Tau Pathology and Parietal White Matter Lesions Have Independent but Synergistic Effects on Early Development of Alzheimer's Disease

BACKGROUND: White matter lesions (WMLs) are a common finding in patients with dementia. This study investigates the relationship between WMLs, hyperphosphorylated tau (P-tau) in cerebrospinal fluid (CSF) and apolipoprotein E (APOE) ε4 genotype in prodromal Alzheimer's disease (AD). METHODS: Baseline levels of tau, P-tau and β-amyloid 1-42 in CSF, the presence of WMLs in the brain, and the APOE genotype were ascertained in 159 patients with mild cognitive impairment (MCI) and 38 cognitively healthy controls. RESULTS: After 5.7 years, 58 patients had developed AD. In this group, patients with normal levels of CSF P-tau had higher levels of WMLs in the parietal regions than those with pathological P-tau levels (p < 0.05). Also, patients without APOE ε4 alleles had more WMLs in the parietal lobes than those with at least one allele (p < 0.05). MCI patients with pathological P-tau levels and parietal WMLs showed a greater risk of developing AD than those with just one of the two pathological parameters. CONCLUSIONS: We suggest that WMLs in parietal lobes and tau pathology likely have independent but synergistic effects on the reduction of the cognitive reserve capacity of the brain. In patients with a more low-grade AD pathology, WMLs in the parietal lobes might increase the risk of developing dementia.