Alzheimer’s disease (AD) is the most prevalent form of dementia. Despite decades of research following several theoretical and clinical lines, all existing treatments for the disorder are purely symptomatic. AD research has traditionally been focused on neuronal and glial dysfunction. Although there is a wealth of evidence pointing to a significant vascular component in the disease, this angle has been relatively poorly explored. In this review, we consider the various aspects of vascular dysfunction in AD, which has a significant impact on brain metabolism and homeostasis and the clearance of β-amyloid and other toxic metabolites. This may potentially precede the onset of the hallmark pathophysiological and cognitive symptoms of the disease. Pathological changes in vessel haemodynamics, angiogenesis, vascular cell function, vascular coverage, blood-brain barrier permeability and immune cell migration may be related to amyloid toxicity, oxidative stress and apolipoprotein E (APOE) genotype. These vascular deficits may in turn contribute to parenchymal amyloid deposition, neurotoxicity, glial activation and metabolic dysfunction in multiple cell types. A vicious feedback cycle ensues, with progressively worsening neuronal and vascular pathology through the course of the disease. Thus, a better appreciation for the importance of vascular dysfunction in AD may open new avenues for research and therapy.

Age of Huntington's disease (HD) motoric onset is strongly related to the number of CAG trinucleotide repeats in the huntingtin gene, suggesting that biological tissue age plays an important role in disease etiology. Recently, a DNA methylation based biomarker of tissue age has been advanced as an epigenetic aging clock. We sought to inquire if HD is associated with an accelerated epigenetic age. DNA methylation data was generated for 475 brain samples from various brain regions of 26 HD cases and 39 controls. Overall, brain regions from HD cases exhibit a significant epigenetic age acceleration effect (p=0.0012). A multivariate model analysis suggests that HD status increases biological age by 3.2 years. Accelerated epigenetic age can be observed in specific brain regions (frontal lobe, parietal lobe, and cingulate gyrus). After excluding controls, we observe a negative correlation (r=-0.41, p=5.5×10-8) between HD gene CAG repeat length and the epigenetic age of HD brain samples. Using correlation network analysis, we identify 11 co-methylation modules with a significant association with HD status across 3 broad cortical regions. In conclusion, HD is associated with an accelerated epigenetic age of specific brain regions and more broadly with substantial changes in brain methylation levels.

Huntington’s disease is an autosomal dominant inherited neurodegenerative disease with motor symptoms that are variably co-expressed with mood and cognitive symptoms, and in which variable neuronal degeneration is also observed in the basal ganglia and the cerebral cortex. We have recently shown that the variable symptomatology in Huntington’s disease correlates with the variable compartmental pattern of GABA_A receptor and cell loss in the striatum. To determine whether the phenotypic variability in Huntington’s disease is also related to variable neuronal degeneration in the cerebral cortex, we undertook a double-blind study using unbiased stereological cell counting methods to determine the pattern of cell loss in the primary motor and anterior cingulate cortices in the brains of 12 cases of Huntington’s disease and 15 controls, and collected detailed data on the clinical symptomatology of the patients with Huntington’s disease from family members and clinical records. The results showed a significant association between: (i) pronounced motor dysfunction and cell loss in the primary motor cortex; and (ii) major mood symptomatology and cell loss in the anterior cingulate cortex. This association held for both total neuronal loss (neuronal N staining) and pyramidal cell loss (SMI32 staining), and also correlated with marked dystrophic changes in the remaining cortical neurons. There was also an association between cortical cell loss and striatal neuropathological grade, but no significant association with CAG repeat length in the Huntington’s disease gene. These findings suggest that the heterogeneity in clinical symptomatology that characterizes Huntington’s disease is associated with variation in the extent of cell loss in the corresponding functional regions of the cerebral cortex whereby motor dysfunction correlates with primary motor cortex cell loss and mood symptomatology is associated with cell loss in the cingulate cortex.