Basic Science and Pathogenesis.

Background: The Apolipoprotein E ε4 (APOE-ε4) allele is common in the population, but acts as the strongest genetic risk factor for late-onset Alzheimer's disease (AD). Despite the strength of the association, there is notable heterogeneity in the population including a strong modifying effect of genetic ancestry, with the APOE-ε4 allele showing a stronger association among individuals of European ancestry (EUR) compared to individuals of African ancestry (AFR). Given this heterogeneity, we sought to identify genetic modifiers of APOE-ε4 related to cognitive decline leveraging APOE-ε4 stratified and interaction genome-wide association analyses (GWAS).

Basic Science and Pathogenesis.

Background: T-cell infiltration into the brain parenchyma is associated with hyperphosphorylated tau (p-tau) accumulation in neurodegenerative diseases. Chronic traumatic encephalopathy (CTE) is a progressive tauopathy caused by exposure to repetitive head impacts (RHI). CTE is defined by the perivascular accumulation of p-tau at the cortical sulcal depths and can be stratified into mild and severe pathological stages.

Basic Science and Pathogenesis.

Background: The term rapidly progressive dementia (RPD) may be applied to patients with precipitous declines in cognitive function resulting in dementia within one year or complete incapacitation within two-years of symptom onset. Although most patients present with subacute, progressive declines, selected patients develop complete incapacitation within seven days of symptom onset. The differential diagnosis and clinical characteristics of patients with abrupt-onset dementia are not known.

Basic Science and Pathogenesis.

Background: Lewy body pathology (LBP) is common in autosomal dominant (ADAD) or sporadic Alzheimer disease (sAD). LBP seems to be the most frequent co-pathology in sAD and even in the relatively young ADAD population, where other co-pathologies are rare. Knowledge of neuropathological distribution patterns of LBP and associated survival and genetic characteristics in both AD variants is incomplete.

Basic Science and Pathogenesis.

Background: The extracellular amyloid plaques, one of the pathological hallmarks of Alzheimers Disease (AD), are frequently also observed in the cortex of cognitively unimpaired subjects or as co-pathology in other neurodegenerative diseases. Progressive deposition of fibrillar amyloid-β (Aβ) as amyloid plaques for two decades prior disease onset leads to extensive isomerization of Aβ N-terminus. Quantifying the extent of isomerized Aβ can be provide insight into the different stages of amyloidosis in the brain.

Basic Science and Pathogenesis.

Background: A better understanding of the molecular process that drive Alzheimer's disease(AD) are required to develop effective biomarkers and therapies. This includes determining how essential elements like Fe, Cu and Zn are involved in the disease. In the literature there is debate over the role of iron in AD and there are reports of increased, decreased and unchanged levels of Fe in AD brain.

Basic Science and Pathogenesis.

Background: An important hallmark of Alzheimer's Disease (AD) is the presence of neurofibrillary tangles (NFTs) composed of phosphorylated tau, which are commonly assessed using AT8 immunostains. Identifying additional markers to characterize the spectrum of NFT pathology is crucial for advancing our understanding and diagnosis of AD. This study introduces new potential markers to differentiate between tangles and healthy neurons.

Basic Science and Pathogenesis.

Background: APOE*4 is the strongest genetic risk for late-onset Alzheimer's disease (AD), but other genetic loci may counter its detrimental effect, providing therapeutic avenues. Expanding beyond non-Hispanic White subjects, we sought to additionally leverage genetic data from non-Hispanic and Hispanic subjects of admixed African ancestry to perform trans-ancestry APOE*4-stratified GWAS, anticipating that allele frequency differences across populations would boost power for gene discovery.

Method: Participants were ages 60+, of European (EU; ≥75%) or admixed African (AFR; ≥25%) ancestry, and diagnosed as cases or controls.

Basic Science and Pathogenesis.

Background: Genetic variants that confer protection from Alzheimer's disease (AD) may be particularly critical in developing therapeutics. To target protective variant identification, we performed genetic association testing among selected individuals with whole genome sequencing (WGS) that remained alive and dementia-free beyond age 85 ("Wellderly").

Methods: We selected 1,873 White and Black Wellderly individuals with documented normal cognition beyond age 85 as determined by direct, in-person assessment with WGS from the NHLBI TOPMed project.

Basic Science and Pathogenesis.

Background: Alzheimer disease (AD) involves neurodegenerative disorders with progressive cognitive decline. Atypical presentations like Posterior Cortical Atrophy (PCA) and Logopenic Variant Primary Progressive Aphasia (lvPPA) exhibit distinct clinical profiles. PCA affects the posterior parietal and occipital lobes, causing visuospatial deficits, while lvPPA manifests as language impairment in the temporoparietal region.

Basic Science and Pathogenesis.

Background: Anticholinergic (AC) use remains common in older adults despite evidence of safety risks, including dementia risk. Evidence from population studies suggests that dementia risk may vary by AC class. This variation might be explained by confounding by indication.

Basic Science and Pathogenesis.

Background: Cardio and cerebrovascular risk factors (CVRFs) increase the risk of cerebrovascular disease and clinical Alzheimer's Disease (AD), and over 70% of the patients with AD coincident cerebrovascular pathology. We previously found that FMNL2 interacts with a burden score of hypertension, diabetes, heart disease, and body mass index (BMI) by altering the normal astroglial-vascular mechanisms that underly amyloid clearance. Stroke, defined by history of a clinical stroke or brain imaging, is a moderately robust risk factor for AD and dementia.

Basic Science and Pathogenesis.

Background: The immerging role of CD8+T cells, interferon and the adaptive immune response in AD is consistent with previous observations of the putative role of neurotrophic herpesvirus family infections contributing to Alzheimer's Disease pathophysiology. An outstanding question is how chronic viral infections over decades may contribute to AD pathogenesis. Our HSV-1 reactivation model aims to provide insights to this question.

Basic Science and Pathogenesis.

Background: "SuperAgers" are older adults (ages 80+) whose cognitive performance resembles that of adults in their 50s to mid-60s. Factors underlying their exemplary aging are underexplored in large, racially diverse cohorts. Using eight cohorts, we investigated the frequency of APOE genotypes in SuperAgers compared to middle-aged and older adults.

Basic Science and Pathogenesis.

Background: A drug cocktail targeting different processes of aging was tested in an aging mouse model of Alzheimer's disease (AD) neuropathologic change as an intervention to improve behaviors corresponding to cognitive dysfunction in AD.

Method: A cocktail of acarbose/rapamycin/phenylbutyrate or a control treatment was administered (medicated vs. non-medicated chow) chronically to 22 months-old mice that received viral vector injections to induce amyloid and tau pathology in the hippocampus at 24 months of age.

Basic Science and Pathogenesis.

Background: Mediterranean diets may reduce Alzheimer's disease (AD) risk and preserve cognitive function relative to Western diets by protecting against inflammation. In a long term controlled randomized trial of Mediterranean vs. Western diet consumption in cynomolgus macaques (Macaca fascicularis), difficult to conduct in humans, we found significant anti-inflammatory effects of Mediterranean diet on circulating monocyte and brain temporal cortex transcriptional profiles.

Basic Science and Pathogenesis.

Background: Cognitive decline represents a significant and gradual clinical manifestation in individuals affected by Alzheimer's disease (AD). Currently, there is a lack of effective treatments to delay its progression. Quantitative genome-wide association studies (GWAS) have yielded limited insights into progression traits.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is a common form of dementia characterized by the accumulation of amyloid beta (Aβ) and phosphorylated tau proteins in the brain. While clinical observations are typically used for AD diagnosis, postmortem studies have revealed individuals without dementia symptoms but with high AD pathology, known as resilient individuals. Calcium permeable AMPA receptors (CP-AMPARs) have been implicated in the calcium dyshomeostasis of AD, but it is unclear whether they are found or behave differently at the electrophysiological level in resilient and control individuals compared to AD patients.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is characterized by the aggregation and accumulation of proteins including amyloid-β and tau. We previously compared the immunological milieus in the brain of mice with amyloid deposition or tau aggregation and found that mice with tauopathy but not amyloid developed a unique adaptive immune response with markedly increased activated T cells in areas with tau pathology. T cell depletion blocked tau-mediated neurodegeneration.

Basic Science and Pathogenesis.

Background: Structural variants (SVs), genomic alterations exceeding 50 base-pairs, are known for their significant impact on disease pathology. However, the role of SVs in Alzheimer's Disease (AD) remains unclear. Using a novel high-accuracy SV calling pipeline, we analyzed a diverse sample from the Alzheimer's Disease Sequencing Project (ADSP).

Basic Science and Pathogenesis.

Background: Murine studies have identified blood proteins that influence brain aging, but translating these findings to humans remains challenging. We used an innovative approach to investigate whether genetically predicted blood levels of proteins linked to brain aging in animal models are associated with cognitive performance in individuals at risk of Alzheimer's disease (AD) [Figure 1].

Method: Through systematic review, we identified 13 circulating proteins with an aging/rejuvenating effect on the mouse brain.

Basic Science and Pathogenesis.

Background: Most research initiatives have emerged from high-income countries (HIC), leaving a gap in understanding the disease's genetic basis in diverse populations like those in Latin American countries (LAC). ReDLat tackles this gap, focusing on LAC's unique genetics and socioeconomic factors to identify specific Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD) risk factors in Mexico, Colombia, Peru, Chile, Argentina, and Brazil.

Method: We employed a comprehensive genetic analysis approach, integrating Whole Genome Sequencing (WGS), Exome Sequencing, and SNP arrays to understand the cohort's unique genetic architecture.

Basic Science and Pathogenesis.

Background: There is growing evidence that epigenetic age acceleration may predict late life cognitive decline and dementia, but it is unknown whether this is due to accelerated neurodegeneration or reduction in cognitive resilience. We examined the relationship between epigenetic clocks and domain specific neuropsychological (NP) factor scores, mild cognitive impairment (MCI), Alzheimer's Disease (AD), and all-cause dementia, before and after accounting for plasma total tau (t-tau), a marker of neurodegeneration.

Method: DNA methylation and plasma t-tau (Simoa assay; Quanterix) data from 2091 Framingham Heart Study Offspring cohort participants were generated from blood at the same Exam 8 visit (2005-2008).

Basic Science and Pathogenesis.

Background: The prevalence of Alzheimer's disease (AD) pathologies in people with Down syndrome (DS) is nearly 100%. In DS, overexpression of APP (on chr21) is associated with increased production of amyloid beta (Aβ) and the formation of phosphorylated tau (ptau) tangles. In the general population, women exhibit higher burdens of ptau compared to age-matched men with AD.

Basic Science and Pathogenesis.

Background: Knowledge of the chemical composition of amyloid plaques and tau tangles at the earlier stages of Alzheimer's disease (AD) pathology is sparse. This is due to limited access to human brain during life and at the earlier stages of AD pathophysiology and technical limitations in quantifying amyloid and tau species at a subcellular level. Understanding the chemical composition of plaques and tangles, how rapidly they grow and what factors drive growth is important for developing and refining therapeutics.