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.

CAG Repeats Within the Non-pathological Range in the HTT Gene Influence Personality Traits in Patients With Subjective Cognitive Decline: A 13-Year Follow-Up Study

“…We already showed that CAG repeat lengths in HTT may differently influence neuropsychological performances according to cognitive status of subjects ( 14 ). In more detail, we showed that a higher number of GAC repeats in the non-pathological range was associated with higher scores in tasks assessing executive function, memory, visual–spatial ability and language in SCD patients but to lower scores in the same cognitive domain in MCIs.…”

“…The biological substrate of this effect might lie in the interaction of HTT protein with a number of proteins with a role in microtubule-based axon trafficking ( 33 , 34 ). In particular, wild-type Hintingtin protein specifically enhances the vesicular transport of Brain Derived Natriuretic Factor (BDNF) ( 35 ), a neurotrophic factor involved in synaptic connections ( 36 ), neural growth ( 37 ), synaptic plasticity ( 38 ), and essential for long-term potentiation underlying hippocampus-related memory ( 14 , 39 ). PolyQ tracts in Huntingtin protein stabilize interactions ( 40 ), according to a non-linear relation with the best function reached at an intermediate number of CAG repeats and then showing a progressive decrease ( 41 ).…”

“…Alzheimer-type lesions, in turns, were found more frequently in autopsy of HD patients [from 67 ( 12 ) to 80% ( 13 )] as compared to healthy controls. Finally, a recent work by our group found that HTT CAG expansions influence neuropsychological functions in individuals experiencing Subjective Cognitive Decline (SCD) or Mild Cognitive Impairment (MCI) ( 14 ).…”

Huntingtin gene intermediate alleles influence the progression from subjective cognitive decline to mild cognitive impairment: A 14‐year follow‐up study

“…Some studies showed that increasing repeat length below the disease threshold in HTT confers advantageous changes in brain structure (cerebral cortex thickness [38] and gray matter within the pallidum [39]) and is associated with greater general intelligence and visual‐perceptual skills [38]. Nevertheless, in a previous study by our group, we showed that a higher number of CAG repeats in the HTT gene (below the pathological threshold) positively influenced memory, visual‐spatial ability, executive function and language in SCD patients, but negatively affected cognitive function in MCI [40]. Therefore, we speculated that higher number of CAG repeats in the HTT gene might enhance cognitive function in cognitively healthy subjects and in patients with subjective impairment, but, as cognitive impairment advances, this advantage fails and longer repeat length begins to play a detrimental effect.…”