What is the neuropathophysiology of Alzheimer disease (AD) in Down syndrome (DS)?

Updated: Nov 13, 2019
  • Author: Norberto Alvarez, MD; Chief Editor: Jasvinder Chawla, MD, MBA  more...
  • Print


The neuropathology of AD in persons with DS closely resembles that of AD in persons without DS. [7, 8, 9, 10, 11]  Autopsy studies in persons with DS showed that almost all had brain lesions meeting the criteria for AD. [12, 13]  As has been observed in persons without DS, autopsies of patients with DS showed the hallmarks of AD: intraneural neurofibrillary tangles (NFT) (mostly composed of tau protein, which is encoded by the microtubule-associated protein tau gen [MAPT]),  extracellular neuritic plaques, amyloid angiopathy, and deposits of amyloid beta (Abeta) protein in senile plaques. [12, 152]  In persons with DS, the Abeta deposits can be seen in the cerebral cortex as early as in their 30s. [153, 154] The overall distribution of these abnormalities in the brain as well as the structural and chemical composition is the same as in persons without DS, however there are some differences. For example, persons with DS have an earlier and also a greater deposition of plaques and tangles in the hippocampal area. [155]  In addition, the deposition of beta-amyloid is lower in the cortex in persons with DS compared with those without DS and AD. [156]  Also, the amyloid plaques are not so homogenous and are also bigger in persons with DS than in those without DS. [157]  Diffuse plaques composed of non-fibrillary deposits of Abeta amyloid, usually not associated with other cytological changes, developed earlier than the dense core plaques that are associated with neuronal and glial changes. [158] These diffuse plaques seem to be a unique feature in DS and are seen in children with DS as young as 8 years. [159]   They seem not to have an important effect on neurons, and do not result in clinical symptoms. [160]

Amyloid also deposits in arterial walls. However, and differently from the non-DS population, the presence of vascular dementia is unusual in persons with DS. [161]

Even though amyloid is deposited in the brains of persons with DS very early in life, the deposits are not directly related to the clinical picture. NFT, never reported in the absence of hard core amyloid, increase in density later in life and are more directly related to the early signs of AD in DS than the presence of amyloid. [162, 163]  NFT are intraneuronal, abnormal, twisted filamentous proteins composed mainly of hyperphosphorylated tau proteins. [164] This might indicate that changes in tau protein are more responsible for neuronal dysfunction and clinical symptoms.

Other neuropatholgical abnormalities have been described in persons with DS and AD, for example Lewy bodies as seen in Lewy body dementia. However, this type of dementia is unususal in DS. Membrane-bound granulovacuolar degenerations have been described with the same frequency as in the non-DS population. The endosomal system is known to be abnormal before birth in persons with DS [165] and recent studies showed that this could be important in the development of AD. [161]

Since the neuropathology typical of AD is observed very early in the life of persons with DS, the study of this condition in persons with DS could result in knowledge that could also be useful for individuals without DS.

Did this answer your question?
Additional feedback? (Optional)
Thank you for your feedback!