The Effect of CAG Repeats within the Non-Pathological Range in the HTT Gene on Cognitive Functions in Patients with Subjective Cognitive Decline and Mild Cognitive Impairment

Abstract

The Huntingtin gene (HTT) is within a class of genes containing a key region of CAG repeats. When expanded beyond 39 repeats, Huntington disease (HD) develops. Individuals with less than 35 repeats are not associated with HD. Increasing evidence has suggested that CAG repeats play a role in modulating brain development and brain function. However, very few studies have investigated the effect of CAG repeats in the non-pathological range on cognitive performances in non-demented individuals. In this study, we aimed to test how CAG repeats' length influences neuropsychological scores in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). We included 75 patients (46 SCD and 29 MCI). All patients underwent an extensive neuropsychological battery and analysis of HTT alleles to quantify the number of CAG repeats. Results: CAG repeat number was positively correlated with scores of tests assessing for executive function, visual-spatial ability, and memory in SCD patients, while in MCI patients, it was inversely correlated with scores of visual-spatial ability and premorbid intelligence. When we performed a multiple regression analysis, we found that these relationships still remained, also when adjusting for possible confounding factors. Interestingly, logarithmic models better described the associations between CAG repeats and neuropsychological scores. CAG repeats in the HTT gene within the non-pathological range influenced neuropsychological performances depending on global cognitive status. The logarithmic model suggested that the positive effect of CAG repeats in SCD patients decreases as the number of repeats grows.

Keywords: APOE; BDNF; CAG repeats; Huntington’s gene; cognitive functions; intermediate alleles; mild cognitive impairment; subjective cognitive decline.

Figure 1

Histogram describing the frequency of CAG repeat lengths in the whole sample ((A) shorter allele, (B) longer allele) and in SCD and MCI separately ((C) shorter allele, (D) longer allele).

Figure 2

Scatter plots with lines of best fit (95% CI) showing the relationship between CAG repeat lengths and z-scores in neuropsychological tests in SCD and MCI. The Spearman correlation coefficient (R) and level of significance (p) are reported (statistical significance at p < 0.05).