Genetic Comparison of Symptomatic and Asymptomatic Persons With Alzheimer Disease Neuropathology

Abstract

Objective To determine whether symptomatic and asymptomatic persons with Alzheimer's disease (AD) neuropathology have different allele counts for single-nucleotide polymorphisms (SNPs) that have been associated with clinical late-onset AD (LOAD). Methods Data came from the National Alzheimer's Coordinating Center Uniform Data Set and Neuropathology Data Set, and the Alzheimer's Disease Genetics Consortium (ADGC). Participants had low to high AD neuropathologic change. The 22 known/suspected genes associated with LOAD were considered. “Symptomatic” was defined as Clinical Dementia Rating global score >0. Results 68 asymptomatic and 521 symptomatic participants met inclusion criteria. SNPs associated with ABCA7 (odds ratio [OR] = 1.66; 95% confidence interval [CI] = 1.03-2.85) and MAPT (OR = 2.18; CI = 1.26-3.77) were associated with symptomatic status. In stratified analyses, loci containing CD2AP (OR = 0.35; 95% CI = 0.16-0.74), ZCWPW1 (OR = 2.98; 95% CI = 1.34-6.86), and MAPT (OR = 3.73, 95% CI = 1.30-11.76) were associated with symptomatic status in APOE e4 carriers. Conclusions These findings potentially explain some of the variation in whether a person with AD neuropathology expresses symptoms. Understanding why some people remain cognitively normal despite having AD neuropathology could identify pathways to disease heterogeneity and guide treatment trials.

Cerebrovascular Reactivity Impairment in Preclinical Alzheimer's Disease

“…This percentage change was divided by 30 seconds (or the actual time subjects held their breath) . Second, BHAI and CVR were calculated by linear regression of the most linear portion of the MFV change during the breath‐hold maneuver …”

“…A customized MATLAB program was written for all processing of TCD envelope waveforms obtained during the experiment. Data were analyzed in the same manner as previously reported . Briefly, the MFV was calculated by averaging the CBFV samples within each cardiac cycle.…”

“…Then, PI for each cardiac cycle was calculated by subtracting diastolic velocity ( Vd ) from the systolic velocity ( Vs ), and then dividing by the MFV . Finally, CVR was calculated using both BHI and BHAI indices …”

“…The BHAI is obtained by linear regression of the most linear portion of CBFV increase during the breath‐hold maneuver. This index has less variability when compared with the conventional BHI measure and is not computationally difficult …”

Genetic Variants and Functional Pathways Associated with Resilience to Alzheimer’s Disease

“…While there has been some prior discovery work using genomic data Yu et al, 2018), previous work characterizing the genetic contributors to asymptomatic AD has primarily focused on candidate genes (Monsell et al, 2013;Monsell et al, 2017;Franzmeier et al, 2019) due to the lack of sufficient sample size to complete full genome-wide analyses. A major barrier in moving analyses forward has been the categorical definitions of asymptomatic AD that drastically reduce the number of participants available for analysis.…”