Amyloid-β Positivity Predicts Cognitive Decline but Cognition Predicts Progression to Amyloid-β Positivity

Abstract

Background: Stage 1 of the National Institute on Aging-Alzheimer's Association's proposed Alzheimer's disease continuum is defined as amyloid-β (Aβ) positive but cognitively normal. Identifying at-risk individuals before Aβ reaches pathological levels could have great benefits for early intervention. Although Aβ levels become abnormal long before severe cognitive impairments appear, increasing evidence suggests that subtle cognitive changes may begin early, potentially before Aβ surpasses the threshold for abnormality. We examined whether baseline cognitive performance would predict progression from normal to abnormal levels of Aβ.

Methods: We examined the association of baseline cognitive composites (Preclinical Alzheimer Cognitive Composite, Alzheimer's Disease Neuroimaging Initiative (ADNI) memory factor composite) with progression to Aβ positivity in 292 nondemented, Aβ-negative ADNI participants. Additional analyses included continuous cerebrospinal fluid biomarker levels to examine the effects of subthreshold pathology.

Results: Forty participants progressed to Aβ positivity during follow-up. Poorer baseline performance on both cognitive measures was significantly associated with increased odds of progression. More abnormal levels of baseline cerebrospinal fluid phosphorylated tau and subthreshold Aβ were associated with increased odds of progression to Aβ positivity. Nevertheless, baseline ADNI memory factor composite performance predicted progression even after controlling for baseline biomarker levels and APOE genotype (Preclinical Alzheimer Cognitive Composite was trend level). Survival analyses were largely consistent: controlling for baseline biomarker levels, baseline Preclinical Alzheimer Cognitive Composite still significantly predicted progression time to Aβ positivity (ADNI memory factor composite was trend level).

Conclusions: The possibility of intervening before Aβ reaches pathological levels is of obvious benefit. Low-cost, noninvasive cognitive measures can be informative for determining who is likely to progress to Aβ positivity, even after accounting for baseline subthreshold biomarker levels.

Keywords: AD; Alzheimer’s disease; Amyloid accumulation; Biomarker trajectories; Cognition; MCI; Mild cognitive impairment; β-amyloid.

Figure 1.. Baseline cognitive performance predicting future conversion to Aβ-positivity.

Results of two logistic regression models using A) the ADNI Memory composite (ADNI_MEM) and B) the Preclinical Alzheimer Cognitive Composite (PACC). Measures are all taken from baseline and predict future progression to Aβ-positivity. Cognitive scores were converted to z-scores and reverse coded such that higher scores indicate poorer performance. Odds ratios are presented with asterisks indicating significant estimates (*p<0.05, **p<0.01, ***p<0.001). Lines represent 95% confidence intervals.

Figure 2.. Baseline cognitive performance and p-tau+ status predicting future conversion to Aβ-positivity.

Results of two logistic regression models using A) the ADNI Memory composite (ADNI_MEM) and B) the Preclinical Alzheimer Cognitive Composite (PACC). Measures are all taken from baseline and predict future progression to Aβ-positivity. Cognitive scores were converted to z-scores and reverse coded such that higher scores indicate poorer performance. P-tau-positivity is entered as a dichotomous variable. Odds ratios are presented with asterisks indicating significant estimates (*p<0.05, **p<0.01, ***p<0.001). Lines represent 95% confidence intervals.

Figure 3.. Baseline cognitive performance and continuous measures of CSF Aβ and p-tau predicting future conversion to Aβ-positivity.

Results of two logistic regression models using A) the ADNI Memory composite (ADNI_MEM) and B) the Preclinical Alzheimer Cognitive Composite (PACC). Measures are all taken from baseline and predict future progression to Aβ-positivity. Cognitive scores were converted to z-scores and reverse coded such that higher scores indicate poorer performance. CSF Aβ and P-tau were entered as continuous variables. Both measures were z-scored and CSF Aβ was reverse coded such that higher values on both indicates abnormality. Odds ratios are presented with asterisks indicating significant estimates (*p<0.05, **p<0.01, ***p<0.001). Lines represent 95% confidence intervals.

Figure 4.. Survival estimates of progression to Aβ-positivity based on baseline cognitive performance.

Cox proportional hazard models were run using continuous measures of baseline performance. For display purposes, scores were grouped based on a median split and adjusted survival curves are shown for better (upper half) and worse (lower half) performance on baseline cognitive measures. Results from 4 models are presented: A) ADNI Memory composite (ADNI_MEM) + covariates; B) the Preclinical Alzheimer Cognitive Composite (PACC) + covariates; C) ADNI_MEM + covariates + baseline CSF Aβ and p-tau; D) PACC + covariates + baseline CSF Aβ and p-tau. CSF Aβ and P-tau were entered as continuous variables. Covariates include: APOE-ε4+ status, age at baseline, and education. P-values of hazard ratios for cognitive measures are shown for each model.