Genetic characterization of the ALFA study: Uncovering genetic profiles in the Alzheimer's continuum.

INTRODUCTION: In 2013, the ALzheimer's and FAmilies (ALFA) project was established to investigate pathophysiological changes in preclinical Alzheimer's disease (AD), and to foster research on early detection and preventive interventions. METHODS: We conducted a comprehensive genetic characterization of ALFA participants with respect to neurodegenerative/cerebrovascular diseases, AD biomarkers, brain endophenotypes, risk factors and aging biomarkers. We placed particular emphasis on amyloid/tau status and assessed gender differences. Multiple polygenic risk scores were computed to capture different aspects of genetic predisposition. We additionally compared AD risk in ALFA to that across the full disease spectrum from the Alzheimer's Disease Neuroimaging Initiative (ADNI). RESULTS: Results show that the ALFA project has been successful at establishing a cohort of cognitively unimpaired individuals at high genetic predisposition of AD. DISCUSSION: It is, therefore, well-suited to study early pathophysiological changes in the preclinical AD continuum. Highlights Prevalence of ε4 carriers in ALzheimer and FAmilies (ALFA) is higher than in the general European population The ALFA study is highly enriched in Alzheimer's disease (AD) genetic risk factors beyond APOE AD genetic profiles in ALFA are similar to clinical groups along the continuum ALFA has succeeded in establishing a cohort of cognitively unimpaired individuals at high genetic AD risk ALFA is well suited to study pathogenic events/early pathophysiological changes in AD.

Compositional structural brain signatures capture Alzheimer's genetic risk on brain structure along the disease continuum.

INTRODUCTION: Traditional brain imaging genetics studies have primarily focused on how genetic factors influence the volume of specific brain regions, often neglecting the overall complexity of brain architecture and its genetic underpinnings. METHODS: This study analyzed data from participants across the Alzheimer's disease (AD) continuum from the ALFA and ADNI studies. We exploited compositional data analysis to examine relative brain volumetric variations that (i) differentiate cognitively unimpaired (CU) individuals, defined as amyloid-negative (A-) based on CSF profiling, from those at different AD stages, and (ii) associated with increased genetic susceptibility to AD, assessed using polygenic risk scores. RESULTS: Distinct brain signatures differentiated CU A-individuals from amyloid-positive MCI and AD. Moreover, disease stage-specific signatures were associated with higher genetic risk of AD. DISCUSSION: The findings underscore the complex interplay between genetics and disease stages in shaping brain structure, which could inform targeted preventive strategies and interventions in preclinical AD.

Association between telomere length and cognitive function among cognitively unimpaired individuals at risk of Alzheimer's disease.

INTRODUCTION: Leukocyte telomere length (LTL) is an objective biomarker of biological aging, and it is proposed to play a crucial role in Alzheimer's disease (AD) risk. We aimed at evaluating the cross-sectional association between LTL and cognitive performance in middle-aged cognitively unimpaired individuals at increased risk of AD. METHODS: A total of 1520 participants from the ALFA cohort were included. Relative telomere length was measured in leukocytes through qPCR. LTL was residualized against age and sex, and associations with cognitive performance were assessed in short and long groups based on residualized LTL (rLTL). Interactions with sex and genetic risk of AD were tested. RESULTS: Non-linear associations were found between LTL and episodic memory (EM). Better EM was associated with longer rLTL among women in the short rLTL group. DISCUSSION: Results suggest a potential role of telomeres in the cognitive aging process with sex-specific patterns.