•The neuropathological diagnosis of Alzheimer’s disease (AD), requires the presence of amyloid plaques and neurofibrillary tangles, which comprise β-amyloid (Aβ) and tau protein fragments respectively. This diagnosis still relies on post-mortem examination for certainty, although this is changing with improved imaging techniques and biomarkers.
•Familial AD (FAD), a rare form of early onset dementia, may result from mutations in one of three genes, APP, PSEN1, or PSEN2, each of which is directly related to the increased production of longer, more toxic forms of Aβ.
•The ‘amyloid hypothesis’ suggests that Aβ is the principal stimulus for both familial and sporadic AD and that the ensuing disease process results from its overproduction or reduced clearance. This is still considered valid although adverse changes in tau are likely to be required to bring about symptoms of dementia.
•Aβ initiates the pathological process. This pathological process is likely to produce variance in pathological and therefore symptomatic outcome due to the large number of genetic, epigenetic and lifestyle variables in individuals, continuing and amplifying this degenerative process.
•The relatively selective vulnerability of projection neurones of the serotonergic, noradrenergic, cholinergic and cortical glutamatergic systems provide the rationale for current pharmacological treatment.
•The most robust risk, after increased age, for sporadic AD is the presence of the APOE e4 allele coding for the apolipoprotein E4 (APOE) protein polymorphism. APOE is involved in Aβ clearance and neuronal repair, whereas APOE4 contributes to an unfavourable outcome through a number of pathways. This may prove a challenge with respect to therapeutic approaches.
•Symptoms become manifest 15–20 years after the initiation of pathological processes. Even mild cognitive impairment may represent an expression of established disease.
|Name||Oxford Neurology Library|
|Publisher||Oxford University Press|