Dementia is a general term for a number of progressive, organic braindiseases affecting around two-thirds of a million people in Englandalone. Most neurodegenerative diseases that lead to dementia are characterized by processes that result in the aberrant polymerization of proteins, and a small proportion of subjects with these diseases develop dementia as a direct result of the presence of mutations or polymorphisms in genes that inﬂuence these processes. The most commoncause of dementia, and the best studied, is Alzheimer’s disease. Other important causes include vascular dementia, dementia with Lewy bodies, and frontotemporal dementia. Management of dementia is largely focused on helping carers to cope with the increase in physical dependence of patients as the disease progresses, or with the emergence of troublesome neuropsychiatric symptoms. Current pharmacological treatments are based on the neurochemical changes that are found in thesediseases. Cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists offer some help in ameliorating the inevitable cognitive decline found in Alzheimer’s disease. However, the treatment of neuropsychiatric symptoms in dementia is still largely empirical and is hampered by either limited efﬁcacy or troublesome adverse effects bodies (DLB) (10%) and frontotemporal dementia (FTD) (2%). Although considered as discrete entities, these diseases are not mutually exclusive and mixed pathologies are common.
The aetiology of dementia is determined by the underlying causative disease. However, it has become increasingly clear that most neurodegenerative diseases that lead to dementia are often characterized by processes that result in the aberrant polymerizationof proteins, and that a proportion of subjects with these diseases develop dementia as a direct result of the presence of mutations or polymorphisms in genes that inﬂuence these processes.
Alzheimer’s disease (AD)
Apart from increasing age, the clearest associated risk factor for AD is a positive family history amounting to an approximately threefold higher risk in ﬁrst-degree relatives of patients with AD. Direct support for a genetic component to AD comes from the recognition of a small number of patients who develop the disease largely before the age of 65 years in an autosomal dominant pattern.
To date, mutations in three genes (amyloid precursor protein,presenilin 1 and presenilin 2) have been described which lead to this early form of AD. These mutations all have the same effect,which is the increased production of a longer version of bamyloid peptide (42 amino acids compared with 40 amino acids); this aggregates to form a condensed core of amyloid protein that becomes surrounded by degenerating neurites. These relatively large extracellular structures, known as plaques, are a characteristic feature of both sporadic and inherited AD. The amyloidcascade hypothesis 2 postulates that b-amyloid peptide aggregates are the underlying cause for all of the other neuropathological features of both sporadic and inherited AD, including the formation of intracellular tangles, inﬂammatory features, widespread neurochemical changes (including loss of acetylcholine and impaired glutamatergic neurotransmission), and ultimately neuronal cell death. However, there is increasing evidence that soluble monomers of b-amyloid peptide, rather than aggregatesin plaques, are the neurotoxic species. In late-onset AD, developing after the age of 65 years, no clear autosomal dominant patterns have been established. However, prevalence studies suggest that a presence of one copy of the apolipo protein E ε4 allele is associated with a three times increased risk of developing late-onset AD, although possession of the apolipoprotein E ε4 allele is neither a necessary or sufﬁcient condition for thedevelopment of AD. Recent, large scale genome-wide association studies have shown that, in addition to apolipoprotein E ε4,