Alzheimer's Dementia — Pathogenesis, Molecular Advances, Drugs and Newer Modalities

Alzheimer's Dementia — Pathogenesis, Molecular Advances, Drugs and Newer Modalities Fifteen–Twenty High-Yield Points Definition and epidemiology

Alzheimer's disease (AD) is a progressive neurodegenerative disorder causing sustained loss of memory and other intellectual functions severe enough to impair daily living. Loss of function separates dementia from MCI.

About 6–8% of people over 65 have AD. Prevalence doubles every 5 years, so nearly 30% of those over 85 are affected. Family history and increasing age are the primary risk factors.

Mixed pathology is the rule in old age. AD change plus vascular disease lowers the threshold at which cognitive decline becomes clinically apparent.

Early-onset familial AD is caused by mutations in three genes: APP (chromosome 21), presenilin 1 (chromosome 14) — the largest group — and presenilin 2 (chromosome 1).

The strongest genetic risk factor for late-onset AD is the apolipoprotein E ε4 allele on chromosome 19. One or more copies carries a relative risk of about 2.5 in whites, but it does not raise risk equally in African-American or Hispanic populations.

ApoE ε4 is neither sensitive nor specific, so it is not recommended as a screening test, even in high-risk groups.

The two histological hallmarks are neuritic (senile) plaques — extracellular masses with an amyloid core surrounded by degenerating neurites — and neurofibrillary tangles of abnormal hyperphosphorylated tau inside neuronal cell bodies.

Amyloid cascade: APP is cleaved by β-secretase (BACE1) and γ-secretase (presenilin) to form Aβ1-42, which oligomerises into soluble protofibrils (the most synaptotoxic species) and then fibrillar plaques.

Tangle spread follows Braak staging — entorhinal cortex first, then hippocampus and association cortex. Tangle burden correlates with cognitive decline; plaque burden correlates poorly and may be present in normal cognition.

Additional interacting mechanisms of brain ageing accelerate AD: mitochondrial dysfunction, oxidative damage, loss of proteostasis (impaired autophagy and proteasome), dysregulated neuronal calcium homeostasis, impaired adaptive stress responses (reduced BDNF/NGF signalling), glial activation and neuroinflammation, impaired DNA repair, stem-cell exhaustion, and aberrant network activity with loss of synaptic plasticity.

Cerebral amyloid angiopathy (CAA) — amyloid deposition in leptomeningeal and cortical vessel walls — is a recognised neuropathological hallmark of AD and causes lobar haemorrhage, microbleeds and white matter lesions.

Biomarker studies show Aβ and tau changes begin years to decades before symptoms. Cognitively normal older people with low CSF Aβ1-42 lose whole-brain and hippocampal volume faster, suggesting a presymptomatic AD phase.

Cholinesterase inhibitors are the primary pharmacological approach. Four have been approved: tacrine, donepezil, rivastigmine and galantamine. Tacrine is hepatotoxic and no longer prescribed.

Mechanism: they inhibit acetylcholinesterase and raise synaptic acetylcholine, partly correcting the cholinergic deficit from basal forebrain neuronal loss. Rivastigmine additionally inhibits butyrylcholinesterase.

Efficacy: randomised placebo-controlled trials show small improvements in cognition, possible prevention of functional decline, a several-month delay in progression, and possible delay of nursing home admission. The clinical importance is marginal in many patients. There is some efficacy in multi-infarct dementia and dementia with Lewy bodies.

Side effects: nausea, vomiting, diarrhoea, anorexia and weight loss; bradycardia and syncope; vivid dreams and nightmares; urinary urgency; muscle cramps. Caution with bradyarrhythmias and peptic ulcer disease.

Memantine is an NMDA receptor antagonist used in moderate-to-severe disease; it reduces glutamate-mediated excitotoxicity and is generally well tolerated (dizziness, headache, confusion).

Behavioural symptoms: non-pharmacological strategies come first. Antipsychotics carry a black-box warning for increased mortality and should be reserved for patients who are psychotic or an immediate danger to self or others. Every patient with new or worsening behaviour needs a medical evaluation for a treatable precipitant — pain is especially hard to detect, and empirical paracetamol has shown efficacy in severe dementia.

Four categories of non-pharmacological intervention are described: restorative cognitive training, compensatory cognitive training, lifestyle interventions and psychotherapeutic interventions. These remain necessary even when drugs are used.

Exercise has an emerging role in preventing and treating cognitive decline; high-intensity resistance training is the most promising form, particularly in MCI. Attention to caregiver health and advance care planning are integral to management.