Epidemiology

In 1996, AD was clinically diagnosed in approximately 4 million people in the United States; this figure is expected to triple in the next 50 years.³ Women are more affected than men at a ratio of almost 2 : 1, partly because of the larger population of women who are older than 70 years; however, the prevalence is still higher in women even after statistical correction for longevity.⁴ Age is another important risk factor. At the age of 60 years, the risk of developing AD is estimated to be 1%, doubling every 5 years to reach 30% to 50% by the age of 85.⁵ Other reported risk factors include lower levels of intelligence and education (defined as primary education only), small head size, and a family history of the disease.⁶ A meta-analysis of head injury as a risk factor for Alzheimer’s disease also demonstrated a definite association in men.⁷

Genetics

Genetic risk factors are clearly involved in the pathogenesis of AD. In particular, the gene for apolipoprotein E (ApoE) on chromosome 19 has gained much recent attention. ApoE is a protein modulator of phospholipid transport that might have a role in synaptic remodeling.⁸ ApoE has three common alleles, ApoE ε2, ε3, and ε4, which are expressed in varying amounts in the normal person. It is the ApoE ε4 genotype that is associated with the risk of AD. Postulated mechanisms include amyloid deposition and abnormal tau phosphorylation, a major component of neurofibrillary tangles. Unlike the chromosomal mutations that are responsible for early-onset AD, the presence of ApoE in itself does not cause AD nor does it guarantee that the carrier will develop any clinical manifestations. Therefore, at this time it should not be used as a screening tool for normal patients who are concerned about developing the disease.

Amyloid Plaques

Although amyloid plaques or senile plaques may be classified further according to their composition, all contain forms of β-amyloid protein (Aβ). Aβ is a 39- to 42-amino acid peptide that is formed by the proteolytic cleavage of β-amyloid precursor protein (APP) and is found in extracellular deposits throughout the central nervous system (CNS).⁹ Aβ is believed to interfere with neuronal activity because of its stimulatory effect on production of free radicals, resulting in oxidative stress and neuronal cell death.⁶

Neurofibrillary Tangles

Neurofibrillary tangles are paired helical filaments composed of tau protein, which in normal cells is essential for axonal growth and development. However, when hyperphosphorylated, the tau protein forms tangles that are deposited within neurons located in the hippocampus and medial temporal lobe, the parietotemporal region, and the frontal association cortices, leading to cell death.

Neuron and Synapse Loss

Areas of neuronal cell death and synapse loss are found throughout a distribution pattern similar to that of the neurofibrillary tangles, but they greatly affect neurotransmitter pathways. The death of cholinergic neurons in the basalis nucleus of Meynert leads to a deficit in acetylcholine (Ach), a major transmitter believed to be involved with memory. In addition, loss of serotoninergic neurons in the median raphe and adrenergic neurons in the locus ceruleus lead to deficits in serotonin and norepinephrine, respectively.

Chromosomal Mutations

Genetic mutations in chromosomes 21, 14, and 1 have been shown to cause familial early-onset AD. Inherited in an autosomal-dominant pattern, the chromosomal mutations account for less than 5% of all cases and result in the overproduction and deposition of Aβ.¹⁰ Chromosome 21, which codes for APP, was first evaluated for an association with AD when Down syndrome patients with the trisomy 21 aberration were observed to develop dementia in the fourth decade. Mutations in presenilin 1 (PS-1) on chromosome 14 and presenilin 2 (PS-2) on chromosome 1 also cause AD and are responsible for the majority of familial early-onset cases.

Inflammation

The exact role of inflammation in the pathogenesis of AD is still controversial. Although some studies have been able to demonstrate the presence of activated microglia (a marker of the brain’s immune response) in patients with probable AD, a number of prospective clinical trials evaluating the use of drugs targeting various aspects of the immune system such as prednisone, hydroxychloroquine, and selective COX-2 inhibitors have been able to demonstrate only marginal benefits at best.¹¹

Although some studies have suggested a neuroprotective role for nonsteroidal anti-inflammatory drugs, a recent large study of 351 patients revealed that these medications did not slow progression and cognitive decline in established mild-to-moderate Alzheimer’s disease.^12,13