Estimating the preclinical Alzheimer's disease course with multimodal data.

Introduction: In observational studies of preclinical AD, an arbitrary "baseline" can obscure where an individual is located along a theoretical continuum. Optimizing longitudinal trajectories can distill multiple, non-linearly distributed observations into a single metric and inform where an individual may be along the disease course.

Methods: We developed a cognitive time (c-time) metric based on longitudinal cognitive data (mean = 7.

The Mobile Toolbox for remote, self-administered cognitive assessment in older adults: associations with in-clinic cognitive testing and Alzheimer's disease biomarkers.

Introduction: Remote, smartphone-based cognitive assessments such as the Mobile Toolbox (MTB) may increase the accessibility of Alzheimer's disease (AD) clinical trials. We examined the feasibility of the MTB among cognitively unimpaired (CU) older adults and investigated its associations with standardized in-clinic cognitive testing and amyloid and tau positron emission tomography imaging.

Methods: A total of 100 CU older adults self-administered the MTB remotely on their personal devices.

Relationship between BrainAge Polygenetic Risk Score and plasma biomarkers in the A4/LEARN studies.

Background And Objectives: To examine the association between genetic predisposition to accelerated brain aging-measured with polygenic risk scores (PRS) derived from BrainAge models-and plasma biomarkers of Alzheimer's disease (AD), with attention to age and sex-specific effects.

Methods: We analyzed 1994 cognitively unimpaired participants from the A4/LEARN studies (71.5±4.

BrainAge moderates associations between Alzheimer's disease biomarkers and cognitive decline: a meta-analysis across A4/LEARN, HABS and ADNI cohorts.

BrainAge delta, the difference between a person's predicted brain age and their chronological age, is a promising marker of the accumulation of neurodegeneration that may increase vulnerability to Alzheimer's disease (AD). We examined whether BrainAge delta moderates the relationship between AD biomarkers and longitudinal cognitive decline performing a meta-analysis across three cohorts (2,279 cognitively unimpaired [CU]; 416 with mild cognitive impairment [MCI]). Higher BrainAge delta was linked to faster decline in CU (β = -0.

Plasma Phosphorylated Tau181 as a Biomarker for Alzheimer's Disease Co-Pathology in Lewy Body Disease.

Background: Plasma phosphorylated tau181 (pTau181) is proving to be a useful predictor of Alzheimer's disease (AD). AD co-pathology is frequently observed across the Lewy body disease (LBD) spectrum.

Objective: To determine whether pTau181 in LBD is associated with postmortem Alzheimer's disease neuropathologic changes (ADNC) and with antemortem positron emission spectrometry measurements of β-amyloid and tau deposition.

Associations between hormone therapy use and tau accumulation in brain regions vulnerable to Alzheimer's disease.

Elucidating the downstream impact of exogenous hormones on the aging brain will have far-reaching consequences for understanding why Alzheimer's disease (AD) predominates in women almost twofold over men. We tested the extent to which menopausal hormone therapy (HT) use is associated with later-life amyloid-β (Aβ) and tau accumulation using PET on  = 146 baseline clinically normal women, aged 51 to 89 years. Women were scanned over a 4.

Sex Differences in Longitudinal Tau-PET in Preclinical Alzheimer Disease: A Meta-Analysis.

Importance: Alzheimer disease (AD) predominates in females at almost twice the rate relative to males. Mounting evidence in adults without AD indicates that females exhibit higher tau deposition than age-matched males, particularly in the setting of elevated β-amyloid (Aβ), but the evidence for sex differences in tau accumulation rates is inconclusive.

Objective: To examine whether female sex is associated with faster tau accumulation in the setting of high Aβ (as measured with positron emission tomography [PET]) and the moderating influence of sex on the association between APOEε4 carrier status and tau accumulation.

Rethinking the residual approach: leveraging statistical learning to operationalize cognitive resilience in Alzheimer's disease.

Cognitive resilience (CR) describes the phenomenon of individuals evading cognitive decline despite prominent Alzheimer's disease neuropathology. Operationalization and measurement of this latent construct is non-trivial as it cannot be directly observed. The residual approach has been widely applied to estimate CR, where the degree of resilience is estimated through a linear model's residuals.

Change in Depressive Symptoms and Longitudinal Regional Amyloid Accumulation in Unimpaired Older Adults.

Importance: Depressive symptoms in older adults may be a harbinger of Alzheimer disease (AD), even in preclinical stages. It is unclear whether worsening depressive symptoms are manifestations of regional distributions of core AD pathology (amyloid) and whether cognitive changes affect this relationship.

Objective: To evaluate whether increasing depressive symptoms are associated with amyloid accumulation in brain regions important for emotional regulation and whether those associations vary by cognitive performance.

Sex-dependent APOE4 neutrophil-microglia interactions drive cognitive impairment in Alzheimer's disease.

APOE4 is the strongest genetic risk factor for Alzheimer's disease (AD), with increased odds ratios in female carriers. Targeting amyloid plaques shows modest improvement in male non-APOE4 carriers. Leveraging single-cell transcriptomics across APOE variants in both sexes, multiplex flow cytometry and validation in two independent cohorts of APOE4 female carriers with AD, we identify a new subset of neutrophils interacting with microglia associated with cognitive impairment.

Differential Vulnerability of Hippocampal Subfields to Amyloid and Tau Deposition in the Lewy Body Diseases.

Background And Objectives: Alzheimer disease (AD) copathologies of β-amyloid and tau are common in the Lewy body diseases (LBD), dementia with Lewy bodies (DLB) and Parkinson disease (PD), and target distinct hippocampal subfields compared with Lewy pathology, including subiculum and CA1. We investigated the hypothesis that AD copathologies impact the pattern of hippocampal subregion volume loss and cognitive function in LBD.

Methods: This was a cross-sectional and longitudinal, single-center, observational cohort study.

Vascular contributions to cognitive decline: Beyond amyloid and tau in the Harvard Aging Brain Study.

In addition to amyloid and tau pathology, elevated systemic vascular risk, white matter injury, and reduced cerebral blood flow contribute to late-life cognitive decline. Given the strong collinearity among these parameters, we proposed a framework to extract the independent latent features underlying cognitive decline using the Harvard Aging Brain Study (N = 166 cognitively unimpaired older adults at baseline). We used the following measures from the baseline visit: cortical amyloid, inferior temporal cortex tau, relative cerebral blood flow, white matter hyperintensities, peak width of skeletonized mean diffusivity, and Framingham Heart Study cardiovascular disease risk.

Longitudinal associations of apathy and regional tau in mild cognitive impairment and dementia: Findings from the Alzheimer's Disease Neuroimaging Initiative.

Introduction: It is important to study apathy in Alzheimer's disease (AD) to better understand its underlying neurobiology and develop effective interventions. In the current study, we sought to examine the relationships between longitudinal apathy and regional tau burden in cognitively impaired older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database.

Methods: Three hundred and nineteen ADNI participants with mild cognitive impairment (MCI) or AD dementia underwent flortaucipir (FTP) tau positron emission tomography (PET) imaging and clinical assessment with the Neuropsychiatric Inventory (NPI) annually.

Cell-type-specific Alzheimer's disease polygenic risk scores are associated with distinct disease processes in Alzheimer's disease.

Many of the Alzheimer's disease (AD) risk genes are specifically expressed in microglia and astrocytes, but how and when the genetic risk localizing to these cell types contributes to AD pathophysiology remains unclear. Here, we derive cell-type-specific AD polygenic risk scores (ADPRS) from two extensively characterized datasets and uncover the impact of cell-type-specific genetic risk on AD endophenotypes. In an autopsy dataset spanning all stages of AD (n = 1457), the astrocytic ADPRS affected diffuse and neuritic plaques (amyloid-β), while microglial ADPRS affected neuritic plaques, microglial activation, neurofibrillary tangles (tau), and cognitive decline.

Capturing learning curves with the multiday Boston Remote Assessment of Neurocognitive Health (BRANCH): Feasibility, reliability, and validity.

Objective: Unsupervised remote digital cognitive assessment makes frequent testing feasible and allows for measurement of learning over repeated evaluations on participants' own devices. This provides the opportunity to derive individual multiday learning curve scores over short intervals. Here, we report feasibility, reliability, and validity, of a 7-day cognitive battery from the Boston Remote Assessment for Neurocognitive Health (Multiday BRANCH), an unsupervised web-based assessment.

Increased intraindividual variability in reaction time performance is associated with emerging cognitive decline in cognitively unimpaired adults.

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: = 109 cognitively unimpaired individuals (age 77.4 ± 5.

Contribution of extracerebral tracer retention and partial volume effects to sex differences in Flortaucipir-PET signal.

Clinically normal females exhibit higher F-flortaucipir (FTP)-PET signal than males across the cortex. However, these sex differences may be explained by neuroimaging idiosyncrasies such as off-target extracerebral tracer retention or partial volume effects (PVEs). 343 clinically normal participants (female = 58%; mean[SD]=73.

Cortical microstructural changes predict tau accumulation and episodic memory decline in older adults harboring amyloid.

Introduction: Non-invasive diffusion-weighted imaging (DWI) to assess brain microstructural changes via cortical mean diffusivity (cMD) has been shown to be cross-sectionally associated with tau in cognitively normal older adults, suggesting that it might be an early marker of neuronal injury. Here, we investigated how regional cortical microstructural changes measured by cMD are related to the longitudinal accumulation of regional tau as well as to episodic memory decline in cognitively normal individuals harboring amyloid pathology.

Methods: 122 cognitively normal participants from the Harvard Aging Brain Study underwent DWI, T1w-MRI, amyloid and tau PET imaging, and Logical Memory Delayed Recall (LMDR) assessments.

Cell-type-specific Alzheimer's disease polygenic risk scores are associated with distinct disease processes in Alzheimer's disease.

Alzheimer's disease (AD) heritability is enriched in glial genes, but how and when cell-type-specific genetic risk contributes to AD remains unclear. Here, we derive cell-type-specific AD polygenic risk scores (ADPRS) from two extensively characterized datasets. In an autopsy dataset spanning all stages of AD (n=1,457), astrocytic (Ast) ADPRS was associated with both diffuse and neuritic Aβ plaques, while microglial (Mic) ADPRS was associated with neuritic Aβ plaques, microglial activation, tau, and cognitive decline.

Associations of the Harvard Automated Phone Task and Alzheimer's Disease Pathology in Cognitively Normal Older Adults: Preliminary Findings.

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.