Distinct Brain Functional Impairment Patterns Between Suspected Non-Alzheimer Disease Pathophysiology and Alzheimer's...

Background: Suspected non-Alzheimer disease pathophysiology (SNAP) refers to the subjects who feature negative β-amyloid (Aβ) but positive tau or neurodegeneration biomarkers. It accounts for a quarter of the elderly population and is associated with cognitive decline. However, the underlying pathophysiology is still unclear. Methods: We included 111 non-demented subjects, then classified them into three groups using cerebrospinal fluid (CSF) Aβ 1-42 (A), phosphorylated tau 181 (T), and total tau (N). Specifically, we identified the normal control (NC; subjects with normal biomarkers, A-T-N-), SNAP (subjects with normal amyloid but abnormal tau, A-T+), and predementia Alzheimer's disease (AD; subjects with abnormal amyloid and tau, A+T+). Then, we used the static amplitude of low-frequency fluctuation (sALFF) and dynamic ALFF (dALFF) variance to reflect the intrinsic functional network strength and stability, respectively. Further, we performed a correlation analysis to explore the possible relationship between intrinsic brain activity changes and cognition. Results: SNAP showed decreased sALFF in left superior frontal gyrus (SFG) while increased sALFF in left insula as compared to NC. Regarding the dynamic metric, SNAP showed a similarly decreased dALFF in the left SFG and left paracentral lobule as compared to NC. By contrast, when compared to NC, predementia AD showed decreased sALFF in left inferior parietal gyrus (IPG) and right precuneus, while increased sALFF in the left insula, with more widely distributed decreased dALFF variance across the frontal, parietal and occipital lobe. When directly compared to SNAP, predementia AD showed decreased sALFF in left middle occipital gyrus and IPG, while showing decreased dALFF variance in the left temporal pole. Further correlation analysis showed that increased sALFF in the insula had a negative correlation with the general cognition in the SNAP group. Besides, sALFF and dALFF variance in the right precuneus negatively correlated with attention in the predementia AD group. Conclusion: SNAP and predementia AD show distinct functional impairment patterns. Specifically, SNAP has functional impairments that are confined to the frontal region, which is usually spared in early-stage AD, while predementia AD exhibits widely distributed functional damage involving the frontal, parietal and occipital cortex.