Neuropathological and Neurobiological Mechanisms in Dementia and Alzheimer's Disease

The pathological cascade in Alzheimer’s disease and related dementias is driven by the misfolding and aggregation of key proteins, chiefly amyloid-β and tau, whose accumulation disrupts neuronal function and synaptic connectivity. Extracellular plaques of amyloid-β peptides initiate a complex response that includes microglial activation, astrocytic gliosis and release of inflammatory mediators. Intraneuronal tau hyperphosphorylation gives rise to neurofibrillary tangles, progressive cytoskeletal destabilisation and eventual neuronal death. Vascular dysfunction and microinfarcts further compromise perfusion and exacerbate proteinopathy. Emerging evidence highlights additional co-pathologies such as TDP-43 inclusions and α-synuclein aggregates that synergise with amyloid and tau to worsen clinical outcomes. Synaptic loss is an early correlate of cognitive decline, reflecting deficits in neuroplasticity and network resilience. Genetic and epigenetic factors modulate susceptibility, while compensatory mechanisms—often subsumed under cognitive reserve—delay symptomatic onset. A holistic understanding of these intertwined mechanisms is essential to develop multifaceted interventions that target protein aggregation, inflammatory networks, vascular health and synaptic repair.

Research from Nature Portfolio

Recent studies have identified a neurodegeneration checkpoint mechanism mediated by the transcriptional repressor REST. In ageing human brains and transgenic mouse models, REST is upregulated at the onset of amyloid-β deposition and tau accumulation, where it binds select gene loci to downregulate γ-secretase activity, tau kinases and pro-apoptotic factors. Loss of REST accelerates amyloid and tau pathology, leading to synaptic loss and cognitive impairment, whereas viral-mediated overexpression in the hippocampus suppresses protein aggregation and preserves function. This work establishes REST as a broad-spectrum protective factor that may be harnessed to restrain early pathological events in Alzheimer’s disease.

Neuropathological and Neurobiological Mechanisms in Dementia and Alzheimer's Disease publication trend

The graph below shows the total number of articles in neuropathological and neurobiological mechanisms in dementia and alzheimer's disease across all publications each year (not limited to Nature Index journals).

Technical terms

Amyloid-β: small peptide that aggregates extracellularly into plaques central to Alzheimer’s pathology.

Tau: microtubule-associated protein that, when hyperphosphorylated, forms neurofibrillary tangles.

Neurofibrillary tangles: intracellular aggregates of hyperphosphorylated tau disrupting neuronal transport.

TDP-43: DNA/RNA-binding protein whose cytoplasmic inclusions characterise limbic age-related encephalopathies.

REST: RE1-silencing transcription factor that represses genes driving amyloid and tau pathology.

Synaptic plasticity: capacity of synapses to strengthen or weaken over time, underlying learning and memory.

References

1. TDP-43 pathology is associated with increased tau burdens and seeding. Molecular Neurodegeneration (2023).
2. A neurodegeneration checkpoint mediated by REST protects against the onset of Alzheimer’s disease. Nature Communications (2023).
3. The prevalence, correlation, and co-occurrence of neuropathology in old age: harmonisation of 12 measures across six community-based autopsy studies of dementia. The Lancet Healthy Longevity (2023).
4. Targeting the Synapse in Alzheimer’s Disease. Frontiers in Neuroscience (2019).
5. Concepts for brain aging: resistance, resilience, reserve, and compensation. Alzheimer's Research & Therapy (2019).