SNAP IS PROBABLY NORMAL AGING: FINDINGS FROM BIOMARKERS SIGNATURE

Abstract

Suspected non-Alzheimer pathophysiology (SNAP) is a biomarker-based entity characterized with neurodegeneration (suggested by high cerebrospinal fluid (CSF) Tau levels, magnetic resonance imaging atrophy in Alzheimer's disease (AD)-vulnerable regions, or positron emission tomography (PET) hypometabolism in AD-vulnerable regions) but lack of amyloidosis (defined by high PET radiotracer binding or low CSF fluid of Aβ levels), regardless of clinical status (clinically normal, mild cognitive impairment or dementia). SNAP is also a complement to the new National Institute on Aging–Alzheimer Association (NIA-AA) research criteria of preclinical AD. We aimed to explore the biomarkers in different clinical status with SNAP. We used the baseline data from Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) and collected the individuals with SNAP (clinically normal, mild cognitive impairment or dementia). The criteria were decreased CSF Aβ1–42 (<192pg/ml) and elevated CSF Tau (total Tau>93pg/ml, or phosphorylated Tau>23pg/ml). The data of biomarkers from CSF (e.g. Aβ, Tau, α-synuclein, sAPPβ, neurogranin, β-secretase, neurofilament, isoprostane, multiplex proteomics) and plasma (e.g. Aβ, Tau, neurofilament) were extracted. Mann-Whitney U tests were carried out between the groups of different clinical status, and P<0.05 was regarded as statistical significance. A total of 31 SNAP individuals were selected from ADNI1 cohort, with 18 clinically normal, 9 MCI and 4 dementia. APOE4 alleles were only 8%. In comparison with clinically normal, CSF CD40 (Mann-Whitney U test, Z=-2.024, P =0.046) and fibrinogen (Mann-Whitney U test, Z=-2.239, P =0.025) significantly changed in MCI, as well as CSF isoprostane (ISO8PGF2A) was elevated in dementia. In comparison with clinically normal, CSF isoprostane (ISO8PGF2A) (Mann-Whitney U test, Z=-2.315, P=0.020) was elevated in dementia. APOE4 is less common in SNAP. Only elevated ISO8PGF2A is observed in dementia in comparison with clinically normal and MCI, which is not found between clinically normal and MCI. Large-sample is required to confirm our findings and seek better biomarkers to differentiate the clinical status of SNAP. As the previous opinion “SNAP individuals are stable over time”, biomarkers signature suggests SNAP may be normal aging rather than pathological changes, in which brain atrophy and cognitive decline progress slowly.