White matter dysfunction in Alzheimer’s disease: a convergence or divergence of hypotheses

Abstract Alzheimer’s disease (AD) is a multifactorial disease with several key hypotheses centred around its pathological hallmarks, including amyloid and tau and other mechanisms, such as vascular dysfunction. Revised criteria for AD diagnosis reflects these hypotheses and includes white matter hyperintensities (WMH) as a biomarker. This highlights the contribution of white matter (WM) dysfunction in AD, and a need for more in-depth investigation of this part of the brain. The WM makes up 50% of the human brain but has been relatively less studied than the grey matter in AD and other neurodegenerative diseases. WMH are a marker of WM damage in brain tissue visualised using magnetic resonance imaging (MRI). However, there are several theories for what these areas of brightness in the WM truly reflect, especially in AD. As WMH have historically been attributed to cerebral small vessel disease (SVD), we explore the hypotheses for WMH in AD including the additive, interactive and AD-driven hypotheses, with the aim of untangling the heterogeneity of this biomarker. We note that WMH have different patterns of regional vulnerability with frontal WMH more associated with vascular changes, while WMH in the posterior regions including the parietal and occipital are more associated with AD pathology. In this narrative review we also explore molecular factors, including genetic and epigenetic factors, contributing to WM dysfunction in AD and WMH. There are still several unsolved questions regarding factors that underlie WM dysfunction in AD, as reflected by several conflicting hypotheses. Expanding molecular research into the WM will provide critical insights into the AD pathophysiology and enhance our understanding of WMH. This will ultimately improve diagnostic accuracy and contribute to the development of effective therapies for AD, which is a global health priority.