RESUMEN
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. Understanding the interplay of these factors is central to understanding resilience and resistance mechanisms explaining maintained cognitive function and reduced pathology accumulation in aging and AD. In this narrative review, the ADDRESS! Special Interest Group (Alzheimer's Association) adopted a multidisciplinary approach to provide the foundations and recommendations for future research into sex- and gender-specific drivers of resilience, including a sex/gender-oriented review of risk factors, genetics, AD and non-AD pathologies, brain structure and function, and animal research. We urge the field to adopt a sex/gender-aware approach to resilience to advance our understanding of the intricate interplay of biological and social determinants and consider sex/gender-specific resilience throughout disease stages. HIGHLIGHTS: Sex differences in resilience to cognitive decline vary by age and cognitive status. Initial evidence supports sex-specific distinctions in brain pathology. Findings suggest sex differences in the impact of pathology on cognition. There is a sex-specific change in resilience in the transition to clinical stages. Gender and sex factors warrant study: modifiable, immune, inflammatory, and vascular.
RESUMEN
BACKGROUND: Variants in APOE and PSEN1 (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 PSEN1 E280A variant who also had two copies of the apolipoprotein E3 Christchurch variant (APOE3 Ch). Heterozygosity for the APOE3 Ch variant may influence the age at which the onset of cognitive impairment occurs. We assessed this hypothesis in a population in which the PSEN1 E280A variant is prevalent. METHODS: We analyzed data from 27 participants with one copy of the APOE3 Ch variant among 1077 carriers of the PSEN1 E280A variant in a kindred from Antioquia, Colombia, to estimate the age at the onset of cognitive impairment and dementia in this group as compared with persons without the APOE3 Ch variant. Two participants underwent brain imaging, and autopsy was performed in four participants. RESULTS: Among carriers of PSEN1 E280A who were heterozygous for the APOE3 Ch variant, the median age at the onset of cognitive impairment was 52 years (95% confidence interval [CI], 51 to 58), in contrast to a matched group of PSEN1 E280A carriers without the APOE3 Ch variant, among whom the median age at the onset was 47 years (95% CI, 47 to 49). In two participants with the APOE3 Ch and PSEN1 E280A variants who underwent brain imaging, 18F-fluorodeoxyglucose positron-emission tomographic (PET) imaging showed relatively preserved metabolic activity in areas typically involved in Alzheimer's disease. In one of these participants, who underwent 18F-flortaucipir PET imaging, tau findings were limited as compared with persons with PSEN1 E280A in whom cognitive impairment occurred at the typical age in this kindred. Four studies of autopsy material obtained from persons with the APOE3 Ch and PSEN1 E280A variants showed fewer vascular amyloid pathologic features than were seen in material obtained from persons who had the PSEN1 E280A variant but not the APOE3 Ch variant. CONCLUSIONS: Clinical data supported a delayed onset of cognitive impairment in persons who were heterozygous for the APOE3 Ch variant in a kindred with a high prevalence of autosomal dominant Alzheimer's disease. (Funded by Good Ventures and others.).
Asunto(s)
Enfermedad de Alzheimer , Apolipoproteína E3 , Presenilina-1 , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Edad de Inicio , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Apolipoproteína E3/genética , Encéfalo/patología , Encéfalo/diagnóstico por imagen , Colombia , Familia , Genes Dominantes , Heterocigoto , Tomografía de Emisión de Positrones , Presenilina-1/genética , Estudios RetrospectivosRESUMEN
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.e., stating words sequentially that are all contained within a subcategory, such as domestic animals) and brain pathology in individuals with autosomal dominant Alzheimer's disease (ADAD). METHODS: A total of 29 non-demented carriers of the Presenilin1 E280A ADAD mutation and 32 noncarrier family members completed the category fluency test (Animals) and the Mini-Mental State Examination (MMSE). The participants also underwent positron emission tomography (PET) scans to evaluate in vivo amyloid-beta in the neocortex and tau in medial temporal lobe regions. Differences between carriers and noncarriers on cognitive tests were assessed with Mann-Whitney tests; associations between cognitive test performance and brain pathology were assessed with Spearman correlations. RESULTS: Animal fluency scores did not differ between carriers and noncarriers. Carriers, however, showed a stronger association between animal fluency clustering and in vivo AD brain pathology (neocortical amyloid and entorhinal tau) relative to noncarriers. CONCLUSION: This study indicates that using category fluency clustering, but not total score, is related to AD pathophysiology in the preclinical and early stages of the disease.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Encéfalo/patología , Péptidos beta-Amiloides/metabolismo , Amiloide/metabolismo , Tomografía de Emisión de Positrones , Proteínas tau/genética , Disfunción Cognitiva/patologíaRESUMEN
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. Here we show that age-related cognitive decline is accelerated in ADAD mutation carriers who also have an APOE e4 allele compared to those who do not and delayed in mutation carriers who also have an APOE e2 allele compared to those who do not. Educational attainment is protective and moderates the effect of APOE on cognition. Despite ADAD mutation carriers being genetically determined to develop dementia, age-related cognitive decline may be influenced by other genetic and environmental factors.
Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/genética , Apolipoproteínas , Apolipoproteínas E/genética , Cognición , Escolaridad , GenotipoRESUMEN
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. RESULTS: As plasma P-tau217 levels increase, cognitively unimpaired female carriers showed better cognitive performance than cognitively unimpaired male carriers. Yet, as disease progresses, female carriers had a greater plasma NfL increase than male carriers. There were no sex differences in the association between age and plasma biomarkers among non-carriers. DISCUSSION: Our findings suggest that, among PSEN1 mutation carriers, females had a greater rate of neurodegeneration than males, yet it did not predict cognitive performance. HIGHLIGHTS: We examined sex differences in plasma P-tau217 and NfL in Presenilin-1 E280A (PSEN1) mutation carriers and non-carriers. Female carriers had a greater plasma NfL increase, but not P-tau217, than male carriers. As plasma P-tau217 levels increase, cognitively unimpaired female carriers showed better cognitive performance than cognitively unimpaired male carriers. The interaction effect of sex by plasma NfL levels did not predict cognition among carriers.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Femenino , Humanos , Masculino , Enfermedad de Alzheimer/complicaciones , Péptidos beta-Amiloides , Biomarcadores , Cognición , Disfunción Cognitiva/complicaciones , Estudios Transversales , Presenilina-1/genética , Proteínas tauRESUMEN
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. Like the APOECh carrier, he had extremely elevated amyloid plaque burden and limited entorhinal Tau tangle burden. He did not carry the APOECh variant but was heterozygous for a rare variant in RELN (H3447R, termed COLBOS after the Colombia-Boston biomarker research study), a ligand that like apolipoprotein E binds to the VLDLr and APOEr2 receptors. RELN-COLBOS is a gain-of-function variant showing stronger ability to activate its canonical protein target Dab1 and reduce human Tau phosphorylation in a knockin mouse. A genetic variant in a case protected from ADAD suggests a role for RELN signaling in resilience to dementia.
Asunto(s)
Enfermedad de Alzheimer , Animales , Femenino , Humanos , Masculino , Ratones , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Heterocigoto , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Transducción de SeñalRESUMEN
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 7.61 years later in non-demented age- and education-matched presenilin-1 E280A carriers (n = 24) and non-carrier (n = 20) family members. RESULTS: Carriers had higher plasma p-tau217 levels than non-carriers. Baseline plasma p-tau217 was associated with subsequent amyloid and tau PET pathology levels and cognitive function. DISCUSSION: Our findings suggest that plasma p-tau217 predicts subsequent brain pathological burden and memory performance in presenilin-1 E280A carriers. These results provide support for plasma p-tau217 as a minimally invasive diagnostic and prognostic biomarker for AD, with potential utility in clinical practice and trials. HIGHLIGHTS: Non-demented presenilin-1 E280A carriers have higher plasma tau phosphorylated at threonine 217 (p-tau217) than do age-matched non-carriers. Higher baseline p-tau217 is associated with greater future amyloid positron emission tomography (PET) pathology burden. Higher baseline p-tau217 is associated with greater future tau PET pathology burden. Higher baseline p-tau217 is associated with worse future memory performance.
Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Proteínas Amiloidogénicas , Biomarcadores , Encéfalo/patología , Cognición , Tomografía de Emisión de Positrones/métodos , Presenilina-1/genética , Proteínas tau/metabolismoRESUMEN
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 (n = 126), Black (n = 74), Asian (n = 33), and White (n = 637) adults. Higher PiL predicted lower SCD in all groups (p-values < .012), except Black participants. Lower loneliness predicted lower SCD in Latino and White groups (p-values < .05), and PiL moderated this association in White adults. PiL and loneliness may play important roles in cognitive decline. Differential predictors of SCD suggest differential targets for preventing cognitive decline and dementia across ethnoracial groups.
Asunto(s)
Disfunción Cognitiva , Demencia , Soledad , Anciano , Humanos , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/psicología , Demencia/epidemiología , Soledad/psicología , Estados Unidos/epidemiologíaRESUMEN
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. Longitudinal changes between LC integrity and tau were evaluated in 10 carriers. RESULTS: LC integrity started to decline at age 32 in carriers, 12 years before clinical onset, and 20 years earlier than in sporadic AD. LC integrity was negatively associated with cortical tau, independent of amyloid beta, and predicted precuneus tau increases. LC integrity was positively associated with memory. DISCUSSION: These findings support LC integrity as marker of disease progression in preclinical ADAD.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Adulto , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Locus Coeruleus , Mutación/genética , Tomografía de Emisión de Positrones/métodos , Presenilina-1/genética , Proteínas tau/genética , Proteínas tau/metabolismoRESUMEN
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. The occipital cortex, the only cortical region showing cerebral amyloid angiopathy (CAA), exhibited a distinctive chronic inflammatory microglial profile and lower APOE expression. Thus, the Christchurch variant may impact the distribution of tau pathology, modulate age at onset, severity, progression, and clinical presentation of ADAD, suggesting possible therapeutic strategies.
Asunto(s)
Enfermedad de Alzheimer , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Encéfalo/patología , Homocigoto , Humanos , Tomografía de Emisión de Positrones , Proteínas tau/genética , Proteínas tau/metabolismoRESUMEN
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. Participants were recruited between September 2011 and July 2012 from the Colombian Alzheimer's Prevention Initiative registry. The studied cohort comprised 50 participants aged between 20 and 55 years, including 20 cognitively unimpaired mutation carriers, 9 cognitively impaired mutation carriers, and 21 non-carriers. Participants completed an MRI, a lumbar puncture for cerebrospinal fluid collection, a florbetapir PET scan, and neurological and neuropsychological examinations. The volume of white matter hyperintensities (WMH) was compared between cognitively unimpaired carriers, cognitively impaired carriers, and non-carriers. Relationships between WMH, age, and cognitive performance were further examined in mutation carriers. RESULTS: The mean (SD) age of participants was 35.8 (9.6) years and 64% were women. Cardiovascular risk factors were uncommon and did not differ across groups. Cognitively impaired carriers [median, 6.37; interquartile range (IQR), 9.15] had an increased volume of WMH compared to both cognitively unimpaired carriers [median, 0.85; IQR, 0.79] and non-carriers [median, 1.07; IQR, 0.71]. In mutation carriers, the volume of WMH strongly correlated with cognition and age, with evidence for an accelerated rate of changes after the age of 43 years, 1 year earlier than the estimated median age of symptom onset. In multivariable regression models including cortical amyloid retention, superior parietal lobe cortical thickness, and cerebrospinal fluid phospho-tau, the volume of WMH was the only biomarker independently and significantly contributing to the total explained variance in cognitive performance. CONCLUSIONS: The volume of WMH is increased among individuals with symptomatic autosomal-dominant Alzheimer's disease, begins to increase prior to clinical symptom onset, and is an independent determinant of cognitive performance in this group. These findings suggest that WMH are a key component of autosomal-dominant Alzheimer's disease that is closely related to the progression of clinical symptoms.
Asunto(s)
Enfermedad de Alzheimer , Sustancia Blanca , Adulto , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Estudios Transversales , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Presenilina-1/genética , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Adulto JovenRESUMEN
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. METHODS: We analyzed cross-sectional data from 16 non-demented carriers of the Presenilin1 E280A ADAD mutation (mean age [SD]: 40.1 [5.3], and 19 non-carrier family members (mean age [SD]: 36.0 [5.5]) from Colombia, who completed olfactory and cognitive testing and underwent amyloid and tau positron emission tomography (PET) imaging. RESULTS: Worse olfactory identification performance was associated with greater age in mutation carriers (râ=â-0.52 pâ=â0.037). In carriers, worse olfactory identification performance was related to worse MMSE scores (râ=â0.55, pâ=â0.024) and CERAD delayed recall (râ=â0.63, pâ=â0.007) and greater cortical amyloid-ß (râ=â-0.53, pâ=â0.042) and tau pathology burden (entorhinal: râ=â-0.59, pâ=â0.016; inferior temporal: râ=â-0.52, pâ=â0.038). CONCLUSION: Worse performance on olfactory identification tasks was associated with greater age, a proxy for disease progression in this genetically vulnerable ADAD cohort. In addition, this is the first study to report olfactory dysfunction in ADAD mutation carriers with diagnosis of MCI and its correlation with abnormal accumulation of tau pathology in the entorhinal region. Taken together, our findings suggest that olfactory dysfunction has promise as an early marker of brain pathology and future risk for dementia.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Trastornos del Olfato , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Biomarcadores , Encéfalo/patología , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/genética , Disfunción Cognitiva/patología , Estudios Transversales , Humanos , Imagen por Resonancia Magnética/métodos , Trastornos del Olfato/etiología , Trastornos del Olfato/genética , Tomografía de Emisión de Positrones/métodos , Proteínas tau/genética , Proteínas tau/metabolismoRESUMEN
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. and the limitations of examining these as binary variables; (2) provide an overview of what is known with regard to sex and gender differences in the risk, prevention, and diagnosis of ADRD; and (3) discuss these sex and gender differences from a global, worldwide perspective. Identifying drivers of sex and gender differences in ADRD throughout the world is a first step in developing interventions unique to each geographical and sociocultural area to reduce these inequities and to ultimately reduce global ADRD risk. HIGHLIGHTS: The burden of dementia is unevenly distributed geographically and by sex and gender. Scientific advances in genetics and biomarkers challenge beliefs that sex is binary. Discrimination against women and sex and gender minority (SGM) populations contributes to cognitive decline. Sociocultural factors lead to gender inequities in Alzheimer's disease and related dementias (ADRD) worldwide.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Femenino , Humanos , Masculino , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/diagnóstico , Factores de RiesgoRESUMEN
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-ß 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-ß 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 â¼13 y on average. Compared to noncarriers, mutation carriers exhibited less functional segregation and integration in posterior default-mode network (DMN) regions, particularly the precuneus, and in the retrospenial cortex, which has been shown to link medial temporal regions and cortical regions of the DMN. Mutation carriers also showed greater functional segregation and integration in regions connected to the salience network, including the striatum and thalamus. Greater tau burden was associated with lower segregated and integrated functional connectivity of DMN regions, particularly the precuneus and medial prefrontal cortex. In turn, greater tau pathology was related to higher segregated and integrated functional connectivity in the retrospenial cortex and the anterior cingulate cortex, a hub of the salience network. These findings enlighten our understanding of how AD-related pathology distinctly alters the brain's functional architecture in the preclinical stage, possibly contributing to pathology propagation and ultimately resulting in dementia.
Asunto(s)
Enfermedad de Alzheimer , Encéfalo , Conectoma , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Heterocigoto , Humanos , Imagen por Resonancia Magnética/métodos , Trastornos de la Memoria/diagnóstico por imagen , Trastornos de la Memoria/genética , Memoria Episódica , Tomografía de Emisión de Positrones/métodos , Presenilina-1/genética , Proteínas tau/metabolismoRESUMEN
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. We examine the importance of considering the effects of cultural factors on clinical presentation and diagnosis, dementia risk, clinical research and recruitment, and caregiving practices, with a focus on minoritized groups in the USA. We highlight critical gaps in the literature to stimulate future research aimed at improving the prevention and early detection of Alzheimer disease and related dementias and developing novel treatments and interventions across ethnoracially diverse populations. In addition, we briefly discuss some of our own initiatives to promote research and clinical care among Latino populations living in the USA.
Asunto(s)
Enfermedad de Alzheimer , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/terapia , Hispánicos o Latinos , HumanosRESUMEN
INTRODUCTION: Females may have greater susceptibility to Alzheimer's disease (AD)-pathology. We examined the effect of sex on pathology, neurodegeneration, and memory in cognitively-unimpaired Presenilin-1 (PSEN1) E280A mutation carriers and non-carriers. METHODS: We analyzed baseline data from 167 mutation carriers and 75 non-carriers (ages 30 to 53) from the Alzheimer's Prevention Initiative Autosomal Dominant AD Trial, including florbetapir- and fludeoxyglucose-PET, MRI based hippocampal volume and cognitive testing. RESULTS: Females exhibited better delayed recall than males, controlling for age, precuneus glucose metabolism, and mutation status, although the effect was not significant among PSEN1 mutation carriers only. APOE ε4 did not modify the effect of sex on AD biomarkers and memory. DISCUSSION: Our findings suggest that, among cognitively-unimpaired individuals at genetic risk for autosomal-dominant AD, females may have greater cognitive resilience to AD pathology and neurodegeneration than males. Further investigation of sex-specific differences in autosomal-dominant AD is key to elucidating mechanisms of AD risk and resilience.
Asunto(s)
Enfermedad de Alzheimer , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Alzheimer/metabolismo , Cognición , Colombia , Pruebas Neuropsicológicas , Presenilina-1/genética , Caracteres SexualesRESUMEN
The Alzheimer's Association hosted the second Latinos & Alzheimer's Symposium in May 2021. Due to the COVID-19 pandemic, the meeting was held online over 2 days, with virtual presentations, discussions, mentoring sessions, and posters. The Latino population in the United States is projected to have the steepest increase in Alzheimer's disease (AD) in the next 40 years, compared to other ethnic groups. Latinos have increased risk for AD and other dementias, limited access to quality care, and are severely underrepresented in AD and dementia research and clinical trials. The symposium highlighted developments in AD research with Latino populations, including advances in AD biomarkers, and novel cognitive assessments for Spanish-speaking populations, as well as the need to effectively recruit and retain Latinos in clinical research, and how best to deliver health-care services and to aid caregivers of Latinos living with AD.
Asunto(s)
Enfermedad de Alzheimer , COVID-19 , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/terapia , Biomarcadores , Hispánicos o Latinos , Humanos , Pandemias , Estados UnidosRESUMEN
OBJECTIVE: Subjective Cognitive Decline (SCD) may be an early indicator of risk for Alzheimer's disease (AD). Findings regarding sex differences in SCD are inconsistent. Studying sex differences in SCD within cognitively unimpaired individuals with autosomal-dominant AD (ADAD), who will develop dementia, may inform sex-related SCD variations in preclinical AD. We examined sex differences in SCD within cognitively unimpaired mutation carriers from the world's largest ADAD kindred and sex differences in the relationship between SCD and memory performance. METHODS: We included 310 cognitively unimpaired Presenilin-1 (PSEN-1) E280A mutation carriers (51% females) and 1998 noncarrier family members (56% females) in the study. Subjects and their study partners completed SCD questionnaires and the CERAD word list delayed recall test. ANCOVAs were conducted to examine group differences in SCD, sex, and memory performance. In carriers, partial correlations were used to examine associations between SCD and memory performance covarying for education. RESULTS: Females in both groups had greater self-reported and study partner-reported SCD than males (all p < 0.001). In female mutation carriers, greater self-reported (p = 0.02) and study partner-reported SCD (p < 0.001) were associated with worse verbal memory. In male mutation carriers, greater self-reported (p = 0.03), but not study partner-reported SCD (p = 0.11) was associated with worse verbal memory. CONCLUSIONS: Study partner-reported SCD may be a stronger indicator of memory decline in females versus males in individuals at risk for developing dementia. Future studies with independent samples and preclinical trials should consider sex differences when recruiting based on SCD criteria.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad de Alzheimer/complicaciones , Disfunción Cognitiva/psicología , Estudios de Cohortes , Colombia , Femenino , Heterocigoto , Humanos , Masculino , Pruebas Neuropsicológicas , Factores SexualesRESUMEN
INTRODUCTION: Cortical thinning is a marker of neurodegeneration in Alzheimer's disease (AD). We investigated the age-related trajectory of cortical thickness across the lifespan (9-59 years) in a Colombian kindred with autosomal dominant AD (ADAD). METHODS: Two hundred eleven participants (105 presenilin-1 [PSEN1] E280A mutation carriers, 16 with cognitive impairment; 106 non-carriers) underwent magnetic resonance imaging. A piecewise linear regression identified change-points in the age-related trajectory of cortical thickness in carriers and non-carriers. RESULTS: Unimpaired carriers exhibited elevated cortical thickness compared to non-carriers, and thickness more negatively correlated with age and cognition in carriers relative to non-carriers. We found increased cortical thickness in child carriers, after which thickness steadied compared to non-carriers prior to a rapid reduction in the decade leading up to the expected age at cognitive impairment in carriers. DISCUSSION: Findings suggest that cortical thickness may fluctuate across the ADAD lifespan, from early-life increased thickness to atrophy proximal to clinical onset.