Associative memory and in vivo brain pathology in asymptomatic presenilin-1 E280A carriers

Abstract

Objective: To determine whether performance on the Free and Cued Selective Reminding Test (FCSRT) is associated with PET in vivo markers of brain pathology and whether it can distinguish those who will develop dementia later in life due to autosomal-dominant Alzheimer disease (AD) from age-matched controls.

Methods: Twenty-four cognitively unimpaired Presenilin-1 E280A carriers (mean age 36 years) and 28 noncarriers (mean age 37 years) underwent Pittsburg compound B-PET (amyloid), flortaucipir-PET (tau), and cognitive testing, including the FCSRT (immediate and delayed free and cued recall scores). Linear regressions were used to examine the relationships among FCSRT scores, age, mean cortical amyloid, and regional tau burden.

Results: Free and total recall scores did not differ between cognitively unimpaired mutation carriers and noncarriers. Greater age predicted lower free recall and delayed free and total recall scores in carriers. In cognitively impaired carriers, delayed free recall predicted greater amyloid burden and entorhinal tau, while worse immediate free recall scores predicted greater tau in the inferior temporal and entorhinal cortices. In turn, in all carriers, lower free and total recall scores predicted greater amyloid and regional tau pathology.

Conclusions: FCSRT scores were associated with in vivo markers of AD-related pathology in cognitively unimpaired individuals genetically determined to develop dementia. Difficulties on free recall, particularly delayed recall, were evident earlier in the disease trajectory, while difficulties on cued recall were seen only as carriers neared the onset of dementia, consistent with the pathologic progression of the disease. Findings suggest that the FCSRT can be a useful measure to track disease progression in AD.

Figure 1. FCSRT performance in mutation carriers and noncarriers

No significant group-differences were seen in Free and Cued Selective Reminding Test (FCSRT) scores between cognitively unimpaired mutation carriers (red) and noncarriers (black). ns = Nonsignificant.

Figure 2. Age, Pittsburgh B binding, and Free and Cued Selective Reminding Test scores

Black circles represent noncarriers; red circles represent cognitively unimpaired PSEN1 mutation carriers. Unfilled red circles represent mutation carriers with mild cognitive impairment. Lines represent 95% CI. (A and B) Age significantly predicts free recall (FR) scores, but not total recall (TR) scores, in cognitively unimpaired mutation carriers. (C and D) There is no association between FR and TR scores and cortical amyloid burden in cognitively unimpaired carriers. DVR = distribution volume ratio.

Figure 3. ¹⁸F-flortaucipir binding and Free and Cued Selective Reminding Test score

Black circles represent noncarriers; red circles represent cognitively unimpaired PSEN1 mutation carriers. Unfilled red circles represent mutation carriers with mild cognitive impairment. (A) Free recall (FR) scores significantly predict tau burden in the entorhinal cortex. (B) There is no association between total recall (TR) and tau in the entorhinal cortex. (C) FR scores significantly predict tau burden in the inferior temporal cortex. (D) There is no association between TR and tau burden in the inferior temporal cortex.

Figure 4. Whole-brain analysis of the relationship between tau pathology and TR score

Greater total recall (TR) scores were related to 18F-flortaucipir binding in mostly the inferior temporal cortex and medial temporal regions in mutation carriers. Regions shown are p < 0.01 after cluster size correction for multiple comparisons (minimum cluster extent k = 100 mm²).