The neuropathological manifestation of AD in DS has been attributed to the triplication and over-expression of the APP gene located on chromosome 21¹². This neuropathology is invariably found in the brains of individuals with DS over the age of 40 years¹³. The characteristic neuropathological changes in AD include the deposition of beta-amyloid (Aß) as both extracellular diffuse and neuritic plaques as well as in meningeal and cerebral blood vessels and the intracellular accumulation of neurofibrillary tangles (NFTs) consisting of hyperphosphorylated tau in the form of paired helical filaments¹. The accumulation of the diffuse plaques, which contain non-fibrillar amyloid, are commonly seen in DS before age 50 years and are not associated with AD whereas the neuritic plaques, which contain fibrillized amyloid and accumulate most commonly after age 50 years in DS, are associated with neuronal degeneration and loss of function¹⁰. NFTs occur at a later age in DS brains than amyloid plaques¹⁴ and have been associated with dementia status in DS³.

Aß, which consists of the two major species Aß 1-40 and Aß1-42, is produced from ß-amyloid precursor protein (APP) by sequential proteolytic cleavage by ß- and γ-secretases¹⁵. Starting from a young age, Aß 1-42 precedes Aß 1-40 in the course of amyloid deposition in the brains of people with DS¹⁶. Plasma Aß levels are also elevated in DS persons from childhood¹⁷. Plasma levels of Aß 1-40 and Aß 1-42 may be correlated with age in older DS adults¹⁸ and plasma Aß 1-42 levels were found to be higher in DS persons with dementia compared to those without in some studies¹⁹ but not others, which found no association between plasma Aß 1-40 and Aß 1-42 levels and the presence of dementia, APOE genotype or duration of dementia²⁰ or age of onset²¹.

Genetic Factors

Studies in the general population with AD have identified mutations in APP, presenilin 1 (PS-1) and presenilin 2 (PS-2) to be associated with early-onset familial forms of AD and the APOE gene polymorphisms with the more common late-onset AD. However, in DS persons, PS-1 polymorphisms do not appear to have the same detrimental effects and are not associated with the development of dementia²².

Apolipoprotein E, which is involved in cholesterol transport and lipid metabolism and occurs in three allelic forms as e2, e3 and e4 on chromosome 19, has been shown to modulate the risk of AD in the general population²³ with the APOEe4 allele associated with both late-onset familial and sporadic AD and the APOEe2 allele conferring a protective effect on the risk of developing AD²⁴. In persons with DS, the relationship between APOEe4 and risk of AD remains controversial. Some studies have shown APOEe4 allele to be associated with increased risk of AD in persons with DS^25-26 while others have not^27,28. A recent meta-analysis showed APOEe4 to be significantly associated with the prevalence of AD in DS²⁹.

The extended tau haplotype occurs in two forms, as H1 and H2, and has been associated with earlier onset of AD in the presence of the APOEe4 allele in the general population. Individuals with DS are at increased risk of developing dementia before age 45 years if they are heterozygous for the extended tau haplotype. Its lack of association with the APOE genotype suggests that it may be an independent risk factor for early onset dementia in DS³⁰.

The genes for proteins that regulate tau phosphorylation, DYRK1A (dual-specificity tyrosine-regulated kinase 1A) and calcipressin, are located on chromosome 21 and their increased expression in DS may promote NFT formation. Furthermore, increased expression of both occur in response to increased Aß load and helps explain why NFTs occur at a later stage in the dementia process³¹.

Tetranucleotide repeat in intron 7 of APP (attt5-8) has been associated with earlier age of onset of dementia by up to 13 years in DS²¹.

Women in the general population are at increased risk of developing AD compared with men and oestrogen deficiency has been implicated in the cascade of pathological processes leading to AD. This has been reviewed recently³².

The evidence for the effect of gender on risk of AD in DS is contradictory, with some studies finding no differences in age of onset³³, earlier onset³⁴ or later onset³⁵. Postmenopausal DS women with low levels of bioavailable oestradiol have been found to have an increased risk of developing AD³⁶. The average age of menopause in DS women was younger than in the general population and the age of onset of AD correlated with the age of menopause, hence it has been suggested that oestrogen deficiency may be a possible independent risk factor for AD in DS³⁷.

The Na+/myo-inositol co-transporter gene (SCL5A3) is located on chromosome 21 and myo -inositol significantly affects neuronal development and survival, neuronal osmolarity, membrane metabolism, signal transduction, protein kinase C activation and amyloid deposition³⁸.

Proton magnetic resonance spectroscopy studies in healthy DS persons have reported significant increases in brain choline and myo- inositol, but no differences in brain NAA or creatine, and it has been suggested that the abnormal membrane turnover/degradation and increase in myo -inositol reflect a ‘predementia’ phase in which the neuropathology of AD is accumulating and precedes the loss of neurons^39,40. The increased brain myo-inositol concentrations in healthy DS persons have been shown to be negatively correlated with overall cognitive and memory abilities⁴¹.

In a study comparing brain metabolites in demented, mild cognitively impaired (MCI) and healthy controls in the general population

Free radicals produced by metabolic processes are kept in check by antioxidant defences and if this balance is disturbed, results in the highly reactive free radicals reacting with lipids in cell membranes to cause cellular damage, which contributes to neurodegeneration. The genetic locus for Cu,Zn-superoxide dismutase (SOD1), a key enzyme in free radical metabolism, is located on chromosome 21⁴³ and has been suggested to have particular relevance to neurodegeneration in DS⁴⁴.

There is increasing evidence to suggest that cytokines have an important role to play in the development and/or progression of AD in the general population. The inflammatory component of AD is dominated by the presence of activated microglial cells⁴⁵. Studies have shown some support for the hypothesis that cytokines may act as a risk factor for the development of dementia in DS^46,47. A small study found positive correlations between serum IL-6 levels with age and severity of AD in people with DS⁴⁸, and there is preliminary evidence to indicate that serum TNF-a levels are elevated in DS persons with AD⁴⁹, suggesting a disease-stage-dependent general activation of the immune system.

Using magnetic resonance imaging (MRI) based measurements of grey matter atrophy as a surrogate marker of neuronal density, various neuroimaging studies have described the macroscopic neuroanatomy of DS. More recent studies using sensitive quantitative measures of region-specific atrophy based on high-resolution MRI have suggested that age-specific atrophy in DS resembles the pattern of brain atrophy in the early stages of AD⁵⁰.

In DS persons, overall brain volume including the cerebellum and cerebral grey and white matter, ventral pons, mammillary bodies and hippocampus is reduced whereas the parahippocampal gyrus are enlarged⁵¹. Reductions in cerebral volume are prominent in the frontal and occipital lobes and there is relative preservation of parietal lobe grey and temporal lobe white matter⁵².

As they age, non-demented DS individuals show volumetric reductions in most cortical brain regions⁵³