1. Dementia with late onset - many causes, (potentially) one disease
Dementia is one of the top causes for of disability and dependency after the 6th decade of life and the fourth most common cause of death in developed countries. The most common cause of dementia in the elderly is Alzheimer's disease (AD), followed by vascular dementia (VD). The latter is also commonly referred to as vascular cognitive impairment (VCI)), a rather unspecific term covering moderate and severe cognitive decline developing after stroke/s and small-vessel disease. The prevalence of AD in those aged 60-65 is less than 1 %. It increases steadily up to the age of 85, when it may reach > 35 % of the elderly [
2. Amyloid deposition in the brain - what, where and how
Two major types of pathological structures are commonly observed in autopsied brains of patients with dementia - amyloid beta-peptide aggregates (amyloid plaques) and tau protein depositions (neurofibrillary tangles). Amyloid plaques and neurofibrillary tangles were described by Dr. Alois Alzheimer in 1907 and have since been considered hallmarks of AD. Amyloid-beta deposits (predominantly 42 amino acid residues long, Abeta42) may be observed in the brain parenchyma (amyloid plaques) and/or in the walls of leptomeningeal and cortical brain vessels (cerebral amyloid angiopathy (CAA) due to deposition of amyloid-beta peptide 40 amino acid residues long, Abeta40) [
Amyloid deposition in the vessel wall is initially confined to the outer basement membrane. In later stages of CAA, the smooth muscle layer in the vessel wall is almost completely obliterated and only the endothelial layer is relatively spared [
Brain ischemia increases the risk for dementia, although indirectly. Ischemic insults to the brain were shown not to have a significant short- and medium-term effect on the cognitive status but increased the risk for development of AD-type dementia later [
Brain amyloidosis is undoubtedly associated with increased risk for dementia, but it is still unclear whether amyloid is a driving factor in the pathogenesis of dementia or an outward manifestation of another pathological process. Amyloid neuropathology is very common in patients of dementia of either vascular or AD origin, but is not uncommon in nondemented aged brains too. In studies in living nondemented patients or patients with MCI aged 80-85, evidence of amyloid deposits was found in 55 % of the nondemented individuals and 68 % of those with MCI [
The prevalence of brain amyloidosis and the degree of involvement is significantly higher in individuals carrying at least one copy of a specific genetic variant - namely, the E4 allele of the apolipoprotein E (APOE) gene. In the study of Mathis et al.[
3. APOE - a simple lipoprotein transporter, a major amyloid peptide metabolism modulator or in-between?
Apolipoprotein E gene codes for a protein involved in the binding, transport and clearance of lipids, lipid-soluble vitamins and cholesterol [
APOE4 has been known for decades as a powerful genetic factor increasing the risk for late-onset dementia. In carriers of a single APOE4 allele, the risk for development of AD and VCI is significantly higher than the population risk (1.5-2 fold for VCI, 3-4-fold for AD) and becomes very high in homozygous carriers of two APOE4 alleles (3-4-fold for VCI; 7-8-fold for AD) [
Hippocampal atrophy may be among the earliest findings in AD, developing years and decades before dementia may become manifest. The rate of loss of neurons from the hippocampus and the amygdala in AD was reported to be dependent on the APOE4 genotype [
Carriership of E2 or E4 APOE alleles was reported to be associated with more severe vascular amyloid pathology [
Carriership of APOE4 increases the risk for post-stroke cognitive decline [
APOE4 has been shown to modulate directly the metabolism of amyloid precursor protein in the amyloidogenic pathway. One of the short-term effects of head trauma is transiently increased metabolism of the amyloid precursor protein, possibly stimulating neurite outgrowth and cell survival [
At present, carriership of APOE variants is considered an independent risk factor for dementia in later life that may be augmented by other factors in the genetic background of susceptible individuals as well as environmental factors. The risks for dementia ('true' AD or cognitive decline after intracerebral haemorrhage/s and ischemic stroke/s) due to carriership of APOE4 are partly associated with modulation of the metabolism of APP that, in turn, increases the risk for parenchymal and/or vascular deposition of amyloid beta peptide, and, probably, partly associated with increased risk for atherosclerotic vascular disease because of the modulating effects of the APOE variant alleles on the lipid metabolism. It is still a subject of debate whether carriership of APOEvariants has direct effect on neuronal loss in dementia. Beta-amyloid has been found to directly upregulate the expression of caspase-3 (a major executor caspase) in vitro [
4. Neuronal cell death in dementia - it breaks where it's thin?
Mass cell death affecting specific neuronal populations in the grain or more generalised brain atrophy is almost universal post-mortem finding in brains of patients with dementia. Mild neuronal loss is normal in the course of brain development and in brain aging, but the rates of neuronal loss and the affected areas of the brain may be different in physiological and pathological brain aging. For example, slowly progressing hippocampal atrophy is commonly seen in aging brains [
Neuronal loss in dementia is rarely diffuse (except, perhaps, in the very advanced stages) but, rather, follows a pattern that may be different depending on the type of the underlying condition. In focal cerebral ischemia, the severe impairment in oxidative phosphorylation and the resultant oxidative stress at the lesion site causes mass cell death by necrosis or apoptosis in a matter of minutes to hours after the ischemic incident. In the penumbra of the ischemic lesion oxidative phosphorylation is impaired due to hypoperfusion and hypoxia and the levels of oxidative stress are significantly higher than normal; but neural tissue in these regions may survive, especially when supportive measures to improve brain perfusion have been instigated in the immediate acute period. Even with active treatment, however, many more neurons (including neurons in locations relatively distant from the lesion site) may succumb to cell death days to months after the incident. This delayed cell death may affect the potentially viable neurons in the penumbra of the stroke as well as the neuronal populations elsewhere in the brain (especially in the hippocampus, the basal ganglia, and the Purkinje cells in the cerebellum) [
The causes for increased susceptibility of some (but not all) neurons in the adult CNS after stroke and in neurodegenerative disease are still elusive. Toxic over-stimulation of the receptors for excitatory amino acids (glutamate, NMDA and others) in neuronal cells (excitotoxicity) has been implicated in the pathogenesis of dementia after acute brain trauma, stroke and in neurodegenerative disease [
Adult CNS neurons are extremely long-lived (potentially, as long as long the organism lives) and are rarely, if ever, replaced. Thus, neurons are subjected to chronic, high-level genotoxic damage (predominantly oxidative damage caused by ROS generated in the course of normal cell metabolism). The capacity to detect and promptly repair genotoxic damage is essential for neuronal survival and the maintenance of their functional capacity. As age advances, the enzymatic activities functioning in the detoxification of oxidised substrates such as superoxide dismutase (SOD), catalase, glutathione transferase, and others gradually decreases. The efficiency of the cellular machinery recognising and repairing genotoxic damage may also decline over time. As a result, the levels of oxidative stress generally increase with age, thereby increasing the risk for accumulation of unrepaired damage. The rates of occurrence of 8-oxoguanine, 8-hydroxydeoxyguanosine and double-strand breaks increase in an age-dependent manner in virtually all types of mammalian cells, including CNS neurons [
5. Breath of life (and death) - increased ATP production is associated with increased oxidative stress
Virtually all cells in multicellular bodies are dependent on oxidative phosphorylation for production of ATP, but neurons are specifically vulnerable to oxygen and ATP deficiency because of their high metabolic rate. Neurons have high mitochondrial content with uneven intracellular distribution and the individual mitochondria are highly mobile within the neuron in order to comply with the requirements for ATP production in different neuronal segments [
The topological site of production of ROS is the inner mitochondrial membrane; therefore, it is the mitochondrial proteins, lipids and DNA that generally bear the brunt of oxidative damage. There are several features in the higher-level organisation of mitochondrial DNA that make it specifically vulnerable to oxidative damage. Among these are the absence of histone packaging and the high gene density of mitochondrial DNA. There are very few regions in mitochondrial DNA where an alteration in DNA sequence or structure would not result in a severe pathological phenotype. The sites in mitochondrial DNA where benign heritable changes in DNA sequence may occur are clustered predominantly in the control region where the origin for replication of the leading strand and the promoters of major genes coded by mitochondrial DNA are located. Several polymorphisms occurring within the same DNA molecule are commonly referred to with the term haplogroup. More than 15 currently existing haplogroups of mitochondrial DNA have been described [
6. Don't throw away, repair it - capacity to repair genotoxic damage may be critically important for the survival of adult CNS neurons
Normal adult neurons employ specific mechanisms in order to extend their lifespan and preserve their functional capacity for years and decades [
Carriership of variant alleles of genes coding for major proteins of DNA repair by BER and mismatch repair has been associated with increased risk for common late-onset diseases. Allelic variants of the BER glycosylase Neil1 conferring subtle enzyme deficiency has been shown to produce an obese, dyslipidemic and insulin resistant phenotype in mice resembling human metabolic syndrome [
The importance of BER notwithstanding, subtle deficiencies of repair by NER may also affect the risk for neurological impairment. Repair of transcribed regions is vitally important for the maintenance of genomic integrity in adult neurons and inherited repair deficiencies affecting transcription-dependent NER usually present with severe, early-onset neurological impairment (xeroderma pigmentosum of complementation groups A, B and D, Cockayne syndrome). Repair of untranscribed genomic regions does not play significant role in the maintenance of genomic integrity in adult neurons, but may be crucial for tissues with rapid turnover (e.g. vascular endothelium), thereby modulating the risk for cerebrovascular disease. NER deficiency may play a role in the pathogenesis of vascular disease, stroke and post-stroke cognitive decline. Recently it was demonstrated that subtle deficiency of a major NER protein due to carriership of an insertion/deletion polymorphism in intron 11 allele of the human XPC gene (coding for one of the components of the complex that recognises damage in untranscribed DNA) may increase the risk for cerebrovascular disease and stroke [
DNA breaks secondary to oxidation are also a common type of damage in mitochondrial DNA. DNA breaks are generally the least tolerated type of DNA damage and their presence may directly activate programmed cell death pathways. Contrary to the long-established no-recombination' rule for mitochondrial DNA, it is now believed that breaks in mitochondrial DNA are repaired by a recombination mechanism mediated by a RAD52-like single-strand binding protein [
Identification and repair of genotoxic damage is only one aspect of the functioning of the cellular repair machinery. Assessment of the genomic integrity (presence of residual unrepaired damage and its potential reparability, proximity to the apoptotic threshold) is another, equally important component of individual repair capacity. Signalling for the presence of unrepaired damage may be relayed via several major proteins with damage-sensing and executive functions - BRCA, ATM, MSH2, MSH6 (all parts of the BRCA1-associated genome surveillance complex involved in the recognition of aberrant DNA structures) and the master regulator protein p53 [
p53 is a master transcription regulator and controller of cell fate [
The effects of carriership of genetic variants conferring subtle variance in repair capacity and/or maintenance of genomic integrity may be modulated by concomitant inheritance of mitochondrial variants conferring increased (haplogroup H) or decreased (haplogroups K, T, U and J) production of ROS and APOEvariant alleles. One may expect that the genotype of the 'successful ager' may be comprised of APOE3/E3 (or E2/E3); mitochondrial DNA of haplogroup K, T, U or J, normal capacity to repair genotoxic damage (that usually means carriership of ancestral (non-variant) alleles of known polymorphisms in genes coding for proteins of DNA damage identification and repair), at least one TP53 72Pro allele and absence of heterozygous ATM mutations. Certainly, environmental factors, lifestyle and habits would also play a role.
Further studies in the field of individual repair capacity and maintenance of genomic integrity are strongly advocated in order to elucidate the mechanisms of neuronal and vascular dysfunction in later age and to identify potential targets for therapeutic intervention. These include population studies of the potential effects of carriership of allelic variants of genes coding for proteins of repair and maintenance of genomic integrity on the risk for late-onset disease [
Until research into the molecular bases of common late-onset disease has progressed sufficiently to ensure reliability of prognostication of the risk for development of common late-onset diseases and their potential complications, there is not much that could be done about genetic predisposition to late-onset disease. Scientific knowledge about the interlinked mechanisms that determine the outcomes of the same disease in different individuals is still limited. The risk assessments based on family history and genetic testing are not always reliable. Etiologic and/or efficient symptomatic therapies are still unavailable for many of the common late-onset diseases, including dementia in late life. One could, however, manage the controllable factors of lifestyle (maintenance of optimal body weight for age and sex, moderate physical activity, arterial pressure 120/80 or lower, blood glucose and cholesterol within reference ranges, use of preventive anticoagulation, diet rich in natural antioxidants and free radical scavengers) so as not to increase further the risk for late-onset disease. It is possible that individuals at increased risk for late-onset dementia (e.g. individuals diagnosed with mild cognitive decline) may benefit from long-term antioxidant therapies (in addition to lifestyle alterations) in order to decrease the risk for cerebrovascular disease due to amyloid or atherosclerotic neuropathology.
Conclusions
Three major factors are likely to play significant roles in the constitution of the genetic risk for sporadic late-onset dementia - 1) carriership of APOE variant alleles (specifically, the E4 allele); 2) mitochondrial DNA haplogroup and 3) genetic capacity to identify and repair oxidative damage and make decisions about the fate of damaged cells (individual repair capacity). The individual contributions of these genetic factors to the risk for late-onset disease may be subtle, but when combined in the same genotype, they may significantly increase in an age-dependent manner the individual risk for Alzheimer's dementia and vascular dementia in susceptible individuals even in the absence of positive family history. More research into the bases of common late-onset disease may be needed in order to establish reliable estimates for the genetic risk of late-onset dementia. Meanwhile, a combined therapeutic approach comprised of minimisation of the environmental factors increasing the risk for vascular disease and antioxidant therapies may be practical in order to decrease the risk for late-onset dementia.
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