Abstract
Alzheimer's disease has recently been classified using three biological markers (amyloid [A], tau [T], and neurodegeneration [N]) to help elucidate its progression. We aimed to investigate whether there were differences between cognitive function and the clinical dementia symptoms over time relative to the ATN classification in the amyloid-negative group. In the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, 310 participants who underwent all the tests required for ATN classification were enrolled. The cognitive function score differences (Alzheimer's Disease Assessment Scale-Cognitive Subscale 13 [ADAS-Cog 13], Clinical Dementia Rating Sum of Boxes [CDR-SOB], and Mini-Mental State Examination [MMSE]) between the groups were analyzed using the analysis of covariance and score changes over time with a linear mixed-effects model. In the cross-sectional analysis, ADAS-Cog 13 scores were higher for A-T-N+ and A-T+N+ than for A-T-N- (p<0.001) and A-T+N- (p<0.001). In the longitudinal analysis, CDR-SOB scores for A-T+N+ deteriorated faster than A-T-N- (p<0.001), A-T+N- (p<0.001) and A-T-N+ (p<0.001). Hippocampal atrophy progressed faster in A-T-N+ (p<0.001) and A-T+N+ (p=0.02) than in A-T-N-. Through this study, we discovered that even in individuals classified as amyloid negative, neurodegeneration with tau deposition exacerbates cognitive decline and worsens clinical symptoms, underscoring the need for continuous monitoring and observation.