Plasma p‐tau231 in the presenilin 1 E280A autosomal dominant Alzheimer’s disease kindred: a cross‐sectional and longitudinal cohort study.

Background: Plasma tau phosphorylated at threonine 231 (p‐tau231) is a promising novel biomarker of emerging Alzheimer's disease (AD) pathology. We aimed to characterize cross‐sectional and longitudinal plasma p‐tau231 measurements and estimated ages of biomarker onset in an exceptionally large number of presenilin (PSEN1) E280A (Glu280Ala) mutation carriers and age‐matched non‐carriers from the Colombian autosomal dominant Alzheimer’s disease kindred.

Method: We included a cohort of 722 PSEN1 E280A mutation carriers (mean age 36.

Associations among Neurofilament light chain (NfL), Depressive Symptoms and Cognition in autosomal dominant Alzheimer´s disease.

Background: Depressive symptoms are associated with neurodegeneration in individuals at increased risk for late‐onset Alzheimer’s disease, but these relationships are less clear in younger individuals and those at risk for autosomal dominant Alzheimer’s Disease (ADAD). Neurofilament light chain (NfL) is a biomarker of axonal damage and neuronal degeneration that becomes abnormal several decades before clinical onset in ADAD. To address this gap, we investigated the associations among depressive symptoms, plasma NfL and cognition in a younger cohort affected by the ‐E280A genetic variant.

Sex hormones and brain pathology in autosomal dominant AD: preliminary findings from the Colombia‐Boston (COLBOS) biomarker study.

Background: Evidence suggests that a history of reduced estrogen exposure associates with greater Alzheimer’s disease (AD) risk. However, the association of sex hormone levels with AD biomarkers has not been studied. We examined plasma levels of sex hormones in males and females with autosomal dominant AD due to the E280A Presenilin‐1 mutation and age‐matched non‐carriers, and their relationship to AD brain pathology.

Association among Cognitive Stress Appraisal, Chronic Stress, and Cognition in Cognitively Normal Older Adults: Preliminary Findings.

Background: Characterizing stress can inform our understanding of direct and indirect pathways impacting mental and physical health outcomes, including age‐related cognitive decline. Chronic stress has been strongly associated with increased risk for cognitive decline, and hair cortisol concentration (HCC) has emerged as a viable neuroendocrine biomarker for its quantification. Cognitive appraisal of stress (CAS) provides key insight into the cognitive framework for responding to a given stressor.

Sleep Apnea Risk, Subjective Cognitive Decline, and Cognitive Performance: Findings from the Boston Latino Aging Study.

Introduction: Obstructive sleep apnea (OSA) is associated with subjective cognitive decline (SCD) and increased risk of cognitive decline and dementia. These relations are understudied in ethnoracially diverse groups. We examined associations among self-reported OSA risk, SCD, and cognitive performance in community-dwelling older Latinos.

Sex/gender effects of glial reactivity on preclinical Alzheimer's disease pathology.

Glial reactivity may contribute to sex/gender differences in Alzheimer's disease (AD) pathophysiology. Here, we investigated the differential effect of cerebrospinal fluid (CSF) glial markers on AD pathology and neurodegeneration by sex/gender among cognitively unimpaired older adults at increased risk of developing AD. We included 397 participants from the ALFA+ cohort with CSF Aβ, p-tau, sTREM2, YKL40, and GFAP, magnetic resonance imaging-based hippocampal volume (n = 299), and amyloid burden (centiloids) measured with [F] flutemetamol positron emission tomography (n = 341).

Physical Activity and Neurocognitive Symptoms in Older Adults During COVID-19 Pandemic.

Examine whether physical activity (PA) changes during the COVID-19 pandemic were related to subjective cognitive decline (SCD), depression, and anxiety in older adults and whether these varied by sociodemographic variables. 301 older adults completed an online survey between May and October 2020 and 3 months later, including self-report questionnaires of SCD, depression, and anxiety. PA changes were determined with a question.

Life course financial mobility and later-life memory function and decline by gender, and race and ethnicity: an intersectional analysis of the US KHANDLE and STAR cohort studies.

Background: Intersectionality has rarely been considered in research studies of cognitive ageing. We investigated whether life-course financial mobility is differentially associated with later-life memory function and decline across intersectional identities defined by gender, and race and ethnicity.

Methods: Data were from two harmonised multiethnic cohorts (the Kaiser Healthy Aging and Diverse Life Experiences cohort and the Study of Healthy Aging in African Americans cohort) in northern California, USA (n=2340).

Cognitive Outcomes in Autosomal-Dominant Alzheimer's Disease: A Comprehensive Review from a Colombian Kindred with the Presenilin-1 E280A Mutation.

Background: The largest identified kindred worldwide with a single mutation causing autosomal-dominant Alzheimer's disease (ADAD) is a family from Antioquia, Colombia, carrying the Presenilin-1 (PSEN1) E280A (Paisa) mutation. The majority of mutation carriers develop dementia, typically commencing in their late 30 s, with a median onset age of 49 years. Cognitive decline is a hallmark feature.

Sex and gender differences in cognitive resilience to aging and Alzheimer's disease.

Sex and gender-biological and social constructs-significantly impact the prevalence of protective and risk factors, influencing the burden of Alzheimer's disease (AD; amyloid beta and tau) and other pathologies (e.g., cerebrovascular disease) which ultimately shape cognitive trajectories.

Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease.

Background: Variants in and (encoding apolipoprotein E and presenilin 1, respectively) alter the risk of Alzheimer's disease. We previously reported a delay of cognitive impairment in a person with autosomal dominant Alzheimer's disease caused by the variant who also had two copies of the apolipoprotein E3 Christchurch variant ( ). Heterozygosity for the variant may influence the age at which the onset of cognitive impairment occurs.

Effect of apolipoprotein genotype and educational attainment on cognitive function in autosomal dominant Alzheimer's disease.

Autosomal dominant Alzheimer's disease (ADAD) is genetically determined, but variability in age of symptom onset suggests additional factors may influence cognitive trajectories. Although apolipoprotein E (APOE) genotype and educational attainment both influence dementia onset in sporadic AD, evidence for these effects in ADAD is limited. To investigate the effects of APOE and educational attainment on age-related cognitive trajectories in ADAD, we analyzed data from 675 Presenilin-1 E280A mutation carriers and 594 non-carriers.

Sex differences in blood biomarkers and cognitive performance in individuals with autosomal dominant Alzheimer's disease.

Introduction: Plasma tau phosphorylated at threonine 217 (P-tau217) and neurofilament light (NfL) have emerged as markers of Alzheimer's disease (AD) pathology. Few studies have examined the role of sex in plasma biomarkers in sporadic AD, yielding mixed findings, and none in autosomal dominant AD.

Methods: We examined the effects of sex and age on plasma P-tau217 and NfL, and their association with cognitive performance in a cross-sectional study of 621 Presenilin-1 E280A mutation carriers (PSEN1) and non-carriers.

Sex and gender considerations in dementia: a call for global research.

Studies have identified sex and/or gender differences in Alzheimer’s disease, but few have examined other dementias. We highlight sex and gender differences in other dementias, discuss sociocultural factors and provide a framework for future global studies.

Resilience to autosomal dominant Alzheimer's disease in a Reelin-COLBOS heterozygous man.

We characterized the world's second case with ascertained extreme resilience to autosomal dominant Alzheimer's disease (ADAD). Side-by-side comparisons of this male case and the previously reported female case with ADAD homozygote for the APOE3 Christchurch (APOECh) variant allowed us to discern common features. The male remained cognitively intact until 67 years of age despite carrying a PSEN1-E280A mutation.

Associations of category fluency clustering performance with brain pathology in autosomal dominant Alzheimer's disease.

Objectives: Alzheimer's disease (AD) is known to impact semantic access, which is frequently evaluated using the Category Fluency (Animals) test. Recent studies have suggested that in addition to overall category fluency scores (total number of words produced over time), poor clustering could signal AD-related cognitive difficulties. In this study, we examined the association between category fluency clustering performance (i.

Plasma p-tau217 predicts in vivo brain pathology and cognition in autosomal dominant Alzheimer's disease.

Introduction: Plasma-measured tau phosphorylated at threonine 217 (p-tau217) is a potential non-invasive biomarker of Alzheimer's disease (AD). We investigated whether plasma p-tau217 predicts subsequent cognition and positron emission tomography (PET) markers of pathology in autosomal dominant AD.

Methods: We analyzed baseline levels of plasma p-tau217 and its associations with amyloid PET, tau PET, and word list delayed recall measured 7.

Associations Among Loneliness, Purpose in Life and Subjective Cognitive Decline in Ethnoracially Diverse Older Adults Living in the United States.

Subjective cognitive decline (SCD), which precedes Mild Cognitive Impairment and dementia, may be affected by purpose in life (PiL) and loneliness in older adults. We investigated associations among PiL, loneliness, and SCD in US Latino ( = 126), Black ( = 74), Asian ( = 33), and White ( = 637) adults. Higher PiL predicted lower SCD in all groups (p-values < .

Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer's dementia.

We describe in vivo follow-up PET imaging and postmortem findings from an autosomal dominant Alzheimer's disease (ADAD) PSEN1 E280A carrier who was also homozygous for the APOE3 Christchurch (APOE3ch) variant and was protected against Alzheimer's symptoms for almost three decades beyond the expected age of onset. We identified a distinct anatomical pattern of tau pathology with atypical accumulation in vivo and unusual postmortem regional distribution characterized by sparing in the frontal cortex and severe pathology in the occipital cortex. The frontal cortex and the hippocampus, less affected than the occipital cortex by tau pathology, contained Related Orphan Receptor B (RORB) positive neurons, homeostatic astrocytes and higher APOE expression.

White matter hyperintensities are a prominent feature of autosomal dominant Alzheimer's disease that emerge prior to dementia.

Background: To promote the development of effective therapies, there is an important need to characterize the full spectrum of neuropathological changes associated with Alzheimer's disease. In line with this need, this study examined white matter abnormalities in individuals with early-onset autosomal dominant Alzheimer's disease, in relation to age and symptom severity.

Methods: This is a cross-sectional analysis of data collected in members of a large kindred with a PSEN1 E280A mutation.

Olfactory Function and Markers of Brain Pathology in Non-Demented Individuals with Autosomal Dominant Alzheimer's Disease.

Background: Olfactory dysfunction is one of the earliest signs of Alzheimer's disease (AD), highlighting its potential use as a biomarker for early detection. It has also been linked to progression from mild cognitive impairment (MCI) to dementia.

Objective: To study olfactory function and its associations with markers of AD brain pathology in non-demented mutation carriers of an autosomal dominant AD (ADAD) mutation and non-carrier family members.

Consideration of sex and gender in Alzheimer's disease and related disorders from a global perspective.

Sex or gender differences in the risk of Alzheimer's disease and related dementias (ADRD) differ by world region, suggesting that there are potentially modifiable risk factors for intervention. However, few epidemiological or clinical ADRD studies examine sex differences; even fewer evaluate gender in the context of ADRD risk. The goals of this perspective are to: (1) provide definitions of gender, biologic sex, and sexual orientation.

Amyloid-β and tau pathologies relate to distinctive brain dysconnectomics in preclinical autosomal-dominant Alzheimer's disease.

The human brain is composed of functional networks that have a modular topology, where brain regions are organized into communities that form internally dense (segregated) and externally sparse (integrated) subnetworks that underlie higher-order cognitive functioning. It is hypothesized that amyloid-β and tau pathology in preclinical Alzheimer’s disease (AD) spread through functional networks, disrupting neural communication that results in cognitive dysfunction. We used high-resolution (voxel-level) graph-based network analyses to test whether in vivo amyloid-β and tau burden was associated with the segregation and integration of brain functional connections, and episodic memory, in cognitively unimpaired Presenilin-1 E280A carriers who are expected to develop early-onset AD dementia in ∼13 y on average.

Waning locus coeruleus integrity precedes cortical tau accrual in preclinical autosomal dominant Alzheimer's disease.

Introduction: Autopsy studies recognize the locus coeruleus (LC) as one of the first sites accumulating tau in Alzheimer's disease (AD). Recent AD work related in vivo LC magnetic resonance imaging (MRI) integrity to tau and cognitive decline; however, relationships of LC integrity to age, tau, and cognition in autosomal dominant AD (ADAD) remain unexplored.

Methods: We associated LC integrity (3T-MRI) with estimated years of onset, cortical amyloid beta, regional tau (positron emission tomography [PET]) and memory (Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word-List-Learning) among 27 carriers and 27 non-carriers of the presenilin-1 (PSEN1) E280A mutation.

A cultural approach to dementia - insights from US Latino and other minoritized groups.

Alzheimer disease and related dementias present considerable challenges to health-care and medical systems worldwide. In the USA, older Black and Latino individuals are more likely than older white individuals to have Alzheimer disease and related dementias. In this Perspective, we leverage our experience and expertise with older US Latino groups to review and discuss the need to integrate cultural factors into dementia research and care.