Endonuclease G promotes hepatic mitochondrial respiration by selectively increasing mitochondrial tRNA production.

Mitochondrial endonuclease G (EndoG) contributes to chromosomal degradation when it is released from mitochondria during apoptosis. It is presumed to also have a mitochondrial function because EndoG deficiency causes mitochondrial dysfunction. However, the mechanism by which EndoG regulates mitochondrial function is not known.

Basic Science and Pathogenesis.

Background: The transfer of mitochondrial DNA into the nuclear genomes of eukaryotes (Numts) has been linked to lifespan in non-human species and recently demonstrated to occur in rare instances from one human generation to the next.

Method: Here we investigated numtogenesis dynamics in humans in two ways. First, we quantified Numts in 1,187 post-mortem brain and blood samples from different individuals.

Basic Science and Pathogenesis.

Background: Sleep dysfunction is commonly seen in Alzheimer's disease (AD) and Progressive Supranuclear Palsy (PSP), potentially worsening these conditions. Investigating early neuropathological changes in human sleep-promoting neurons, which often precede cognitive decline, is crucial for understanding the basis for sleep dysfunction as possible treatments yet remain underexplored. We used postmortem brains of AD and PSP patients to quantify neuronal numbers and tau burden in the intermediate nucleus of the hypothalamus (IntN), VLPO analog, known for its role in sleep maintenance.

SNP rs6543176 is associated with extreme human longevity but increased risk for cancer.

Using whole-genome sequencing (WGS) might offer insights into rare genetic variants associated with healthy aging and extreme longevity (EL), potentially pointing to useful therapeutic targets. In this study, we conducted a genome-wide association study using WGS data from the Long Life Family Study and identified a novel longevity-associated variant rs6543176 in the SLC9A2 gene. This SNP also showed a significant association with reduced hypertension risk and an increased, though not statistically significant, cancer risk.

Basic Science and Pathogenesis.

Background: With a rapidly aging population, South Korea anticipates a surge in Alzheimer disease (AD). However, the genetic basis of AD in Koreans is not well understood.

Method: We sequenced the genomes of 3,540 Koreans (1,583 AD cases and 1,957 controls) older than age 60 and performed a genome-wide association study (GWAS) of AD using logistic regression models that included covariates for age, sex, five ancestry principal components, and an empirical genetic relationship matrix.

Basic Science and Pathogenesis.

Background: Vascular dysfunction, blood-brain barrier (BBB) dysregulation, and neuroinflammation are thought to participate in Alzheimer`s disease (AD) pathogenesis, though the mechanism is poorly understood. Among pathways of interest, AD pathology appears to affect vascular endothelial growth factor-A (VEGFA) signaling in a bidirectional manner. Higher VEGF levels are thought to have a protective role and slow cognitive decline.

Basic Science and Pathogenesis.

Background: A significant proportion of individuals preserve cognitive function despite meeting neuropathological criteria for Alzheimer's disease (AD) at autopsy, known as cognitive resilience. We aimed to define the molecular and cellular signatures of cognitive resilience against AD.

Method: We integrated multi-modal data from the Religious Order Study and Memory and Aging Project (ROSMAP), including bulk (n = 631) and multi-regional single nucleus (n = 48) RNA sequencing.

Basic Science and Pathogenesis.

Background: A growing body of research has focused on inflammation as both a potential biomarker and a risk factor for Alzheimer's disease (AD). The cytokine Interleukin-6 (IL-6) is involved in the pathogenesis of inflammatory disorders and in the physiological homeostasis of neural tissue. AD has been associated with increased IL-6 expression in brain, however, increased levels of IL-6 have also been linked to conditions such as diabetes and hypertension.

Basic Science and Pathogenesis.

Background: APOEε4 significantly increases the risk of developing Alzheimer's disease (AD). Cognitively healthy APOEε4-carriers exist, suggesting potential protective mechanisms against APOEε4. We hypothesized that some APOEε4-carriers may have genetic variations protecting them from developing APOEε4-mediated AD pathology.

Basic Science and Pathogenesis.

Background: Individuals meeting neuropathological criteria for Alzheimer's disease (AD) may manifest with atypical clinical syndromes. Past work showed that the neurobiological basis for these differences is related to specific neuronal vulnerabilities for tau pathology. For instance, amnestic cases have a higher burden of neurofibrillary changes in CA1.

Basic Science and Pathogenesis.

Background: Genome-Wide Association Studies (GWAS) have identified 86 SNPs associated with Alzheimer's disease (AD). GWAS-SNPs are markers of genetic variation in linkage disequilibrium (LD), which may drive the association with AD. One major class of genetic variation are Structural Variants (SVs), which can regulate transcription and translation of nearby genes.

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: TBI is the 3rd greatest risk factor for developing AD, behind genetics and aging. TBI is associated with a 3-4 year earlier onset of cognitive impairment, and increased cortical thinning and amyloid plaques in people with AD. The underlying mechanisms of this relationship are not understood, and as a result there are no treatments that protect patients from accelerated AD after TBI.

Basic Science and Pathogenesis.

Background: Patients with Alzheimer's Disease and related dementias associated with the accumulation of pathological tau (tauopathies) in neurons have an increased incidence of epileptic episodes and sub-clinical epileptiform activity. This neuronal hyperexcitability represents some of the earliest changes in patient brains, is associated with more severe symptoms, and presents an opportunity for early therapeutic intervention. Despite these provocative observations, the molecular details of how tau and neuronal excitability are connected in tauopathies remain unknown.

Basic Science and Pathogenesis.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare, hereditary cerebrovascular disease which causes stroke, complex migraine, and cognitive impairment. Given its monogenic nature, CADASIL is considered a 'pure' model of small vessel disease and vascular dementia. CADASIL is caused by NOTCH3 pathogenic variants with a broad resulting phenotypic spectrum.

Basic Science and Pathogenesis.

Background: The cerebrovasculature is an essential component of brain homeostasis. Cerebrovascular disorders are associated with an increased risk for neurodegenerative diseases, including Alzheimer's disease (AD). However, the mechanisms by which cerebrovascular dysfunction contributes to neurodegeneration are poorly understood.

Basic Science and Pathogenesis.

Background: Subjective Cognitive Complaints (SCCs) can often precede mild cognitive impairment and dementia longitudinally. While increasingly considered an early prodromal stage of dementia, SCCs can also be a symptom of depression. Previous research found that SCCs in the absence of cognitive impairment, controlling for symptoms of depression, were moderately heritable and genetically associated with memory.

Basic Science and Pathogenesis.

Background: The efficacy of Calorie Restriction (CR) in enhancing cognition, promoting healthy aging, and extending lifespan is well-established. Yet, it remains unclear whether the apolipoprotein E (APOE) genotype, a known modifier for aging and age-related disorders, influences the beneficial effects of CR in countering aging.

Methods: To investigate this question, we utilized humanized APOE mouse models, which express APOE2, APOE3, or APOE4 alleles systematically (refer to as E2, E3, and E4 mice).

Basic Science and Pathogenesis.

Background: Inflammation plays a pivotal role in driving the development and progression of Alzheimer's disease (AD) in the human brain, offering a promising avenue for therapeutic intervention. However, the initiation phase of inflammation and its potential sex differences remain elusive. In this study, we aim to provide translational validity to our preclinical findings by testing two hypotheses: 1) the inflammatory profile of late-onset AD (LOAD) is initiated and detectable during midlife aging, and 2) sex differences manifest in the brain by midlife.

Basic Science and Pathogenesis.

Background: Synaptic loss, a key indicator of cognitive decline in neurodegenerative diseases, lacks a clinical biomarker, but emerging PET-scan tracers targeting synaptic vesicle protein 2A (SV2A) show promise. The current understanding of regional changes in neurodegenerative disorders and the distribution of SV2A in the human brain is quite limited. This knowledge gap presents challenges when assessing the feasibility of using SV2A tracers in therapeutic applications.

Basic Science and Pathogenesis.

Background: Understanding the molecular mechanisms underlying selective neuronal vulnerability is crucial for developing effective treatments for Alzheimer's disease (AD). Our group has shown that RORB/CDH9-positive excitatory neurons in the entorhinal cortex (EC) display selective vulnerability as early as Braak stage (BB) 2. However, not all RORB/CDH9-positive neurons are vulnerable.

Basic Science and Pathogenesis.

Background: The molecular mechanisms underlying individuals with neuropathologically confirmed Alzheimer disease (AD) but who were cognitively healthy prior to death (i.e., cognitively resilient) remain largely unknown.

Clinical Manifestations.

Background: The most common and prevalent dementia worldwide is Alzheimer's disease (AD). AD is a continuum composed of Subjective Cognitive Impairment (SCD), Mild Cognitive Impairment (MCI), and Alzheimer's Disease dementia (ADD) stage. One of the main clinical variables in patients with dementia is performance in functional capacity since its alterations are associated with poor prognosis and disease progression.

Clinical Manifestations.

Background: Harmonization of neuropsychological assessment for vascular cognitive disorders (VCD) is important for ensuring the highest standards for diagnostic and post-diagnostic care. A battery jointly proposed by the NINDS-CSN has received much support. Considering significant developments in the field, and an urgent need for consensus on remote and computerised assessment methods, an international expert group was commissioned to develop an updated harmonized battery and associated assessment guidelines for VCD using the Delphi process.

Basic Science and Pathogenesis.

Background: Frontotemporal lobar degeneration (FTLD)- TAR DNA-binding protein 43 (TDP) type C is commonly associated with a clinical diagnosis of semantic dementia (SD). Although anterior temporal lobe (ATL) is one of the primary atrophy centers, it is yet to be defined which other areas are involved in the TDP-type C pathology early in the disease course.

Methods: We included 16 patients with autopsy-confirmed FTLD-TDP type C from the database of the UCSF Memory and Aging Center: 13 patients with semantic variant primary progressive aphasia (svPPA) and predominant left ATL atrophy, and 3 patients with semantic behavioral variant frontotemporal dementia (sbvFTD) and predominant right ATL atrophy.