Alzheimer’s disease (AD) is considered the most common pathology contributing to dementia.
Although genomic analyses have identified the apolipoprotein E (apoE) ?4 allele as
a major risk factor for late-onset AD, cerebral small vessel disease (SVD) may also
play a significant role in decline to dementia. Despite increased efforts to elucidate
the complex relationships between AD, SVD, and apoE genotype, the evidence remains
equivocal, posing a challenge for understanding the pathogenic mechanisms underlying
aging and dementia.
Prevailing models of AD pathogenesis suggest that the aggregation of oligomeric amyloid-beta
(A?) proteins initiates a pathophysiological cascade hallmarked by extracellular A?
plaques in the interstitium and along cerebral vessels, and intraneuronal neurofibrillary
tangles of hyperphosphorylated tau. Neurodegenerative sequelae include synaptic dysfunction,
cortical atrophy, and progressive cognitive decline. In vivo models of AD pathogenesis
have identified several potential mechanisms by which apoE ?4 may contribute to amyloidogenic
processes (Fig. 1) 1].
Fig. 1. Effects of apolipoprotein E (apoE) ?4 on amyloid-beta (A?) metabolism and deposition.
apoE may facilitate cellular uptake of A? by the endocytosis of apoE-containing lipoprotein
particles bound to soluble A? (yellow circles), or via binding of this apoE-A? complex
(mauve-blue circles) to extracellular heparin sulfate proteoglycans (HSPG). Alternatively,
apoE may impair A? clearance by slowing the transport of A? across the blood–brain
barrier 1]. LDLR, low-density lipoprotein receptor; LRP, lipoprotein receptor-related protein;
PgP, permeability-glycoprotein. Reproduced with permission from Elsevier 1]
In recent decades, a more nuanced view of AD pathogenesis has emerged, with evidence
for the putative co-contributions of vascular pathology. SVD is commonly observed
at autopsy in patients with AD and, although neuropathological studies have consistently
shown additive, not interactive effects of vasculopathy 2], white matter hyperintensities (WMHs) are more difficult to capture at end-stage
disease. Several neuroimaging-derived biomarkers for SVD have been identified, including
periventricular and deep WMHs of presumed vascular origin, lacunes, and enlarged perivascular
Virchow-Robin spaces, which may be visualized earlier in disease progression 3]. Recent studies using amyloid positron emission tomography (PET) support a relationship
between SVD and amyloid pathology 4], but also confirm that significant subcortical ischemic vasculopathy alone may be
sufficient to cause dementia 5]. Combined with early clinical evidence for the role of apoE ?4 in the development
of cerebral amyloid angiopathy independent of AD 6], and observational associations between dementia and vascular risk factors, these
advances have initiated new lines of investigation into whether white matter vasculopathy
represents a synergistic or independent mechanism of AD pathogenesis.
In a recent article in Alzheimer’s Research Therapy, Morgen and colleagues 7] retrospectively examined relationships between apoE genotype, WMHs, and cognitive
performance in a cohort of patients with mild to moderate AD (N = 183). They compared
apoE ?4 carriers to non-carriers with respect to global and regional WMH volume and
performance on standardized neuropsychological tests. Results indicated that apoE
?4 carriers showed reduced WMH volumes compared with non-carriers and, among non-carriers,
global WMH volume was correlated with performance on the Trail Making Test-A of executive
function. The authors interpreted these findings as evidence that WMHs had a functional
impact on cognition and that SVD represents an independent mechanism of AD pathogenesis.
The Morgen et al. study is consistent with prior work demonstrating that WMHs primarily
impact the domain of executive function 8] and are associated with amyloid plaques on Pittsburg compound B retention PET in
apoE ?4 non-carriers with subcortical vascular cognitive impairment 9]. In a recent meta-analysis of 42 studies, however, an association between apoE ?4
and magnetic resonance imaging markers of cerebrovascular disease was reported 10], suggesting that vascular mechanisms may differentially co-contribute to multiple
pathophysiological cascades with distinct clinical sequelae.
A strength of the Morgen et al. study 7] is in the specificity of case selection. To minimize the potential for misclassification,
the authors excluded those with ‘severe’ WMH burden suggestive of vascular dementia
according to new AD diagnostic guidelines 11]. They then adjusted all multivariate models for multiple vascular risk factors, to
increase the likelihood of observing apoE-dependent effects. In restricting their
cohort to patients without a presumed vascular etiology, Morgen et al. provide novel
evidence for an association between WMH and apoE genotype that modified executive
function independent of vascular risk.
A major source of bias in clinical imaging studies is that template-matching approaches,
such as statistical parametric mapping, do not include a head size correction or account
for cortical atrophy. In many clinical populations, particularly AD, the degree of
atrophy is high, impacting ventricle size and total intracranial volume and resulting
in the potential misattribution of WMH to the grey matter tissue compartment 12]. To partially address this limitation, Morgen et al. corrected for total intracranial
volume and still showed greater WMH burden in apoE ?4 non-carriers, strengthening
their argument that this association reflects pathogenic mechanisms of AD independent
of apoE ?4-mediated neurodegeneration.
As arterial hypertension correlated with WMHs in their cohort, Morgen et al. suggest
blood pressure may have synergistic effects on amyloid-mediated endothelial damage.
Recent animal studies have described a ‘G-lymphatic’ system that removes amyloid in
the perivascular spaces toward the deep periventricular veins 13] and confirmed an association between arterial hypertension and venous collagenosis
in spontaneously hypertensive rats 14]. Neuropathological analyses also suggest that periventricular WMHs may represent
perivenular vasogenic edema correlating with collagenosis of the deep medullary venules
15]. Venous insufficiency thus represents a potential mechanism of impaired A? clearance
that may exacerbate amyloid accumulation and increase clinical decline into dementia.
Increasing evidence for the role of small vessel vasculopathy in dementia highlights
the importance of multifactorial mechanisms in AD pathogenesis. The findings of Morgen
and colleagues are timely and offer support for the co-contributions of WMHs to cognitive
impairment in AD, not mediated by apoE ?4 genotype. A greater understanding of amyloid
clearance will be required for the development of targeted therapies to mitigate the
risk and clinical progression of AD. Amyloid PET imaging offers new opportunities
to elucidate additive/interactive effects of WMHs in AD and unravel the pathogenic
mechanisms of this complex phenotype.