Dataset Information

Assessment of the Genetic Architecture of Alzheimer's Disease Risk in Rate of Memory Decline.

ABSTRACT: Many genetic studies for Alzheimer's disease (AD) have been focused on the identification of common genetic variants associated with AD risk and not on other aspects of the disease, such as age at onset or rate of dementia progression. There are multiple approaches to untangling the genetic architecture of these phenotypes. We hypothesized that the genetic architecture of rate of progression is different than the risk for developing AD dementia. To test this hypothesis, we used longitudinal clinical data from ADNI and the Knight-ADRC at Washington University, and we calculated PRS (polygenic risk score) based on the IGAP study to compare the genetic architecture of AD risk and dementia progression. Dementia progression was measured by the change of Clinical Dementia Rating Sum of Boxes (CDR)-SB per year. Out of the 21 loci for AD risk, no association with the rate of dementia progression was found. The PRS rate was significantly associated with the rate of dementia progression (?=?0.146, p?=?0.03). In the case of rare variants, TREM2 (?=?0.309, p?=?0.02) was also associated with the rate of dementia progression. TREM2 variant carriers showed a 23% faster rate of dementia compared with non-variant carriers. In conclusion, our results indicate that the recently identified common and rare variants for AD susceptibility have a limited impact on the rate of dementia progression in AD patients.

SUBMITTER: Del-Aguila JL

PROVIDER: S-EPMC5989565 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Assessment of the Genetic Architecture of Alzheimer's Disease Risk in Rate of Memory Decline.

Del-Aguila Jorge L JL Fernández Maria Victoria MV Schindler Suzanne S Ibanez Laura L Deming Yuetiva Y Ma Shengmei S Saef Ben B Black Kathleen K Budde John J Norton Joanne J Chasse Rachel R Harari Oscar O Goate Alison A Xiong Chengjie C Morris John C JC Cruchaga Carlos C

Journal of Alzheimer's disease : JAD 20180101 2

Many genetic studies for Alzheimer's disease (AD) have been focused on the identification of common genetic variants associated with AD risk and not on other aspects of the disease, such as age at onset or rate of dementia progression. There are multiple approaches to untangling the genetic architecture of these phenotypes. We hypothesized that the genetic architecture of rate of progression is different than the risk for developing AD dementia. To test this hypothesis, we used longitudinal clin ...[more]

PMID: 29480181

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Project description:An unfortunate result of the rapid rise in geriatric populations worldwide is the increasing prevalence of age-related cognitive disorders such as Alzheimer's disease (AD). AD is a devastating neurodegenerative illness that is characterized by a profound impairment of cognitive function, marked physical disability, and an enormous economic burden on the afflicted individual, caregivers, and society in general. The rise in elderly populations is also resulting in an increase in individuals with related (potentially treatable) conditions such as "Mild Cognitive Impairment" (MCI) which is characterized by a less severe (but abnormal) level of cognitive impairment and a high-risk for developing dementia. Even in the absence of a diagnosable disorder of cognition (e.g., AD and MCI), the perception of increased forgetfulness and declining mental function is a clear source of apprehension in the elderly. This is a valid concern given that even a modest impairment of cognitive function is likely to be associated with significant disability in a rapidly evolving, technology-based society. Unfortunately, the currently available therapies designed to improve cognition (i.e., for AD and other forms of dementia) are limited by modest efficacy and adverse side effects, and their effects on cognitive function are not sustained over time. Accordingly, it is incumbent on the scientific community to develop safer and more effective therapies that improve and/or sustain cognitive function in the elderly allowing them to remain mentally active and productive for as long as possible. As diagnostic criteria for memory disorders evolve, the demand for pro-cognitive therapeutic agents is likely to surpass AD and dementia to include MCI and potentially even less severe forms of memory decline. The purpose of this review is to provide an overview of the contemporary therapeutic targets and preclinical pharmacologic approaches (with representative drug examples) designed to enhance memory function.

Project description:Studies of Alzheimer's disease risk-weighted polygenic risk scores (PRSs) for cognitive performance have reported inconsistent associations. This inconsistency is particularly evident when PRSs are assessed independent of APOE genotype. As such, the development and assessment of phenotype-specific weightings to derive PRSs for cognitive decline in preclinical AD is warranted. To this end a episodic memory-weighted PRS (emPRS) was derived and assessed against decline in cognitive performance in 226 healthy cognitively normal older adults with high brain A?-amyloid burden participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. The effect size for decline in a verbal episodic memory was determined individually for 27 genetic variants in a reference sample (n = 151). These were then summed to generate a emPRS either including APOE (emPRSc?APOE) or excluding APOE (emPRSs?APOE ). Resultant emPRS were then evaluated, in a test sample (n = 75), against decline in global cognition, verbal episodic memory and a pre-Alzheimer's cognitive composite (AIBL-PACC) over 7.5 years. The mean (SD) age of the 226 participants was 72.2 (6.6) years and 116 (51.3%) were female. Reference and test samples did not differ significantly demographically. Whilst no association of emPRSs were observed with baseline cognition, the emPRSc? APOE was associated with longitudinal global cognition (-0.237, P = 0.0002), verbal episodic memory (-0.259, P = 0.00003) and the AIBL-PACC (-0.381, P = 0.02). The emPRSs? APOE was also associated with global cognition (-0.169, P = 0.021) and verbal episodic memory (-0.208, P = 0.004). Stratification by APOE ?4 revealed that the association between the emPRS and verbal episodic memory was limited to carriage of no ?4 or one ?4 allele. This was also observed for global cognition. The emPRS and rates of decline in AIBL-PACC were associated in those carrying one ?4 allele. Overall, the described novel emPRS has utility for the prediction of decline in cognition in preclinical AD. This study provides evidence to support the further use and evaluation of phenotype weightings in PRS development.

Project description:BackgroundSubjective memory impairment (SMI), or the perception of memory problems in the absence of objective memory deficits, is associated with negative outcomes of individual and societal significance, including a substantially increased risk of Alzheimer's disease (AD). However, little is known regarding the mediators that link SMI and memory decline in some individuals, or which older adults with SMI are at greatest risk for memory decline. In this study, we will examine modifiable AD risk factors (specifically affective symptoms and activity participation) as mediators underlying linkages among SMI and memory decline over time; furthermore, we will characterize SMI subgroups at highest risk for memory decline via this pathway.MethodsThis study utilizes a series of construct-level replication analyses across four large longitudinal datasets to maximize the unique aspects of each dataset as well as test the reproducibility of findings across multiple populations to establish generalizability. The current study's sample (n?>?40,000) is drawn from the Einstein Aging Study, Health and Retirement Study, Minority Aging Research Study, and National Health and Aging Trends Study. Participants must meet the following basic criteria for inclusion: age 55 or older and no evidence of cognitive impairment at baseline. We will use multilevel modeling to determine whether higher levels of SMI are related to increased affective symptoms and decreased activity participation, as well as whether this relationship is moderated by neuroticism, family history of AD, and race/ethnicity. Finally, we will test our full conceptual model that examines whether changes in affective symptoms and activity participation mediate the relationship between SMI and objective memory decline. Specifically, we will test moderated mediation as we hypothesize these relationships to hold among subgroups of older adults.DiscussionDiscovery of modifiable AD risk factors that mediate the association between SMI and memory decline (the earliest and most central deficit in AD) will provide explicit, and potentially novel, targets for intervention. Additionally, identifying individuals at highest risk for negative reactions to SMI will serve to enrich samples for future research as well as to help guide the development of SMI assessment tools to identify older adults at greatest risk for debilitating outcomes.

Dataset Information

Assessment of the Genetic Architecture of Alzheimer's Disease Risk in Rate of Memory Decline.

Publications

Assessment of the Genetic Architecture of Alzheimer's Disease Risk in Rate of Memory Decline.

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