APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease.

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.).

Study Partner Report of Apathy in Older Adults is Associated with AD Biomarkers: Findings from the Harvard Aging Brain Study.

OBJECTIVES: We examined relationships between apathy (self and study-partner-reported) and markers of Alzheimer's disease (AD) in older adults. DESIGN: The study utilized a well-characterized sample of participants from the Harvard Aging Brain Study (HABS), a longitudinal cohort study. Participants were cognitively unimpaired without clinically significant neuropsychiatric symptoms at HABS baseline. The dependent variables, apathy evaluation scale-self (AES-S) and informant (AES-I), were administered cross-sectionally between years 6-9 and compared to the independent variables, amyloid and tau PET neuroimaging, from the same year. SETTING: Community-dwelling participants assessed at research visits in an academic medical center. PARTICIPANTS: Participants (n = 170) completed assessments within 1.5 years of their neuroimaging visit. At the time of apathy assessment, N = 156 were cognitively unimpaired and 14 had progressed to mild cognitive impairment (n = 8) or dementia (n = 6). MEASUREMENTS: We utilized linear regression models to assess cross-sectional associations of AES-S and AES-I with AD PET imaging measures (beta-amyloid (Pittsburgh Compound B) and tau (Flortaucipir)), covarying for age, sex, education, and the time between PET scan-apathy assessment. RESULTS: AES-I was significantly associated with beta-amyloid and temporal lobe tau, and the associations were retained after further adjusting for depressive symptoms. The associations between AES-S and AD biomarkers were not significant. In an exploratory subgroup analysis of cognitively unimpaired individuals with elevated Aß, we observed an association between AES-I and inferior temporal tau. CONCLUSIONS: Study-partner-reported, but not self-reported, apathy in older adults is associated with AD pathology, and we observed this relationship starting from the preclinical stage. Our findings highlight the importance of collateral information in capturing AD-related apathy.

Primary lateral sclerosis associated with PSEN1 Pro284Leu variant in a Colombian family: Clinical and neuropathological features.

INTRODUCTION: This study investigates primary lateral sclerosis (PLS) as a rare manifestation of the presenilin 1 (PSEN1) NM_000021 c.851C > T p.Pro284Leu variant in three siblings of a Colombian family, outlining its clinical and neuropathological features and their relationship to Alzheimer's disease (AD). METHODS: Data were gathered using clinical evaluations, next-generation genetic sequencing, magnetic resonance imaging, biomarker analysis, and neuropathological examination. RESULTS: Carriers of the PSEN1 Pro284Leu variant exhibited classic PLS symptoms, including unilateral onset and bulbar syndromes, along with cognitive decline. Neuropathology showed corticospinal tract degeneration without amyloid beta deposition in spinal white matter. DISCUSSION: Our findings suggest an overlap between PLS and AD pathology in PSEN1 variant carriers. Results support considering PLS when diagnosing AD-related motor syndromes and including PSEN1 evaluation when performing genetic testing for PLS. The study highlights the need for further research to clarify the PLS-AD relationship, informing future treatments and clinical trials. HIGHLIGHTS: Pathogenic variants in presenilin 1 (PSEN1) can manifest as hereditary primary lateral sclerosis PSEN1 Pro284Leu carriers present motor, cognitive, and behavioral alterations  Cases had corticospinal tract microgliosis and severe Aß pathology in motor cortex  There was no evidence of amyloid deposition in the spinal cord white matter  All the neuropathology images are available for online visualization  Myelin pallor in the spinal cord is confined to the lateral corticospinal tracts.

Novel avenues of tau research.

INTRODUCTION: The pace of innovation has accelerated in virtually every area of tau research in just the past few years. METHODS: In February 2022, leading international tau experts convened to share selected highlights of this work during Tau 2022, the second international tau conference co-organized and co-sponsored by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation. RESULTS: Representing academia, industry, and the philanthropic sector, presenters joined more than 1700 registered attendees from 59 countries, spanning six continents, to share recent advances and exciting new directions in tau research. DISCUSSION: The virtual meeting provided an opportunity to foster cross-sector collaboration and partnerships as well as a forum for updating colleagues on research-advancing tools and programs that are steadily moving the field forward.

APOE3 Christchurch modulates ß-catenin/Wnt signaling in iPS cell-derived cerebral organoids from Alzheimer's cases.

A patient with the PSEN1 E280A mutation and homozygous for APOE3 Christchurch (APOE3Ch) displayed extreme resistance to Alzheimer's disease (AD) cognitive decline and tauopathy, despite having a high amyloid burden. To further investigate the differences in biological processes attributed to APOE3Ch, we generated induced pluripotent stem (iPS) cell-derived cerebral organoids from this resistant case and a non-protected control, using CRISPR/Cas9 gene editing to modulate APOE3Ch expression. In the APOE3Ch cerebral organoids, we observed a protective pattern from early tau phosphorylation. ScRNA sequencing revealed regulation of Cadherin and Wnt signaling pathways by APOE3Ch, with immunostaining indicating elevated ß-catenin protein levels. Further in vitro reporter assays unexpectedly demonstrated that ApoE3Ch functions as a Wnt3a signaling enhancer. This work uncovered a neomorphic molecular mechanism of protection of ApoE3 Christchurch, which may serve as the foundation for the future development of protected case-inspired therapeutics targeting AD and tauopathies.

Association of loneliness, social isolation, and daily cognitive function in Mexican older adults living in community during the first wave of COVID-19 pandemic / Asociación del aislamiento social, soledad y la función cognitiva cotidiana en adultos mayores mexicanos de la comunidad durante la primera ola del COVID-19

Abstract Introduction Loneliness and social isolation are known risk factors for cognitive decline; their effect in older adults (OA) after COVID-19 lockdown is emerging. Objective To establish an association between loneliness and social isolation, with daily cognitive function in Mexican OA during the first wave of the COVID-19 pandemic. Method Cross-sectional study, derived from the cohort "The impact of COVID 19 on well-being, cognition, and discrimination among older adults in the United States and Latin America", which included 308 OA recruited between March-August 2020 whose daily cognitive function were determined with the Everyday Cognition Scale (E-Cog) as dichotomized score (cut point: 1.31 for normal cognition). Loneliness and social isolation were binomial variables. Results The mean age was 65.4 ± 7.9 years, 75.7% were women. The mean continuous E-Cog score was 57.4 (SD = ± 19.1), 49.1% had a score < 1.31 (normal cognition), while 50.9% had a higher score (cognitive impairment). Eighty four percent of participants reported loneliness, 79.9% reported social isolation. Multivariate regression model showed a negative and statistically significant association between social isolation and loneliness and E-Cog, adjusted by age, sex and education level (β = -.046, 95% CI = [-.8, -.013], p = .007; β = -.16, 95% CI = [-.08, -.018], p = .003), and a positive association with subjective memory complaint (β = .81, 95% CI = [-.16, -.11], p = < .001). Discussion and conclusion These data suggest the need for increased vigilance of those who have loneliness and social isolation due to its potential deleterious effect on cognitive function.

Resumen Introducción La soledad y el aislamiento social son factores de riesgo conocidos para el deterioro cognitivo; su efecto en las personas mayores (PM) después del confinamiento por COVID-19 está emergiendo. Objetivo Establecer una asociación entre la soledad y el aislamiento social, con la función cognitiva diaria en PM mexicanas durante la primera ola de la pandemia por COVID-19. Método Estudio transversal derivado de la cohorte "The impact of COVID 19 on well-being, cognition, and discrimination among older adults in the United States and Latin America", incluyó 308 AM reclutados de marzo-agosto 2020, la función cognitiva diaria fue evaluada con Everyday Cognition Scale (E-Cog) con un punto de corte 1.31 (cognición normal); la soledad y el aislamiento social fueron variables binomiales. Resultados La media de edad fue 65.4 ± 7.9 años, 75.7% mujeres. E-Cog promedio fue 57.4 (DE = ± 19.1), 49.1 % tenía una puntuación < 1.31 (cognición normal), 50.9% > 1.31 (deterioro cognitivo). Ochenta y cuatro por ciento de los participantes reportaron soledad, 79.9% aislamiento social. El modelo de regresión multivariado mostró una asociación negativa y estadísticamente significativa entre aislamiento social y soledad con E-Cog (β = -.046, IC 95% = [-.8, -.013], p = .007; β = -.16, IC 95% = [-.08, -.018], p = .003), y una asociación positiva con queja de memoria subjetiva (β = .81, IC 95% = [-.16, -.11], p = < .001) ajustado a edad, sexo y escolaridad. Discusión y conclusión Estos datos sugieren la necesidad de una mayor vigilancia de quienes presentan soledad y aislamiento social debido a su potencial efecto deletéreo sobre la función cognitiva.

Cross-cultural adaptation of the everyday cognition scale (M-ECog) in older Mexican adults with cognitive impairment / Adaptação transcultural da escala de cognição cotidiana (M-ECog) em idosos mexicanos com comprometimento cognitivo

Abstract The Everyday Cognition (ECog) scale was created to evaluate the functional abilities of older adults across a wide range of abilities between normal aging and dementia. ECog screens cognitive alterations such as subjective cognitive decline (SCD) and mild cognitive impairment (MCI). This early recognition is done by the measurement of the ability to perform the activities of daily living (ADLs). Objective: To establish the cross-cultural adaptation, validity, and reliability of the ECog Mexican version (M-ECog) in participants with: SCD, MCI, and dementia coming from a memory clinic. Methods: There were 200 patients and their respective informants in a memory clinic of a third level hospital in Mexico City. Four groups were studied: 50 cognitively healthy (CH), 50 SCD, 50 MCI, and 50 dementia. The clinical evaluation included: sociodemographic and health characteristics, cognitive status by the Mini-Mental State Evaluation (MMSE) and Montreal Cognitive Evaluation Spanish version (MoCA-E), and caregiver information (informants) about the difficulty in ADLs as well as the ECog Spanish version (M-ECog). Results: The M-ECog was significantly correlated with MMSE, MoCA-E, and ADLs. It showed the ability to discriminate the different cognitive declines (Cronbach's alpha 0.881). The intra-class correlation coefficient was 0.877 (95% confidence interval — CI, 0.850-0.902; p<0.001). The patient's group area under curve (AUC) of M-ECog for SCD was 0.70 (95%CI 0.58-0.82, p<0.005), for MCI it was 0.94 (95%CI 0.89-0.99, p<0.001) and for dementia 0.86 (95%CI 0.79-0.92, p<0.001). Conclusion: The M-ECog scale proves to be valid and reliable for measuring everyday abilities mediated by cognition. It is self-applicable without requiring extensive prior formation. It is useful to screen for SCD and MCI in older Mexican adults.

RESUMO A escala Cognição Cotidiana (ECog) foi criada para avaliar as habilidades funcionais de idosos em uma ampla gama de habilidades entre o envelhecimento normal e a demência. O ECog rastreia alterações cognitivas como declínio cognitivo subjetivo (DCS) e comprometimento cognitivo leve (CCL). Esse reconhecimento precoce é feito pela mensuração da capacidade de realizar as atividades de vida diária (AVD). Objetivo: Estabelecer a adaptação transcultural, validade e confiabilidade da versão mexicana do ECog (M-ECog) em participantes com: SCD, MCI e demência provenientes de uma clínica de memória. Métodos: Foram 200 pacientes e seus respectivos informantes em uma clínica de memória de um hospital de terceiro nível na Cidade do México. Quatro grupos foram estudados: 50 cognitivamente saudáveis (CH), 50 SCD, 50 MCI e 50 com demência. A avaliação clínica incluiu: características sociodemográficas e de saúde, estado cognitivo pelo Mini-Mental State Evaluation (MMSE) e Montreal Cognitive Evaluation versão em espanhol (MoCA-E), bem como informações do cuidador (informantes) sobre a dificuldade nas AVD e o ECog versão em espanhol (M-ECog). Resultados: O M-ECog foi significativamente correlacionado com MMSE, MoCA-E e AVD. Mostrou capacidade de discriminar os diferentes declínios cognitivos (alfa de Cronbach 0,881). O coeficiente de correlação intraclasse foi de 0,877 (intervalo de confiança de 95% — IC95%, 0,850-0,902; p<0,001). A AUC do grupo do paciente de M-ECog para SCD foi de 0,70 (IC95% 0,58-0,82, p<0,005), para MCI foi de 0,94 (IC95% 0,89-0,99, p<0,001) e para demência foi de 0,86 (IC95% 0,79-0,92, p<0,001). Conclusão: A escala M-ECog mostra-se válida e confiável para medir habilidades cotidianas mediadas pela cognição. É autoaplicável sem exigir extensa formação prévia. É útil para rastrear MSC e MCI em adultos mexicanos mais velhos.