👤 Alberto Serrano-Pozo

Cerebral small vessel disease (CSVD) contributes to the development of Alzheimer's disease (AD) dementia and co-occurs with AD-associated proteinopathies. However, how sex modulates the interaction between CSVD and AD-associated proteinopathies in the medial temporal lobe (MTL) remains unclear. One hundred fifty-two autopsy cases from the Massachusetts Alzheimer's Disease Research Center were included. Deep-learning and semiquantitative scores were applied to MTL histological sections to obtain quantitative measures of proteinopathies and CSVD (cerebral amyloid angiopathy [CAA] and arteriolosclerosis). The effect of sex on AD-associated proteinopathies and the interaction between sex, CSVD, and apolipoprotein E (APOE) genotype were analyzed using linear mixed-effect models. In women, higher CAA burden was associated with lower amyloid beta (Aβ) plaques but higher tau tangles density. No interaction effect was found for arteriolosclerosis. Women <75 years of age carrying the APOE ε4 allele had higher Aβ plaque burden than ε4 non-carriers. Our results highlight the complex effect of sex on microvascular and AD-associated pathologies in the MTL. Show less

The apolipoprotein E ( APOE ) genotype has traditionally been associated with Alzheimer's disease (AD) and, more specifically, with the severity of cerebral β-amyloidosis in the form of Aβ plaques and cerebral amyloid angiopathy (CAA). However, a growing body of research has examined its potential impact on Tau pathology. Here we critically review the evidence supporting a differential effect of APOE alleles on Tau in the context of AD and non-AD tauopathies, from genetic, neuropathological, and biomarker studies to preclinical studies in mouse models and human inducible pluripotent stem-cells (hiPSCs)-derived brain cells. Genetic, neuropathological, and preclinical studies in transgenic mice have yielded somewhat conflicting results, whereas most multitracer PET imaging studies on individuals along the normal aging to AD dementia continuum support an Aβ-independent effect of the APOE ε4 allele on the tauopathy of AD. More clinical and preclinical research is needed to elucidate the link between APOE and Tau. Show less