Basic Science and Pathogenesis.

Background: Abnormal brain insulin signaling has been associated with Alzheimer's disease pathology and a faster rate of late-life cognitive decline. However, the underlying mechanisms remain unclear. In this study, we examined whether AD-related cortical proteins identified using targeted-proteomics play a role in the association of brain insulin signaling and cognitive decline.

Basic Science and Pathogenesis.

Background: The accumulation of misfolded tau proteins, an Alzheimer's disease (AD) hallmark, starts decades before the emergence of cognitive decline and clinical diagnosis. Autopsy studies support a predictable progression of tau pathology through large-scale systems. However, less is known about the specific progression patterns.

Basic Science and Pathogenesis.

Background: Autosomal dominant progranulin (GRN) mutations are a common genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN-related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that presymptomatic GRN carriers exhibit thalamocortical hyperconnectivity that increases with age when they are presumably closer to symptom onset.

Basic Science and Pathogenesis.

Background: Lateral entorhinal cortex (LEC), medial entorhinal cortex (MEC), and hippocampal area exhibit cell damage due to B-Amyloid depositions, intracellular tau aggregates, and neurofibrillay tangles. AD mouse models allow us to investigate how AD neurodegeneration affects specific brains circuits and resulting behaviors. Specifically, the PS1 and APP NL-G-F knock in (APP-KI) mouse models are relevant due to their genetic modifications, episodic memory impairment, early AD pathophysiology, and novelty designed for study.

Basic Science and Pathogenesis.

Background: In Alzheimer's disease (AD), changes in intestinal microbiota and systemic inflammation are concomitant with neuroinflammation and cognitive decline. This has led to the theory of microbial communities or infections as being causative in the development of neuroinflammation and immunosenescence seen in AD. Our research has demonstrated a decreased taxonomic diversity and an increased abundance of pathobionts in the gut of AD patients (Haran, mBio 2019), which is sufficient to promote amyloid and tau deposition in a mouse model (Chen, Gut 2023).

Basic Science and Pathogenesis.

Background: Tauopathies are a class of neurodegenerative diseases marked by tau protein spread and aggregation. Recently, our group described the cellular receptor Low-density lipoprotein Receptor-related Protein 1 (LRP1) as a regulator of tau spread. Knockdown of LRP1 halts tau spread in human induced pluripotent stem cell-derived neurons and the mouse brain, indicating potential therapeutic implications.

Basic Science and Pathogenesis.

Background: The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is analyzing the genetic etiology of early onset (40-64 years) cognitive impairment, including amyloid-positive early-onset Alzheimer's disease (EOAD) and amyloid-negative early-onset Alzheimer's disease (EOnonAD). One goal of this investigation is to identify novel or under-characterized genetic variants.

Methods: Cognitively impaired (CI) LEADS participants, including amyloid-positive and amyloid-negative early-onset cases, were whole exome or genome sequenced (N = 361).

Basic Science and Pathogenesis.

Background: Amyloid-targeting antibodies have been shown to be remarkably effective at clearing amyloid plaques from the Alzheimer's disease (AD) brain. To date, preclinical assessments have used animal models that develop only amyloid pathology, whereas AD patients present with tau pathology, neuroinflammation, and other concurrent neuropathologies. Deciphering how successful anti-amyloid therapies impact the synergistic interplay of amyloid and tau will be critical in determining which secondary disease processes can be slowed, interrupted, or reversed by amyloid-targeting immunotherapies.

Basic Science and Pathogenesis.

Background: Although the rate of Alzheimer's disease (AD) in African-ancestry (AA) Americans is higher than that of persons from European-ancestry (EA) populations, AA participants have been underrepresented in AD neuropathological studies.

Method: Utilizing the AD Research Centers (ADRC) infrastructure, we obtained AA donor pre-frontal cortex (PFC) tissue from brain repositories of 12 ADRC and generated bulk RNA sequencing (RNA-seq) data for 179 samples that met QC and inclusion criteria. Previously generated PFC RNAseq data were obtained for 28 additional AA donors from the Columbia University ADRC.

Basic Science and Pathogenesis.

Background: Brain deposits of amyloid-β (Aβ), one of the hallmark pathologies of Alzheimer disease (AD), are consistently present in people with Down syndrome (DS) after the age of 30 years. Positron emission tomography (PET) radioligands like [3H]Pittsburgh Compound-B (PiB) allow for visualizing Aβ accumulation in living people. In DS, the earliest and strongest PiB-PET retention is in the striatum, differing from late-onset AD.

Basic Science and Pathogenesis.

Background: Neuron loss exceeds tau tangle formation (Gomez-Isla et al. 1997) and p-tau vulnerability differs by layer and subfield in entorhinal cortex (Llamas-Rodriguez et al., 2022).

Clinical Manifestations.

Background: This study responds to the urgent need for automated and reliable methods to detect cognitive impairments on a large scale. It leverages natural language processing (NLP) techniques to predict dementia and mild cognitive impairment (MCI) using clinical notes from electronic health records (EHR).

Method: Our study used an EHR dataset from Massachusetts General Brigham, which included clinical notes from a 2-year period (2017-2018) covering 12 types of patient encounters.

Clinical Manifestations.

Background: Endogenous estrogen history across the life course may be associated with better cognitive maintenance. Few large longitudinal studies have evaluated this prospectively, and results have been inconsistent. We assessed the association of reproductive span, an indicator of endogenous estrogen history, with cognitive change in older women.

Clinical Manifestations.

Background: The ability to discriminate very similar objects by implementing the binding between their multiple features is assumed to be supported by the medial temporal lobe (MTL). MTL is the first brain region that shows abnormal tau accumulation in Alzheimer's disease (AD). However, whether binding ability is impaired since the preclinical stage of AD and relates to MTL tau burden is not well-established.

Clinical Manifestations.

Background: Individuals with preclinical Alzheimer's disease (AD) show reduced practice effects on annually repeated neuropsychological testing, suggesting a decreased ability to learn over repeated exposures. Remote, digital testing enables the assessment of learning over more frequent time intervals, thereby facilitating a more rapid detection of those early learning deficits. We previously showed that multi-day learning on the Boston Remote Assessment for Neurocognitive Health (BRANCH) was indeed diminished in Αβ+ cognitively unimpaired (CU) older adults.

Clinical Manifestations.

Background: In cognitively unimpaired (CU) older adults, the presence of a subjective cognitive decline (SCD) combined with evidence of abnormal b-amyloid (Ab) is proposed as stage 2 of Alzheimer's disease (AD) by the NIA-AA framework (Jack et al., 2018). However, the associations found between SCD and preclinical AD are inconsistent across studies, highlighting the importance of better understanding which specific SCD features are associated with either Ab or tau burden.

Clinical Manifestations.

Background: Latinos represent the fastest-growing subpopulation of U.S. older adults and are 1.

Clinical Manifestations.

Background: The brainstem locus coeruleus (LC) is among the first sites of Alzheimer's disease (AD) pathology, accruing hyperphosphorylated tau as early as in young adulthood. Animal studies indicate that the LC is crucially involved in sleep-wake regulation, a recently established factor contributing to AD-related pathophysiological processes. However, the associations between LC integrity and sleep-wake phenotypes in the context of AD pathology remain poorly characterized in humans.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) and other neurodegenerative diseases (NDs) cause substantial health-related and economic burdens, but progress towards preventative or ameliorative treatments has been limited. Genome-wide association studies have identified hundreds of risk loci containing single nucleotide polymorphisms (SNPs) that alter risk for these diseases, but >90% of these SNPs are in noncoding regions, which are cell type-specific and difficult to study. To address this gap, we have characterized the epigenomes of iPSC-derived neuronal and glial cells and performed CRISPRi single cell screening to dissect the molecular and cellular mechanisms underlying 10 ND risk loci.

Clinical Manifestations.

Background: Posterior Cortical Atrophy (PCA) is a syndrome characterized by a progressive decline in higher-order visuospatial processing, leading to symptoms such as space perception deficit, simultanagnosia, and object perception impairment. While PCA is primarily known for its impact on visuospatial abilities, recent studies have documented language abnormalities in PCA patients. This study aims to delineate the nature and origin of language impairments in PCA, hypothesizing that language deficits reflect the visuospatial processing impairments of the disease.

Clinical Manifestations.

Background: Accelerated long-term forgetting (LTF) is characterized by unimpaired retention of information after short-term delays (e.g., 20-30 minutes) with increased forgetting at longer intervals (e.

Clinical Manifestations.

Background: PET quantifies tau and amyloid-ß (Aß) pathology in preclinical AD. A 2-min digital clock-drawing test (DCTclock ) captures clock-drawing outcomes and processes, potentially more sensitive to cognitive deficits in preclinical AD than pencil-and-paper tests. The DCTclock summary score comprised subscores targeting multi-domain cognitive performance (i.

Clinical Manifestations.

Background: Traditional pen-and-paper neuropsychological assessments fail to capture subtle cognitive changes in the early stages of Alzheimer's disease (AD). Remote and unsupervised digital assessments available on smartphones, tablets, and personal computers may offer a solution to this by increasing the amount and types of data available to researchers and clinicians, while simultaneously improving ecological validity and alleviating patient burden. As these remote and unsupervised digital cognitive assessment tools become more widely available, it is important that they are validated in a systematic way.

Clinical Manifestations.

Background: Automated analysis of natural speech is emerging as a promising digital biomarker of Alzheimer's disease (AD). As speech is a complex process, relying on multiple interacting cognitive functions, fine-grained analysis of speech may have the potential to capture subtle cognitive deficits in the very early stages of AD. Here, we examined the association between amyloid-beta (Aβ) pathology and acoustic speech characteristics in a group of cognitively normal Dutch adults.

Clinical Manifestations.

Background: Neuropsychiatric symptoms (NPS) are common in early stages of Alzheimer's disease (AD) and may be early markers of cognitive decline and dementia in older individuals. The Mild Behavioral Impairment Checklist (MBI-C) was developed to capture new-onset transdiagnostic NPS in individuals at risk of dementia. We sought to determine whether mild behavioral impairment symptoms are elevated in non-demented Presenilin-1 (PSEN1) E280A carriers, who are genetically determined to develop dementia by their 50s.