Impact of amyloid and tau positivity on longitudinal brain atrophy in cognitively normal individuals

Abstract Background Individuals on the preclinical Alzheimer's continuum, particularly those with both amyloid and tau positivity (A + T +), display a rapid cognitive decline and elevated disease progression risk. However, limited studies exist on brain atrophy trajectories within this continuum over extended periods. Methods This study involved 367 ADNI participants grouped based on combinations of amyloid and tau statuses determined through cerebrospinal fluid tests. Using longitudinal MRI scans, brain atrophy was determined according to the whole brain, lateral ventricle, and hippocampal volumes and cortical thickness in AD-signature regions. Cognitive performance was evaluated with the Preclinical Alzheimer's Cognitive Composite (PACC). A generalized linear mixed-effects model was used to examine group × time interactions for these measures. In addition, progression risks to mild cognitive impairment (MCI) or dementia were compared among the groups using Cox proportional hazards models. Results A total of 367 participants (48 A + T + , 86 A + T − , 63 A − T + , and 170 A − T − ; mean age 73.8 years, mean follow-up 5.1 years, and 47.4% men) were included. For the lateral ventricle and PACC score, the A + T − and A + T + groups demonstrated statistically significantly greater volume expansion and cognitive decline over time than the A − T − group (lateral ventricle: β = 0.757 cm 3 /year 95% confidence interval 0.463 to 1.050, P < .001 for A + T − , and β = 0.889 cm 3 /year 0.523 to 1.255, P < .001 for A + T + ; PACC: β = − 0.19 /year − 0.36 to − 0.02, P = .029 for A + T − , and β = − 0.59 /year − 0.80 to − 0.37, P < .001 for A + T +). Notably, the A + T + group exhibited additional brain atrophy including the whole brain (β = − 2.782 cm 3 /year − 4.060 to − 1.504, P < .001), hippocampus (β = − 0.057 cm 3 /year − 0.085 to − 0.029, P < .001), and AD-signature regions (β = − 0.02 mm/year − 0.03 to − 0.01, P < .001). Cox proportional hazards models suggested an increased risk of progressing to MCI or dementia in the A + T + group versus the A − T − group (adjusted hazard ratio = 3.35 1.76 to 6.39). Conclusions In cognitively normal individuals, A + T + compounds brain atrophy and cognitive deterioration, amplifying the likelihood of disease progression. Therapeutic interventions targeting A + T + individuals could be pivotal in curbing brain atrophy, cognitive decline, and disease progression.