Abstract
To the best of our knowledge, there are no research studies about socioeconomic factors, family stigma, and their psychological impact on early-onset dementia caregivers. We assessed the ...impact of family stigma and socioeconomic factors on psychological outcomes, quality of life (QoL), and caregiver burden among 150 caregivers of patients with early-onset Alzheimer’s disease due to E280A mutation in presenilin 1 (EOAD), frontotemporal dementia (FTD), and late-onset Alzheimer’s disease (LOAD). Caregivers of patients with EOAD presented a higher frequency of socioeconomic risk factors. Caregivers of FTD presented higher levels of family stigma and a higher prevalence of negative outcomes. We found family stigma to be a more suitable predictor of all outcomes. After adjusting for the type of dementia, dementia stage and behavioral changes, and caregiver age and education, family stigma was the most important factor associated with a higher risk of caregiver burden and a reduction in QoL in terms of energy fatigue and emotional wellbeing among early-onset dementia caregivers.
Summary Background We have previously characterised functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's disease. To gain further knowledge on the preclinical ...phase of Alzheimer's disease, we sought to characterise structural and functional MRI, CSF, and plasma biomarkers in a cohort of young adults carrying a high-penetrance autosomal dominant mutation that causes early-onset Alzheimer's disease. Methods Between January and August, 2010, 18–26-year-old presenilin 1 (PSEN1) E280A mutation carriers and non-carriers from the Colombian Alzheimer's Prevention Initiative Registry in Medellín Antioquia, Colombia, had structural MRI, functional MRI during associative memory encoding and novel viewing and control tasks, and cognitive assessments. Consenting participants also had lumbar punctures and venepunctures. Outcome measures were task-dependent hippocampal or parahippocampal activations and precuneus or posterior cingulate deactivations, regional grey matter reductions, CSF Aβ1–42 , total tau and phospho-tau181 concentrations, and plasma Aβ1–42 concentrations and Aβ1–42 :Aβ1–40 ratios. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to Alzheimer's disease. Cognitive and fluid biomarkers were compared using Mann-Whitney tests. Findings 44 participants were included: 20 PSEN1 E280A mutation carriers and 24 non-carriers. The carrier and non-carrier groups did not differ significantly in their dementia ratings, neuropsychological test scores, or proportion of apolipoprotein E (APOE) ε4 carriers. Compared with non-carriers, carriers had greater right hippocampal and parahippocampal activation (p=0·001 and p<0·014, respectively, after correction for multiple comparisons), less precuneus and posterior cingulate deactivation (all p<0·010 after correction), and less grey matter in several parietal regions (all p<0·002 uncorrected and corrected p=0·009 in the right parietal search region). In the 20 participants (ten PSEN1 E280A mutation carriers and ten non-carriers) who had lumbar punctures and venepunctures, mutation carriers had higher CSF Aβ1–42 concentrations (p=0·008) and plasma Aβ1–42 concentrations (p=0·01) than non-carriers. Interpretation Young adults at genetic risk for autosomal dominant Alzheimer's disease have functional and structural MRI findings and CSF and plasma biomarker findings consistent with Aβ1–42 overproduction. Although the extent to which the underlying brain changes are either neurodegenerative or developmental remain to be determined, this study shows the earliest known biomarker changes in cognitively normal people at genetic risk for autosomal dominant Alzheimer's disease. Funding Banner Alzheimer's Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Boston University Department of Psychology, Colciencias, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the State of Arizona.
INTRODUCTION
Rate of cognitive decline (RCD) in Alzheimer's disease (AD) determines the degree of impairment for patients and of burden for caretakers. We studied the association of RCD with genetic ...variants in AD.
METHODS
RCD was evaluated in 62 familial AD (FAD) and 53 sporadic AD (SAD) cases, and analyzed by whole‐exome sequencing for association with common exonic functional variants. Findings were validated in post mortem brain tissue.
RESULTS
One hundred seventy‐two gene variants in FAD, and 227 gene variants in SAD associated with RCD. In FAD, performance decline of the immediate recall of the Rey‐Osterrieth figure test associated with 122 genetic variants. Olfactory receptor OR51B6 showed the highest number of associated variants. Its expression was detected in temporal cortex neurons.
DISCUSSION
Impaired olfactory function has been associated with cognitive impairment in AD. Genetic variants in these or other genes could help to identify risk of faster memory decline in FAD and SAD patients.
Summary Background Mild cognitive impairment (MCI) and pre-MCI have been proposed as stages preceding Alzheimer's disease (AD) dementia. We assessed descendants of individuals with a mutation in ...presenilin 1 ( PSEN1 ) that causes familial AD, with the aim of identifying distinct stages of clinical progression to AD dementia. Methods We retrospectively studied a cohort of descendants of carriers of the PSEN1 E280A mutation. Pre-dementia cognitive impairment was defined by a score 2 SD away from normal values in objective cognitive tests, and was subdivided as follows: asymptomatic pre-MCI was defined by an absence of memory complaints and no effect on activities of daily living; symptomatic pre-MCI was defined by a score on the subjective memory complaints checklist higher than the mean and no effect on activities of daily living; and MCI was defined by a score on the subjective memory complaints checklist higher than the mean, with no effect on basic activities of daily living and little or no effect on complex daily activities. Dementia was defined according to the diagnostic and statistical manual of mental disorders, fourth edition. Reference mean scores were those of participants who did not carry the PSEN1 E280A mutation. We used the Turnbull survival analysis method to identify ages at onset of each stage of the disease. We measured the time from birth until onset of the three pre-dementia stages, dementia, and death, and assessed decline in cognitive domains for each stage. Findings Follow-up was from Jan 1, 1995, to Jan 27, 2010. 1784 patients were initially identified, 449 of whom were PSEN1 E280A carriers who had complete clinical follow-up. Median age at onset was 35 years (95% CI 30–36) for asymptomatic pre-MCI, 38 years (37–40) for symptomatic pre-MCI, 44 years (43–45) for MCI, and 49 years (49–50) for dementia. The median age at death was 59 years (95% CI 58–61). The median time of progression from asymptomatic to symptomatic pre-MCI was 4 years (95% CI 2–8), from symptomatic pre-MCI to MCI was 6 years (4–7), from MCI to dementia was 5 years (4–6), and from dementia to death was 10 years (9–12). The cognitive profile was predominantly amnestic and was associated with multiple domains. Affected domains showed variability in initial stages, with some transient recovery in symptomatic pre-MCI followed by continuous decline. Interpretation Clinical deterioration can be detected as measurable cognitive impairment around two decades before dementia onset in PSEN1 E280A carriers. Onset and progression of pre-dementia stages should be considered in the investigation and use of therapeutic interventions for familial AD. Funding Departamento Administrativo de Ciencia, Tecnología e Innovación, COLCIENCIAS, Republic of Colombia.
Background
Caregiving itself does not lead to adverse psychological outcomes, burden, stigma, and/or quality of life reduction but socioeconomic factors have been hypothesized as risk factors among ...dementia caregivers. We aimed to analyze the associations between socioeconomic factors and type of dementia as potential predictors of family stigma, Quality of life (QoL.), depressive symptoms, anxiety, and caregiver burden
Method
We assessed 151 family caregivers distributed as early‐onset Alzheimer disease group (EOAD), frontotemporal dementia (FTD), and late‐onset dementia group (LOAD) for comparative means. Participants underwent questionnaires about family stigma, caregiver burden, depression, anxiety, QoL., and a questionnaire to explore socioeconomic factors. We performed a multivariable regression model with socioeconomic factors and the group as predictors. We included age, education, patient’s clinical‐stage, and behavioral changes as covariates.
Result
Being a caregiver of an FTD patient reduced physical functioning (β=‐13,5 p=0,018), working part‐time increased physical functioning (β=22,1 p=0,032) while working from home increased general health (β=22,4 p=0,028). The perception of living in a safe neighborhood reduced role limitation due to emotional problems (β=46,2 p=0,013). The perception of financial problems related to patients' care or disease cost increased the role limitation due to emotional problems (β=‐29,8 p=0,007). The caregiver burden increased together with the perception of financial problems related to patient's care or disease cost (β=13,9 p<0,001) and was mediated by patient’s behavioral changes (β=0,47 p<0,001). Family stigma is increased by the perception of financial problems related to patient's care or disease cost (β=0,31 p=0,013) and was mediated by the caregiver’s education (β=0,04 p=0,026) and patient’s behavioral changes (β=0,10 p=0,001). Depression increased by the perception of financial problems related to patient's care or disease cost (β=2,01 p=0,033) and the mediation of patient’s behavioral changes (β=0,06 p=0,015).
Conclusion
Socioeconomic factors can predict disturbances in QoL. among dementia caregivers. Education, being an FTD caregiver, and patient’s behavioral changes mediated among socioeconomic factors and negative psychological outcomes. When a caregiver may have low education and is caring for a patient with FTD and/or behavioral problems the risk of negative outcomes and family stigma increases significantly.
Summary Background Fibrillar amyloid-β (Aβ) is thought to begin accumulating in the brain many years before the onset of clinical impairment in patients with Alzheimer's disease. By assessing the ...accumulation of Aβ in people at risk of genetic forms of Alzheimer's disease, we can identify how early preclinical changes start in individuals certain to develop dementia later in life. We sought to characterise the age-related accumulation of Aβ deposition in presenilin 1 (PSEN1) E280A mutation carriers across the spectrum of preclinical disease. Methods Between Aug 1 and Dec 6, 2011, members of the familial Alzheimer's disease Colombian kindred aged 18–60 years were recruited from the Alzheimer's Prevention Initiative's registry at the University of Antioquia, Medellín, Colombia. Cross-sectional assessment using florbetapir PET was done in symptomatic mutation carriers with mild cognitive impairment or mild dementia, asymptomatic carriers, and asymptomatic non-carriers. These assessments were done at the Banner Alzheimer's Institute in Phoenix, AZ, USA. A cortical grey matter mask consisting of six predefined regions.was used to measure mean cortical florbetapir PET binding. Cortical-to-pontine standard-uptake value ratios were used to characterise the cross-sectional accumulation of fibrillar Aβ deposition in carriers and non-carriers with regression analysis and to estimate the trajectories of fibrillar Aβ deposition. Findings We enrolled a cohort of 11 symptomatic individuals, 19 presymptomatic mutation carriers, and 20 asymptomatic non-carriers, ranging in age from 20 to 56 years. There was greater florbetapir binding in asymptomatic PSEN1 E280A mutation carriers than in age matched non-carriers. Fibrillar Aβ began to accumulate in PSEN 1E280A mutation carriers at a mean age of 28·2 years (95% CI 27·3–33·4), about 16 years and 21 years before the predicted median ages at mild cognitive impairment and dementia onset, respectively.18 F florbetapir binding rose steeply over the next 9·4 years and plateaued at a mean age of 37·6 years (95% CI 35·3–40·2), about 6 and 11 years before the expected respective median ages at mild cognitive impairment and dementia onset. Prominent florbetapir binding was seen in the anterior and posterior cingulate, precuneus, and parietotemporal and frontal grey matter, as well as in the basal ganglia. Binding in the basal ganglia was not seen earlier or more prominently than in other regions. Interpretation These findings contribute to the understanding of preclinical familial Alzheimer's disease and help set the stage for assessment of amyloid-modifying treatments in the prevention of familial Alzheimer's disease. Funding Avid Radiopharmaceuticals, Banner Alzheimer's Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Colciencias, National Institute on Aging, and the State of Arizona.
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.
Background
Intellectual disability (ID) is the limitation of intellectual functioning and adaptive behavior before 18 years of age. In a consanguineous family of 149 members, this disease is ...expressed in 9 individuals. Here, we report one branch of a family tree with three siblings, presenting severe ID, delayed speech development, cataracts, strabismus, gait disturbance, cerebellar syndrome, seizures in one of them, and eyelid ptosis in two. Brain magnetic resonance imaging (MRI) with hippocampal malrotation, brain atrophy and white matter hyperintensities in all cases. Thinning of the corpus callosum in two of them.
Method
We conducted whole exome sequencing analysis in nine subjects from one multigenerational family of Colombian origin. The study was carried out at the University of Antioquia,Colombia with the approval of the ethics committee. A medical, neurological, neuropsychological examination and brain MRI were performed in all cases.
Result
We identified a single nucleotide deletion in the SPAG9 gene, which codes for the JIP4 protein. The frameshift generates a premature stop codon (p.Tyr914Ter). The deletion is classified as pathogenic, according to the ACMG / AMP guidelines. The variant co‐segregated in the respective family as an autosomal recessive trait.
Conclusion
JIP 4 has two functions: As scaffold protein that potentiates the p38 MAPK signaling cascade under stress conditions and as dynein‐dynactin motor adapter for lysosomal retrograde flow, regulating the constitutive transport of lysosomes. Both functions could be associated in the disease mechanism. The absence of JIP 4 may be responsible for the disease in the family, altering neuronal homeostasis.
Introduction
The Alzheimer's Prevention Initiative Autosomal‐Dominant Alzheimer's Disease (API ADAD) Trial evaluated the anti‐oligomeric amyloid beta (Aβ) antibody therapy crenezumab in cognitively ...unimpaired members of the Colombian presenilin 1 (PSEN1) E280A kindred. We report availability, methods employed to protect confidentiality and anonymity of participants, and process for requesting and accessing baseline data.
Methods
We developed mechanisms to share baseline data from the API ADAD Trial in consultation with experts and other groups sharing data from Alzheimer's disease (AD) prevention trials, balancing the need to protect anonymity and trial integrity with making data broadly available to accelerate progress in the field. We pressure‐tested deliberate and inadvertent potential threats under specific assumptions, employed a system to suppress or mask both direct and indirect identifying variables, limited and firewalled data managers, and put forth specific principles requisite to receive data.
Results
Baseline demographic, PSEN1 E280A and apolipoprotein E genotypes, florbetapir and fluorodeoxyglucose positron emission tomography, magnetic resonance imaging, clinical, and cognitive data can now be requested by interested researchers.
Discussion
Baseline data are publicly available; treatment data and biological samples, including baseline and treatment‐related blood‐based biomarker data will become available in accordance with our original trial agreement and subsequently developed Collaboration for Alzheimer's Prevention principles. Sharing of these data will allow exploration of important questions including the differential effects of initiating an investigational AD prevention therapy both before as well as after measurable Aβ plaque deposition.
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.
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