Functional brain imaging in early Alzheimer’s disease may show reduced blood flow and glucose metabolism in the posterior temporo-parietal regions and hippocampus (Fig. 12.3), before obvious structural changes are evident on MRI. Over time there is progressive brain atrophy, with ventricular dilatation, cortical thinning and hippocampal atrophy. Longitudinal studies show that people with Alzheimer’s disease lose brain tissue at a rate of 2% per year on average (up to 5% per year in the hippocampus), which is four times higher than in age-matched controls (Fig. 12.4).

Fig. 12.3 Reduced hippocampal blood flow in early Alzheimer’s disease.
These images were obtained via single photon emission computer tomography (SPECT) scanning using a radioactive tracer and show regional cerebral blood flow. The upper image is a normal control subject and the lower image is from a patient with early Alzheimer’s disease. The sections are in the axial (horizontal) plane and pass through the temporal lobe. The black box shows the position of the hippocampus in the medial temporal lobe. From Rodriguez, G. et al.: Hippocampal perfusion in mild Alzheimer’s disease. Psychiatry Research: Neuroimaging (2000, pp. 65–74) with permission.

Progression and death

The rate of progression is highly variable, with typical disease duration ranging from 5 to 15 years. Patients may initially be able to remain at home, but will require assistance with day-to-day activities and become increasingly dependent on carers. Ultimately, supervision is required for all activities of daily living including bathing and toileting. At some point specialized institutional care is usually most appropriate, particularly if the primary carers are themselves elderly. In the advanced stages of dementia, most sufferers tend to be become bed-bound and mute. Death is often due to a complication of immobility such as pneumonia.

Key Points

Alzheimer’s disease is the leading cause of dementia in all age groups. Early features include (i) marked loss of episodic memory and (ii) spatial disorientation (both reflecting severe medial temporal lobe degeneration).

As the disease progresses there is a gradual decline in all aspects of cognitive ability over a variable period of around 5–15 years, together with changes in mood, personality and behaviour.

The frontal variant of Alzheimer’s disease is characterized by striking personality and behavioural changes. In posterior cortical atrophy the clinical picture is dominated by visuospatial problems, with relative preservation of memory and language.

Risk factors

The most important risk factor for Alzheimer’s disease, apart from advancing age, is possession of a particular variant of the Apolipoprotein E gene (APOE) on chromosome 19 (discussed below). It is also more common in people with ischaemic heart disease, in those with limited educational attainments or lower socioeconomic status – and in association with previous head injury (Clinical Box 12.4).

Clinical Box 12.4: Dementia pugilistica

Dementia pugilistica or ‘punch drunk’ syndrome is a form of acquired cognitive impairment that occurs in up to a fifth of professional boxers (Latin: pugilator, boxer). It also occurs in other sports in which there may be mild head trauma, such as football and horse racing. The microscopic features are similar to Alzheimer’s disease, but the anatomical distribution is different. Pathology is often found in the substantia nigra of the midbrain and cognitive decline may be combined with features of Parkinson’s disease (in which nigral degeneration is a key pathological feature; see Ch. 13).

Familial clustering of APOE alleles, together with a large number of unknown susceptibility genes, may help to explain the observation that Alzheimer’s disease is more common in people with an affected parent or sibling and that concordance rates are significantly higher in identical twins.

Apolipoprotein E

There are three common APOE alleles: epsilon-2 (APOE2), epsilon-3 (APOE3) and epsilon-4 (APOE4). These encode a lipoprotein that is involved in plasma lipid transport, including the uptake and distribution of cholesterol. APOE4 is associated with a higher incidence of sporadic Alzheimer’s disease, such that two copies of the allele increase risk approximately 20-fold and more than 50% of patients with Alzheimer’s disease have at least one copy. In contrast, APOE2 appears to be protective. The role of Apolipoprotein E in the pathogenesis of Alzheimer’s disease is incompletely understood, but it has been shown to bind to and influence the removal of amyloid beta peptide from the brain, accumulation of which is a key event in the pathogenesis of Alzheimer’s disease (discussed below).

Other genetic factors

Possession of a rare variant of the TREM2 gene (triggering receptor expressed on myeloid cells 2) on chromosome 6 is associated with a three-fold increase in Alzheimer’s disease risk. The mechanism is uncertain at present, but the gene is involved in microglial activation and brain inflammation, providing an important clue to pathogenesis in sporadic disease.

Genome-wide analysis has revealed single nucleotide polymorphisms or SNPs (‘snips’) in three genes that may be associated with modestly increased risk of Alzheimer’s disease: CLU (clusterin or Apolipoprotein J); PICALM (phosphatidylinositol-binding clathrin assembly protein); and CR1 (complement component 3b/4b receptor 1).

The associations of these SNPs are much weaker than for APOE but are most significant for the related gene CLU. Both encode apolipoprotein molecules that bind amyloid beta and are involved in its clearance from the brain: ApoE protein promotes amyloid beta clearance, whereas ApoJ is involved in its uptake into the brain from the bloodstream.

Protective factors

Alzheimer’s disease is more common in females, even after accounting for greater longevity, and hormone-replacement therapy (HRT) may be protective in post-menopausal women. Moderate consumption of alcohol also appears to be beneficial, together with regular mental, physical and social activities. It has been claimed that use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced risk, but clinical trials have failed to show a protective effect.

Key Points

The most important risk factor for Alzheimer’s disease (apart from advancing age) is possession of one or more copies of the APOE4 allele, which is present in more than 50% of patients.

Alzheimer’s disease is also more common in people with ischaemic heart disease, in those with limited educational attainments, lower socioeconomic status or a history of head injury.

It is more common in females and hormone-replacement may be beneficial in post-menopausal women. The positive effect of anti-inflammatory drugs is unproven.

Moderate consumption of alcohol may also be beneficial, together with regular mental, physical and social activities.

Pathological features

Post-mortem examination of the brain in Alzheimer’s disease shows reduced brain weight, with cortical atrophy and enlarged ventricles. Loss of brain tissue is often particularly obvious in the medial temporal lobes and hippocampi and there may be marked thinning of the cerebral cortex with widening of the sulci. Microscopic examination shows characteristic ‘plaques’ and ‘tangles’.

Plaques (Fig. 12.5)

A pathological hallmark of Alzheimer’s disease is the presence of plaques in the cerebral cortex, consisting of insoluble protein aggregates. Plaques are found in the extracellular space (between neurons) and are predominantly composed of amyloid beta peptide (Aβ). Like all forms of amyloid, the deposits take up the tissue stain Congo red and show apple-green birefringence under polarized light (see Ch. 8). Plaques can be identified using silver staining, but are best demonstrated using immunohistochemistry (antibody labelling).

Fig. 12.5 Cortical plaques in Alzheimer’s disease.
This micrograph demonstrates extensive amyloid beta deposits (amyloid plaques) in the cerebral cortex of a person who died of Alzheimer’s disease. *Inset*: a single ‘cored plaque’ with a dense central core of amyloid is shown at higher magnification [immunohistochemical preparation for Aβ peptide].

Although widespread, plaques are most common in the hippocampus, entorhinal cortex and amygdala. They are found in moderate numbers in frontal, parietal and temporal association cortices, but are uncommon in the primary sensory and motor areas. There are two main types:

Diffuse plaques are composed of amyloid beta peptide in a non-fibrillary (non-amyloid) form and may be numerous in older people who do not have dementia.

Neuritic plaques are surrounded by abnormal dystrophic neurites (thickened, tortuous neuronal processes) and sometimes have a dense, central core of amyloid (‘cored plaques’; see Fig. 12.5).

Unlike diffuse plaques, neuritic plaques are strongly associated with cognitive decline. Aβ is also deposited in the walls of blood vessels, leading to cerebral amyloid angiopathy (Clinical Box 12.5).

Clinical Box 12.5: Cerebral amyloid angiopathy

Aβ is deposited in cortical blood vessels in 90% of patients with Alzheimer’s disease, which is termed cerebral amyloid angiopathy (CAA) (see Ch. 8, Fig. 8.14). Amyloid deposition leads to degeneration of vascular smooth muscle, weakening the vessel wall and predisposing to microinfarctions and intracerebral haemorrhage (see Ch. 10, Fig. 10.2B). CAA can occur in the absence of dementia and accounts for a quarter of intracerebral haemorrhages in the elderly. The bleeding is superficial or ‘cortical’ rather than deep (in contrast to hypertension-related haemorrhages, which frequently occur in the region of the basal ganglia).