This is the commonest cause of dementia, accounting for 70–80 % of cases. It typically presents after the age of 60 with memory disturbance progressing with dysphasia and dyspraxia. After a period of several years patients become immobile and mute. Approximately 10 % of cases are familial, although this is more common in the early onset cases which are associated with mutations in Presenilin 1, Presenilin 2 and β amyloid precursor protein gene (βAPP). Alzheimer’s disease develops in virtually all patients with Down’s Syndrome related to trisomy 21 by the age of 40, due to the dose effect of having three copies of the β amyloid precursor protein gene (which is located on chromosome 21). It should be noted that mutations in the tau gene do not lead to Alzheimer’s disease, providing strong evidence that disorder of amyloid metabolism is of primary importance in this disorder. There are large number of genetic polymorphisms that have been linked to increase risk of Alzheimer’s disease [1], but the apolipoprotein E gene polymorphism is best known, with individuals having the ε4 allele having the greatest risk and ε2 allele, the lowest. Previous head injury is also risk factor for Alzheimer’s disease, and adverse outcome from head injury is also associated with the ε4 allele, which has a number of effects on Aβ metabolism [2].

Pathologically the brain shows atrophy (Fig. 12.2), most marked in the medial temporal lobes, and there is relative preservation of the primary motor cortex and occipital lobes. There is accumulation of two proteins, amyloid and abnormally phosphorylated tau. Amyloid accumulates extracellularly in the form of aggregates (plaques) which are composed of the Aβ peptide, a breakdown product of βAPP. Diffuse plaques are common in normal aging, but neuritic plaques (classical senile plaques) are more closely associated with Alzheimer’s disease (Fig. 12.3). In addition, Aβ also accumulates in the small arteries and arterioles within the cerebral and cerebellar cortex and leptomeninges (amyloid angiopathy) (Fig. 12.4). Hyperphosphorylated tau accumulates within neurons diffusely, and in paired helical filaments forming neurofibrillary tangles (Fig. 12.5). Tau also accumulates in the neuropil as small thread-like structures (neuropil threads) and surrounding neuritic plaques, as small bulbous swellings (dystrophic neurites). An early pathological change is loss of synapses, and other common microscopic abnormalities include loss of neurons from the cortex, granulovacuolar degeneration of the pyramidal neurons within the hippocampus and actin accumulation within hippocampal neurons (Hirano bodies).

Neuronal loss is associated with neurochemical alterations, in particular loss of neurons from the nucleus basalis of Meynert leads to marked reduction of acetylcholine in the cerebral cortex, depletion of the dorsal raphe nucleus and locus ceruleus results in reduced 5 hydroxytryptamine and noradrenaline input into the cortex respectively.

The severity of the histological changes can be classified using either the density and distribution of tangles within the brain (Braak stage – I to VI) [3, 4], or by the density of amyloid plaques (CERAD score – mild, moderate or frequent) [5]. The correlation between the severity of the pathology and of dementia is not absolute, and there are cases with moderately severe Alzheimer’s disease pathology with minimal cognitive impairment [6].

In some elderly patients (particularly women) with dementia the only pathological change may be the presence of neurofibrillary tangles and dystrophic neurites, principally in the medial temporal lobe and substantia nigra (tangle-only dementia).

Another condition which presents with dementia in the elderly, argyrophilic grain dementia, is characterised by small granular and filamentous tau deposits in the hippocampus and other medial temporal lobe structures.

This is the second commonest neurodegenerative cause of dementia, accounting for 10–20 % of cases in hospital-based series. The clinical presentation overlaps with that of Alzheimer’s disease, although features such as pronounced fluctuation in symptoms, well-formed visual hallucinations, parkinsonian features and neuroleptic sensitivity are helpful pointers. The pathology overlaps with that of Parkinson’s disease and distinguishing the disorder from Parkinson’s disease with dementia is based upon the presentation, with the latter being defined as dementia occurring at least a year after the presentation of a pure motor Parkinson’s disease.

The brain shows atrophy, particularly in the temporal lobes and microscopically many cases have varying degrees of Alzheimer’s disease type-pathology. However, in addition there are Lewy bodies (Fig. 12.6) and Lewy neurites, including within the limbic system and insular cortex. Lewy bodies and neurites are characterised by accumulation of α synuclein. Lewy body pathology may also be seen in the brain stem. In some cases there may be areas of laminar microvacuolation, resembling the spongiform changes seen in Creutzfeldt-Jakob disease. Severe involvement of the basal nucleus of Meynert leads to cholinergic deficiency, and neuronal loss from the substantia nigra leads to dopamine deficiency.

Lewy body disorders can be classified pathologically into brain stem predominant (Parkinson’ disease, Lewy body dysphagia) or limbic, neocortical and amygdala predominant forms, using consensus criteria [4].

Frontotemporal lobar degeneration (FTLD) accounts for 10–20 % of cases of dementia and may present as either a behavioural variant with changes in social and personal conduct, progressive non-fluent aphasia with an expressive dysphasia, or as semantic dementia with impairment of verbal and visual memory. Some patients may also have motor neuron disease or parkinsonian features. Overall about 50 % of cases of frontotemporal dementia are familial, with an autosomal dominant pattern of inheritance. These dementias may be classified according to the type of protein accumulation (Table 12.1).

FTLD-tau is seen in the chromosome 17-linked dementia, associated with mutations in the tau gene, and in Pick’s disease, which is largely sporadic, and associated with swollen neurons (Pick’s cells) and rounded intracellular neuronal inclusions (Pick bodies) (Fig. 12.7), both of which are associated with tau accumulation. FTLD-TDP is the most common subtype and is seen in cases of dementia associated with sporadic motor neuron disease and in association with mutations in progranulin or valosin containing protein (VCP) genes. Patients may have Paget’s disease and inclusion body myopathy. An expansion of the hexanucleotide repeat in the C9orf72 gene on chromosome 9 is associated with either motor neuron disease or dementia with FTLD-TDP pathology, and is a common cause of familial FTLD. In a small number of cases of FTLD there may be accumulation of fused in sarcoma protein (FUS), ubiquitin-only immunoreactive changes (FTLD-UPS), some of which are associated with mutations in the charged multivesicular body protein 2B (CHMP2B). A few cases of FTLD have no identifiable inclusions (FTLD-ni).