Molecular genetics of early‐onset Alzheimer's disease revisited

Abstract

As the discovery of the Alzheimer's disease (AD) genes, APP, PSEN1, and PSEN2, in families with autosomal dominant early-onset AD (EOAD), gene discovery in familial EOAD came more or less to a standstill. Only 5% of EOAD patients are carrying a pathogenic mutation in one of the AD genes or a apolipoprotein E (APOE) risk allele ε4, most of EOAD patients remain unexplained. Here, we aimed at summarizing the current knowledge of EOAD genetics and its role in ongoing approaches to understand the biology of AD and disease symptomatology as well as developing new therapeutics. Next, we explored the possible molecular mechanisms that might underlie the missing genetic etiology of EOAD and discussed how the use of massive parallel sequencing technologies triggered novel gene discoveries. To conclude, we commented on the relevance of reinvestigating EOAD patients as a means to explore potential new avenues for translational research and therapeutic discoveries.

Can Creutzfeldt-Jakob disease unravel the mysteries of Alzheimer?

“…Indeed, Aβ plaques can be detected in cognitively normal individuals from 30 y of age, 11 particularly associated with the ε4 allele of the APOE gene 13 . In young patients with widespread Aβ pathology, mutations in the amyloid precursor protein gene ( APP ) and presenilin ( PSEN ) 1 and 2 must be also excluded 14 . Furthermore, Aβ can deposit in the cerebral blood vessels in the form of cerebral amyloid angiopathy (CAA), which can associate with AD but can also be seen independent of AD 15 …”

The first case series of Chinese patients in Hong Kong with familial Alzheimer’s disease compared with those with biomarker-confirmed sporadic late-onset Alzheimer’s disease

“…This explains the much earlier AOO. 19 Second, pathological studies of the brain of FAD patients seldom noted non-AD pathological changes. On the contrary, 42% of LOAD patients exhibited at least one other concurrent clinicopathological diagnosis such as vascular dementia, dementia with Lewy bodies, hippocampal sclerosis, or Pick's disease.…”

How Should Clinicians Counsel a Woman with a Strong Family History of Early-Onset Alzheimer's Disease about Her Pregnancy?

“…The earlyonset form of the disease (EOAD) represents 10 percent of all AD cases [5]. Strikingly, the inherited genetic contribution to EOAD is estimated to be 92-100 percent [6].…”

“…By contrast, mutations in PSEN2 are 95 percent penetrant [4]. Although mutations in any of the three known EOAD genes are causative, these mutations only account for 5-10 percent of all cases of EOAD [5]. In short, a person can receive a negative test result for these mutations and remain significantly at risk for developing EOAD.…”

“…Insofar as mutations in the three identified EOAD genes account for only a small percentage of all cases of EOAD, in this scenario, Mrs. Castle could still face a significant risk of developing the disease [5]. Assuming that information about the sister's genetic status is not available, Mrs. Castle must be supported in making a difficult decision about whether to be tested herself so as to make a decision about her pregnancy.…”