Telomere shortening reflecting physical aging is associated with cognitive decline and dementia conversion in mild cognitive impairment due to Alzheimer's disease

Abstract

We investigated whether telomere length (TL) reflecting physical rather than chronological aging is associated with disease progression in the different cognitive stages of Alzheimer's disease (AD). Study participants included 89 subjects with amyloid pathology (A+), determined through amyloid PET or cerebrospinal fluid analysis, including 26 cognitively unimpaired (CU A+) individuals, 28 subjects with mild cognitive impairment (MCI A+), and 35 subjects with AD dementia (ADD A+). As controls, 104 CU A- individuals were selected. The participants were evaluated annually over two years from baseline. Compared to the highest TL quartile group of MCI A+ participants, the lowest TL quartile group yielded 2-year differences of -9.438 (95% confidence interval [CI] = -14.567 ~ -4.309), -26.708 (-41.576 ~ -11.839), 3.198 (1.323 ~ 5.056), and 2.549 (0.527 ~ 4.571) on the Mini-Mental State Examination, Consortium to Establish a Registry for AD, Clinical Dementia Rating-Sum of Boxes, and Blessed Dementia Scale-Activities of Daily Living, respectively. With this group, the lowest TL quartile group had a significantly greater probability of progressing to ADD than the highest TL quartile group (hazard ratio = 13.16, 95% CI = 1.11 ~ 156.61). Telomere shortening may be associated with rapid cognitive decline and conversion to dementia in MCI A+.

Keywords: Alzheimer’s disease; amyloid; mild cognitive impairment; progression; telomere.

Figure 1

Associations between telomere length (TL) and baseline cognitive function in each Alzheimer’s disease (AD) cognitive stage group. Simple linear regression was performed with TL as independent variable and each cognitive function test as dependent variable. (A) Significant positive association between TL and Mini-Mental State Examination (MMSE) scores in the cognitively unimpaired (CU) A+ group (R² = 0.190). (B) Significant positive association between TL and Consortium to Establish a Registry for AD (CERAD) scores in the AD dementia (ADD) A+ group (R² = 0.152). (C) No significant association was detected between TL and Clinical Dementia Rating-Sum of Boxes (CDR-SB) in each AD cognitive stage group. (D) Significant positive association between TL and Logical Memory delayed recall scores in the mild cognitive impairment (MCI) A+ group (R² = 0.245). Higher scores suggest better cognition in MMSE, CERAD, and LM delayed recall test, and lower scores suggest better performance in CDR-SB.

Figure 2

Changes in cognitive performance over 2 years according to telomere length (TL) in mild cognitive impairment (MCI) A+ participants. (A) Mini-Mental State Examination (MMSE). (B) Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). (C) Clinical Dementia Rating-Sum of Boxes (CDR-SB). (D) Blessed Dementia Scale-Activities of Daily Living (BDS-ADL). Figures show estimated means of clinical outcome measures from baseline to 1- and 2-year follow-up in each TL quartile group. The relationship of baseline TL quartile level (as the explanatory variable) with each clinical outcome measure (as a dependent variable) was analyzed using linear mixed models with a function of TL quartile group, age, time, and group x time interaction. Lower scores suggest worse cognition in MMSE and CERAD, and higher scores suggest worse performance in CDR-SB and BDS-ADL.

Figure 3

Conversion from mild cognitive impairment (MCI) to dementia according to the telomere length (TL) quartile groups in MCI A+. Normalized cumulative conversion data are based on Cox proportional hazards regression analysis adjusted for age as a covariate. The lowest TL quartile group (TL ≤ 6.61 kb) had a significantly greater probability of progressing to dementia compared with the highest TL quartile group (TL > 7.85 kb) in the MCI A+ participants (hazard ratio = 13.16, 95% confidence interval = 1.11 ~ 156.61, P = 0.041).