Effects of APOE-ε4 allele load on brain morphology in a cohort of middle-aged healthy individuals with enriched genetic risk for Alzheimer's disease

INTRODUCTION: Apolipoprotein E (APOE)-ε4 is the major genetic risk factor for Alzheimer's disease. However, the dose-dependent impact of this allele on brain morphology of healthy individuals remains unclear. METHODS: We analyzed gray matter volumes (GMvs) in a sample of 533 healthy middle-aged individuals with a substantial representation of ε4-carriers (207 heterozygotes and 65 homozygotes). RESULTS: We found APOE-ε4 additive GMv reductions in the right hippocampus, caudate, precentral gyrus, and cerebellar crus. In these regions, the APOE genotype interacted with age, with homozygotes displaying lower GMv after the fifth decade of life. APOE-ε4 was also associated to greater GMv in the right thalamus, left occipital gyrus, and right frontal cortex. DISCUSSION: Our data indicate that APOE-ε4 exerts additive effects on GMv in regions relevant for Alzheimer's disease pathophysiology already in healthy individuals. These findings elucidate the mechanisms underlying the increased Alzheimer's disease risk in ε4-carriers, suggesting a dose-dependent disease vulnerability on the brain structure level

Interactive effect of age and APOE-ε4 allele load on white matter myelin content in cognitively normal middle-aged subjects

The apolipoprotein E gene (APOE) ε4 allele has a strong and manifold impact on cognition and neuroimaging phenotypes in cognitively normal subjects, including alterations in the white matter (WM) microstructure. Such alterations have often been regarded as a reflection of potential thinning of the myelin sheath along axons, rather than pure axonal degeneration. Considering the main role of APOE in brain lipid transport, characterizing the impact of APOE on the myelin coating is therefore of crucial interest, especially in healthy APOE-ε4 homozygous individuals, who are exposed to a twelve-fold higher risk of developing Alzheimer's disease (AD), compared to the rest of the population. We examined T1w/T2w ratio maps in 515 cognitively healthy middle-aged participants from the ALFA study (ALzheimer and FAmilies) cohort, a single-site population-based study enriched for AD risk (68 APOE-ε4 homozygotes, 197 heterozygotes, and 250 non-carriers). Using tract-based spatial statistics, we assessed the impact of age and APOE genotype on this ratio taken as an indirect descriptor of myelin content. Healthy APOE-ε4 carriers display decreased T1w/T2w ratios in extensive regions in a dose-dependent manner. These differences were found to interact with age, suggesting faster changes in individuals with more ε4 alleles. These results obtained with T1w/T2w ratios, confirm the increased vulnerability of WM tracts in APOE-ε4 healthy carriers. Early alterations of myelin content could be the result of the impaired function of the ε4 isoform of the APOE protein in cholesterol transport. These findings help to clarify the possible interactions between the APOE-dependent non-pathological burden and age-related changes potentially at the source of the AD pathological cascade

Genotypic effects of APOE-epsilon 4 on resting-state connectivity in cognitively intact individuals support functional brain compensation

The investigation of resting-state functional connectivity (rsFC) in asymptomatic individuals at genetic risk for Alzheimer's disease (AD) enables discovering the earliest brain alterations in preclinical stages of the disease. The APOE-ε4 variant is the major genetic risk factor for AD, and previous studies have reported rsFC abnormalities in carriers of the ε4 allele. Yet, no study has assessed APOE-ε4 gene-dose effects on rsFC measures, and only a few studies included measures of cognitive performance to aid a clinical interpretation. We assessed the impact of APOE-ε4 on rsFC in a sample of 429 cognitively unimpaired individuals hosting a high number of ε4 homozygotes (n = 58), which enabled testing different models of genetic penetrance. We used independent component analysis and found a reduced rsFC as a function of the APOE-ε4 allelic load in the temporal default-mode and the medial temporal networks, while recessive effects were found in the extrastriate and limbic networks. Some of these results were replicated in a subsample with negative amyloid markers. Interaction with cognitive data suggests that such a network reorganization may support cognitive performance in the ε4-homozygotes. Our data indicate that APOE-ε4 shapes the functional architecture of the resting brain and favor the idea of a network-based functional compensation

Astrocyte biomarkers GFAP and YKL-40 mediate early Alzheimer's disease progression

INTRODUCTION: We studied how biomarkers of reactive astrogliosis mediate the pathogenic cascade in the earliest Alzheimer's disease (AD) stages.// METHODS: We performed path analysis on data from 384 cognitively unimpaired individuals from the ALzheimer and FAmilies (ALFA)+ study using structural equation modeling to quantify the relationships between biomarkers of reactive astrogliosis and the AD pathological cascade.// RESULTS: Cerebrospinal fluid (CSF) amyloid beta (Aβ)42/40 was associated with Aβ aggregation on positron emission tomography (PET) and with CSF p-tau181, which was in turn directly associated with CSF neurofilament light (NfL). Plasma glial fibrillary acidic protein (GFAP) mediated the relationship between CSF Aβ42/40 and Aβ-PET, and CSF YKL-40 partly explained the association between Aβ-PET, p-tau181, and NfL.// DISCUSSION: Our results suggest that reactive astrogliosis, as indicated by different fluid biomarkers, influences the pathogenic cascade during the preclinical stage of AD. While plasma GFAP mediates the early association between soluble and insoluble Aβ, CSF YKL-40 mediates the latter association between Aβ and downstream Aβ-induced tau pathology and tau-induced neuronal injury

Reference Data for Attentional, Executive, Linguistic, and Visual Processing Tests Obtained from Cognitively Healthy Individuals with Normal Alzheimer's Disease Cerebrospinal Fluid Biomarker Levels

BACKGROUND: Conventional neuropsychological norms likely include cognitively unimpaired (CU) individuals with preclinical Alzheimer's disease (AD) pathology (amyloid-β, tau, and neurodegeneration) since they are based on cohorts without AD biomarkers data. Due to this limitation, population-based norms would lack sensitivity for detecting subtle cognitive decline due to AD, the transitional stage between healthy cognition and mild cognitive impairment. We have recently published norms for memory tests in individuals with normal cerebrospinal fluid (CSF) AD biomarker levels. OBJECTIVE: The aim of the present study was to provide further AD biomarker-based cognitive references covering attentional, executive function, linguistic, and visual processing tests. METHODS: We analyzed 248 CU individuals aged between 50-70 years old with normal CSF Aβ, p-tau, and neurodegeneration (t-tau) biomarker levels. The tests included were the Trail Making Test (TMT), Semantic Fluency Test, Digit and Symbol Span, Coding, Matrix Reasoning, Judgement of Line Orientation and Visual Puzzles. Normative data were developed based on regression models adjusted for age, education, and sex when needed. We present equations to calculate z-scores, the corresponding normative percentile tables, and online calculators. RESULTS: Age, education, and sex were associated with performance in all tests, except education for the TMT-A, and sex for the TMT-B, Coding, and Semantic Fluency. Cut-offs derived from the current biomarker-based reference data were higher and more sensitive than standard norms. CONCLUSION: We developed reference data obtained from individuals with evidence of non-pathologic AD biomarker levels that may improve the objective characterization of subtle cognitive decline in preclinical AD

Genetically predicted telomere length and Alzheimer’s disease endophenotypes: a Mendelian randomization study

Telomere length (TL) is associated with biological aging, consequently influencing the risk of age-related diseases such as Alzheimer's disease (AD). We aimed to evaluate the potential causal role of TL in AD endophenotypes (i.e., cognitive performance, N = 2233; brain age and AD-related signatures, N = 1134; and cerebrospinal fluid biomarkers (CSF) of AD and neurodegeneration, N = 304) through a Mendelian randomization (MR) analysis. Our analysis was conducted in the context of the ALFA (ALzheimer and FAmilies) study, a population of cognitively healthy individuals at risk of AD. A total of 20 single nucleotide polymorphisms associated with TL were used to determine the effect of TL on AD endophenotypes. Analyses were adjusted by age, sex, and years of education. Stratified analyses by APOE-epsilon 4 status and polygenic risk score of AD were conducted. MR analysis revealed significant associations between genetically predicted longer TL and lower levels of CSF A beta and higher levels of CSF NfL only in APOE-epsilon 4 non-carriers. Moreover, inheriting longer TL was associated with greater cortical thickness in age and AD-related brain signatures and lower levels of CSF p-tau among individuals at a high genetic predisposition to AD. Further observational analyses are warranted to better understand these associations

Impact of Alzheimer's disease risk factors on white matter hyperintensities and cognition in cognitively unimpaired individuals

White matter hyperintensities (WMH) have been associated with increased risk and progression of Alzheimer’s disease (AD). However, the range to which this association can be extended to AD risk factors and WMH burden in cognitively unimpaired (CU) middle-aged individuals has not yet been fully explored. Thus, the main goal of this thesis is to study how AD risk factors impact on WMH burden in CU middle-aged participants. In addition, we aim to explore the mechanisms by which WMH impact on cognition. We gathered clinical data, lifestyle habits, cognitive assessments and MRI acquisitions in a sample of more than 500 CU middle-aged individuals. The results show that despite the low WMH burden and a low prevalence of AD risk factors in the participants, AD risk factors were associated with a higher WMH burden. Regionally, WMH burden showed an impact on cognition in CU middle-aged individuals. Finally, it was found that WMH volume mediates the relationship with cortical gray matter volume in regions involved in executive functioning. The main conclusion of this study is that even very low levels of AD risk factors have a significant impact on brain structure and cognition in CU individuals. These findings support, the control of modifiable AD risk factors in individuals at higher risk of developing WMH as a practical way to reduce or delay the onset of dementia.Les hiperintensitats de substància blanca (HSB) s'han associat amb un augment del risc i la progressió de la malaltia d'Alzheimer (MA). No obstant, encara no s’ha explorat completament fins a quin punt aquesta associació pot relacionar-se amb els factors de risc de la MA en persones cognitivament sanes. Per tant, l’objectiu principal d’aquesta tesi és estudiar com els factors de risc de la MA tenen impacte sobre la càrrega de les HSB en participants d’edat mitjana cognitivament sanes. També s’exploraràn els mecanismes pels quals les HSB tenen un impacte sobre la cognició. S’han recopilat dades clíniques, hàbits d’estil de vida, avaluacions cognitives i adquisicions de ressonància magnètica en una mostra de més de 500 persones cognitivament sanes de mitjana edat. Els resultats mostren que, tot i la baixa càrrega de HSB i una baixa prevalença de factors de risc de la MA en els participants, els factors de risc es van associar amb una major càrrega de HSB. A nivell regional, la càrrega de HBS va mostrar un impacte en la cognició en persones de mitjana edat. Finalment, es va trobar que el volum de les HBS media la relació amb el volum cortical de la substància gris en regions implicades en la funció executiva. La conclusió principal d’aquest estudi és que tot i el baix nivell de factors de risc de la MA, aquests tenen un impacte significatiu en l’estructura cerebral i la cognició en persones cognitivament sanes. Aquestes troballes donen suport al control dels factors de risc modificables de la MA en individus amb un major risc de desenvolupar HSB com una forma pràctica de reduir o retardar l’inici de la demència

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

Data de publicació electrònica: 08-04-2022Sex 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

Incidental findings on brain MRI of cognitively normal first-degree descendants of patients with Alzheimer's disease: a cross-sectional analysis from the ALFA (Alzheimer and Families) project

Objectives: To describe the prevalence of brain MRI incidental findings (IF) in a cohort of cognitively normal first-degree descendants of patients with Alzheimer's disease (AD). Design: Cross-sectional observational study. Setting: All scans were obtained with a 3.0 T scanner. Scans were evaluated by a single neuroradiologist and IF recorded and categorised. The presence of white matter hyperintensities (WMH) was determined with the Fazekas scale and reported as relevant if ≥2. Participants: 575 participants (45–75 years) underwent high-resolution structural brain MRI. Participants were cognitively normal and scored over the respective cut-off values in all the following neuropsychological tests: Mini-Mental State Examination (≥26), Memory Impairment Screen (≥6), Time Orientation Subtest of the Barcelona Test II (≥68), verbal semantic fluency (naming animals ≥12). Clinical Dementia Rating (CDR) had to be 0. Results: 155 participants (27.0%) presented with at least one IF. Relevant WMH were present in 7.8% of the participants, and vascular abnormalities, cyst and brain volume loss in 10.7%, 3.1% and 6.9% of the study volunteers, respectively. Neoplastic brain findings were found in 2.4% of participants and within these, meningiomas were the most common (1.7%) and more frequently found in women. A positive correlation between increasing age and the presence of IF was found. Additionally, brain atrophy greater than that expected by age was significantly more prevalent in participants without a parental history of AD. Conclusions: Brain MRIs of healthy middle-aged participants show a relatively high prevalence of IF even when study participants have been screened for subtle cognitive alterations. Most of our participants are first-degree descendants of patients with AD, and therefore these results are of special relevance for novel imaging studies in the context of AD prevention in cognitively healthy middle-aged participants.The research leading to these results has received funding from ‘la Caixa’ Foundation. Additional funding was obtained from Fondo de Investigación Sanitaria (FIS), Instituto de Salud Carlos III (ISC-III) under grant PI12/00326 and Barcelona city council under agreement #0724/13 and 0940/16. JDG holds a ‘Ramón y Cajal’ fellowship (RYC-2013-13054)

Care partner needs of people with neurodegenerative disorders:What are the needs, and how well do the current assessment tools capture these needs? A systematic meta-review

Objectives: The burden on care partners, particularly once dementia emerges, is among the greatest of all caregiving groups. This meta-review aimed to (1) synthesis evidence on the self-reported needs of care partners supporting people living with neurodegenerative disorders; (2) compare the needs according to care partner and care recipient characteristics; and (3) determine the face validity of existing care partner needs assessment tools. Methods: We conducted a systematic review of reviews involving a thematic synthesis of care partner needs and differences in needs according to demographic and other characteristics. We then conducted a gap analysis by identifying the themes of needs from existing needs assessment tools specific to dementia and cross-matching them with the needs derived from the thematic synthesis. Results: Drawing on 17 published reviews, the identified range of needs fell into four key themes: (1) knowledge and information, (2) physical, social and emotional support, (3) care partner self-care, and (4) care recipient needs. Needs may differ according to disease trajectory, relationship to the care recipient, and the demographic characteristics of the care partner and recipient. The ‘captured needs’ range between 8% and 66% across all the included needs assessment tools. Conclusions: Current tools do not fully or adequately capture the self-identified needs of care partners of people living with neurodegenerative disorders. Given the high burden on care partners, which has been further exacerbated by the COVID-19 (SARS CoV-2) pandemic, the needs assessment tools should align with the self-reported needs of care partners throughout the caregiving trajectory to better understand unmet needs and target supportive interventions