure resulted in increased perceived risk and mild distress in those learning an elevated result. Although this study did not assess psychological safety, observed associations intrusive thoughts and distress could be important considerations in the future clinical practice.
Language	English
Publishing date	2024-01-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	2645818-4
ISSN	2163-0933 ; 2163-0402
ISSN (online)	2163-0933
ISSN	2163-0402
DOI	10.1212/CPJ.0000000000200265
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Article ; Online: Atrophy links lower novelty-related locus coeruleus connectivity to cognitive decline in preclinical AD.

Schneider, Christoph / Prokopiou, Prokopis C / Papp, Kathryn V / Engels-Domínguez, Nina / Hsieh, Stephanie / Juneau, Truley A / Schultz, Aaron P / Rentz, Dorene M / Sperling, Reisa A / Johnson, Keith A / Jacobs, Heidi I L

Alzheimer's & dementia : the journal of the Alzheimer's Association

2024

Abstract: Introduction: Animal research has shown that tau pathology in the locus coeruleus (LC) is associated with reduced norepinephrine signaling, lower projection density to the medial temporal lobe (MTL), atrophy, and cognitive impairment. We investigated ... ...

Abstract	Introduction: Animal research has shown that tau pathology in the locus coeruleus (LC) is associated with reduced norepinephrine signaling, lower projection density to the medial temporal lobe (MTL), atrophy, and cognitive impairment. We investigated the contribution of LC-MTL functional connectivity (FC Methods: We analyzed functional magnetic resonance imaging and amyloid beta (Aβ) positron emission tomography data from 128 cognitively normal participants, associating novelty-related FC Results: Cross-sectionally, lower FC Discussion: FC Highlights: Novelty-related functional magnetic resonance imaging (fMRI) LC-medial temporal lobe (MTL) connectivity links to longitudinal Aβ-dependent atrophy. This relationship extended to higher Braak stage regions with increasing Aβ burden. Longitudinal MTL atrophy mediated the LC-MTL connectivity-cognition relationship. Our findings mirror the animal data on MTL atrophy following NE signal dysfunction.
Language	English
Publishing date	2024-04-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.13839
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Article ; Online: Tau positron emission tomography in preclinical Alzheimer's disease.

Insel, Philip S / Young, Christina B / Aisen, Paul S / Johnson, Keith A / Sperling, Reisa A / Mormino, Elizabeth C / Donohue, Michael C

Brain : a journal of neurology

2022 Volume 146, Issue 2, Page(s) 700–711

Abstract: Rates of tau accumulation in cognitively unimpaired older adults are subtle, with magnitude and spatial patterns varying in recent reports. Regional accumulation also likely varies in the degree to which accumulation is amyloid-β-dependent. Thus, there ... ...

Abstract	Rates of tau accumulation in cognitively unimpaired older adults are subtle, with magnitude and spatial patterns varying in recent reports. Regional accumulation also likely varies in the degree to which accumulation is amyloid-β-dependent. Thus, there is a need to evaluate the pattern and consistency of tau accumulation across multiple cognitively unimpaired cohorts and how these patterns relate to amyloid burden, in order to design optimal tau end points for clinical trials. Using three large cohorts of cognitively unimpaired older adults, the Anti-Amyloid Treatment in Asymptomatic Alzheimer's and companion study, Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (n = 447), the Alzheimer's Disease Neuroimaging Initiative (n = 420) and the Harvard Aging Brain Study (n = 190), we attempted to identify regions with high rates of tau accumulation and estimate how these rates evolve over a continuous spectrum of baseline amyloid deposition. Optimal combinations of regions, tailored to multiple ranges of baseline amyloid burden as hypothetical clinical trial inclusion criteria, were tested and validated. The inferior temporal cortex, fusiform gyrus and middle temporal cortex had the largest effect sizes of accumulation in both longitudinal cohorts when considered individually. When tau regions of interest were combined to find composite weights to maximize the effect size of tau change over time, both longitudinal studies exhibited a similar pattern-inferior temporal cortex, almost exclusively, was optimal for participants with mildly elevated amyloid β levels. For participants with highly elevated baseline amyloid β levels, combined optimal composite weights were 53% inferior temporal cortex, 31% amygdala and 16% fusiform. At mildly elevated levels of baseline amyloid β, a sample size of 200/group required a treatment effect of 0.40-0.45 (40-45% slowing of tau accumulation) to power an 18-month trial using the optimized composite. Neither a temporal lobe composite nor a global composite reached 80% power with 200/group with an effect size under 0.5. The focus of early tau accumulation on the medial temporal lobe has resulted from the observation that the entorhinal cortex is the initial site to show abnormal levels of tau with age. However, these abnormal levels do not appear to be the result of a high rate of accumulation in the short term, but possibly a more moderate rate occurring early with respect to age. While the entorhinal cortex plays a central role in the early appearance of tau, it may be the inferior temporal cortex that is the critical region for rapid tau accumulation in preclinical Alzheimer's disease.
MeSH term(s)	Humans ; Aged ; Alzheimer Disease/diagnostic imaging ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Positron-Emission Tomography ; Temporal Lobe/metabolism ; Brain/diagnostic imaging ; Brain/metabolism ; Cognitive Dysfunction ; Magnetic Resonance Imaging
Chemical Substances	Amyloid beta-Peptides ; tau Proteins
Language	English
Publishing date	2022-08-12
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80072-7
ISSN	1460-2156 ; 0006-8950
ISSN (online)	1460-2156
ISSN	0006-8950
DOI	10.1093/brain/awac299
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Article ; Online: Meaningful benefits: a framework to assess disease-modifying therapies in preclinical and early Alzheimer's disease.

Assunção, Sheila Seleri / Sperling, Reisa A / Ritchie, Craig / Kerwin, Diana R / Aisen, Paul S / Lansdall, Claire / Atri, Alireza / Cummings, Jeffrey

Alzheimer's research & therapy

2022 Volume 14, Issue 1, Page(s) 54

Abstract: Background: The need for preventive therapies that interrupt the progression of Alzheimer's disease (AD) before the onset of symptoms or when symptoms are emerging is urgent and has spurred the ongoing development of disease-modifying therapies (DMTs) ... ...

Abstract	Background: The need for preventive therapies that interrupt the progression of Alzheimer's disease (AD) before the onset of symptoms or when symptoms are emerging is urgent and has spurred the ongoing development of disease-modifying therapies (DMTs) in preclinical and early AD (mild cognitive impairment [MCI] to mild dementia). Assessing the meaningfulness of what are likely small initial treatment effects in these earlier stages of the AD patho-clinical disease continuum is a major challenge and warrants further consideration. BODY: To accommodate a shift towards earlier intervention in AD, we propose meaningful benefits as a new umbrella concept that encapsulates the spectrum of potentially desirable outcomes that may be demonstrated in clinical trials and other studies across the AD continuum, with an emphasis on preclinical AD and early AD (i.e., MCI due to AD and mild AD dementia). The meaningful benefits framework applies to data collection, assessment, and communication across three dimensions: (1) multidimensional clinical outcome assessments (COAs) including not only core disease outcomes related to cognition and function but also patient- and caregiver-reported outcomes, health and economic outcomes, and neuropsychiatric symptoms; (2) complementary analyses that help contextualize and expand the understanding of COA-based assessments, such as number-needed-to-treat or time-to-event analyses; and (3) assessment of both cumulative benefit and predictive benefit, where early changes on cognitive, functional, or biomarker assessments predict longer-term clinical benefit. Conclusion: The concept of meaningful benefits emphasizes the importance of multidimensional reporting of clinical trial data while, conceptually, it advances our understanding of treatment effects in preclinical AD and mild cognitive impairment due to AD. We propose that such an approach will help bridge the gap between the emergence of DMTs and their clinical use, particularly now that a DMT is available for patients diagnosed with MCI due to AD and mild AD dementia.
MeSH term(s)	Alzheimer Disease/diagnosis ; Alzheimer Disease/drug therapy ; Cognition ; Cognitive Dysfunction/diagnosis ; Dementia/diagnosis ; Disease Progression ; Humans
Language	English
Publishing date	2022-04-19
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2506521-X
ISSN	1758-9193 ; 1758-9193
ISSN (online)	1758-9193
ISSN	1758-9193
DOI	10.1186/s13195-022-00984-y
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