• ε4 --> strongest genetic risk factor for late-onset AD (especially if homozygous)

• ε2 --> less likely to develop AD

• BUT not determinative (other factors/genes involved)

Amyloid plaques themselves don't always cause cognitive symptoms, but a single mutation in the AβPP gene is sufficient to cause disease --> confused field

ε4 allele increases risk of developing Alzheimer's later in life BUT correlates with cognition and immune benefits early in life --> selected for!

• Young ε4 carriers have higher IQs than noncarriers

• ε4 carriers may recruit additional right hemisphere frontal regions in order to achieve cognitive advantage

These kinetic traps are not 'smoothed' by evolution bc. doing so would disrupt protein function

ε4 allele increases risk of developing Alzheimer's later in life BUT correlates with cognitive benefits early in life --> selected for!

• Young ε4 carriers have higher IQs than noncarriers

• ε4 carriers may recruit additional right hemisphere frontal regions in order to achieve cognitive advantage

• 25% of people carry the ε4 allele

• 'LS' topology of individual subunits

  • N-terminus L-shaped

  • C-terminus S-shaped

• Staggered arrangement of non-planar subunits in a zipper-like manner

• Dimer interface shields hydrophobic C-termini from the solvent

• Different fibril ends ('groove' and 'ridge') with different binding pathways (and possibly energy barriers)

Strain-like properties: Aβ fibril polymorph may correlate with AD phenotype (e.g. rapidly progressive vs. prolonged-duration)

It is likely that AD prevention and treatment must also address the infection and inflammatory response that triggers Aβ production

• Likely mediated by pro-inflammatory cytokines TNF and IF-γ

Aβ may also stimulate inflammatory protein production by microglial cells and astrocytes --> positive feedback likely involved in mediating an inflammatory response

Aβ degradation mechanisms are often impaired in patients with AD

• Herpes viruses HSV1, HHV6 and HHV7 implicated in AD pathogenesis

• Opportunistic infection of commensal microbes (e.g. candida, chlamydia) implicated in AD pathogenesis

• β-sheets contribute to the aggregation and stability of the filaments

• Includes AD, frontotemporal dementia (Pick's disease), angle-only dementia, chronic traumatic encephalopathy, argyrophilic grain disease, progressive supranuclear palsy, corticobasal degeneration, globular glial tauopathy

  • Diseases other than AD lack Aβ plaques

• 'Strain-like' properties: different diseases display different compositions of tau isoforms and have distinct filament morphologies

• Intrinsically disordered

• Function unknown (KO mice normal), but normally found in CNS neurons where it plays a crucial role in stabilising microtubules in axons

• Six tau isoforms of varying length are expressed in the human brain, alternatively spliced at N-terminal exons (N1, 2) and the microtubule repeat domains (R)

• Domains of tau bind many different types of molecules, suggesting a central role in signalling pathways and cytoskeletal organization

• Paired helical fibre (PHF) - filaments twist around each other like a double helix

  • Major components of NFTs in AD

• Straight fibre (SF) - straighter and slightly thicker

• In both polymorphs, individual tau proteins form C shapes which stack to form filaments

Associates with vesicle membranes through protein-membrane interactions and acts as a chaperone of SNARE complex assembly through protein-protein interactions

BUT not present at all synaptic terminals (--> selective expression, targeting, and pathogenic vulnerability in certain neuronal populations) and expression also not confined to neurons (e.g. present in RBCs)

• This region also contains a NAC domain (residues 60–95) implicated in aggregation

• Most identified mutations associated with synucleinopathies are located in this region --> lipid binding or lack of may be associated with αS pathology

• Target of PTMs

• Interacts with proteins

• Modulates membrane-binding

• Protects against aggregation

Oligomeric intermediates are likely the most cytotoxic species and may permeabilise membranes (including mitochondrial membranes --> release of cytochrome C --> caspase activation --> apoptosis

• Mutations in PARK2, which encodes parkin --> accumulation of protein aggregates (including αS fibrils) and damaged mitochondria --> cellular damage --> early onset PD

• Parkin dysfunction leading to impaired mitophagy is especially detrimental in neurons due to their high energy needs

May accumulate within the nervous system of PD individuals bc. of an inflammatory/immune response

--> strain specificity e.g. sheep Scrapie has never infected humans

No nucleic acid involved in 'infection' - all disease information comes from the misfolded protein's ability to convert the normal protein into the pathogenic form

e.g. Familial CJD, fatal familial insomnia

'Anticipation' - number of CAG repeats correlates with earlier disease onset and increased severity

• Up-regulation of chaperones --> assist folding

• Translational attenuation --> reduced protein load

• Up-regulation of ERAD and autophagy --> removal of dnagerous unfolded proteins

Characterised by disorientation, impaired memory, judgement and intellect

“There are an estimated 850,000 people living with dementia in the UK and this figure is expected to double over the next 20 years. The devastating disease costs the NHS, local authorities and families around £26 billion each year but there are currently no treatments available that can stop or reverse the disease. This is primarily because of our limited understanding of how dementia develops”.

Presenilin's are membrane-embedded proteases that cleave other transmembrane proteins in a regulated manner

• Can be determinative

• 20 known missense mutations of AβPP cause human disease

Virtually any protein can form amyloid fibres at sufficient concentration and under denaturing conditions

• ApoE and Aβ interact with each other and share common receptors including LRP1, LDLR, and HSPG

• Interactions among apoE, Aβ, and their receptors probably vary depending on their concentrations, the apoE isoform involved, lipidation status, Aβ aggregation status, and receptor distribution patterns

• ApoE isoforms have different, sometimes seemingly conflicting, roles in Aβ aggregation and clearance

  • Reduces Aβ oligomerization and fibril formation but is also essential for amyloid deposition

  • Competes with Aβ for their receptor binding but can also facilitate cellular Aβ uptake by forming apoE/Aβ complexes.

  • Facilitates the enzymatic degradation and phagocytosis of Aβ by glial cells, but also compromises Aβ elimination through the BBB

• Absence of functional Trem2 leads to increased amyloid plaque seeding in the brain, which is accompanied by decreased microglial clustering around newly-seeded plaques and reduced plaque-associated ApoE

• Absence of functional Trem2 may accelerate early amyloidogenesis due to reduced phagocytic clearance of amyloid seeds, despite the reduction in plaque-associated ApoE

Microglia have normal roles in brain development and CNS homeostasis, including programmed cell death and clearance of apoptotic newborn neurons, as well as pruning developing axons and synapses. Later in development and into adulthood, microglia processes are highly motile and continually survey their local environment, contacting neurons, axons, and dendritic spines. Microglia have diverse physiological roles, including regulating neuronal and synaptic plasticity.

Microglia have complex roles that are both beneficial and detrimental to disease pathogenesis, including engulfing or degrading toxic proteins (i.e., amyloid plaques) and promoting neurotoxicity through excessive inflammatory cytokine release. Aberrations in microglia’s normal homeostatic functions such as surveillance, synaptic pruning, and plasticity may also contribute to excessive synapse loss and cognitive dysfunction in AD and other diseases.

Increased expression of TREM2 in Alzheimer’s disease has a protective function slowing disease progression, and hence loss of function due to the presence of the Trem2 R47H mutation increases the chance of AD reaching the stage of diagnosis

In persons with early Alzheimer’s disease, lecanemab reduced brain amyloid levels and was associated with moderately less decline on clinical measures of cognition and function than placebo at 18 months but was associated with adverse events

A still uncertain route to dementia. The diagram illustrates three putative disease models of AD. A) The top flowchart illustrates a simplified view of the ACH; Aβ dysmetabolism leads to amyloid and Tau protein deposition eventually triggering, neuronal death, brain atrophy, and dementia. Genetic factors contribute, with different degrees, to shape the risk of developing Aβ- and Tau-pathology. B) The middle diagram depicts a non-linear, multifactorial disease model in which the combination of molecular (including protein misfolding), genetics, and lifestyle factors – individually or in association – contribute the development and progression of AD. C) The bottom flowchart depicts an alternative view in which the combination of many molecular, genetic, and epigenetic factors shape the disease process. In parallel these factors also impair cellular systems in charge of protein disposal (lysosomes, ubiquitin-proteasome system, chaperones) thereby producing the build-up of misfolded proteins (Aβ, Tau, α-syn, TDP-43) that is not per se the cause of the disease but rather the molecular signature of failing clearance mechanisms. Thus, in this case the removal of amyloid only helps cleansing the brain of deposits of discarded proteins while minimally affecting the course of the disease.

Recent trials with monoclonal antibodies targeting amyloid-β (Aβ) in Alzheimer’s disease (AD) have sparked a renewed interest in disease-modifying therapies. Despite their promise, these trials leave the issue open and posit some doubts about the validity of the Amyloid Cascade Hypothesis (ACH). While some scores of neurocognitive tests improved upon treatment, real-world clinical benefits were minimal. This Viewpoint discusses additional, often overlooked findings from these trials. We also emphasize the multifactorial nature of AD and the need for a broader research perspective beyond the simplistic disease model provided by the ACH.

The brain is an organ with multiple tissue types

• Functional loss of TREM2 leads to increased amyloid plaque seeding in the brain, which is marked by decreased microglial clustering around newly formed plaques and reduced deposition of ApoE in these plaques

• Absence of functional Trem2 accelerates early amyloidogenesis due to reduced phagocytic clearance of amyloid seeds, despite the reduction in plaque-associated ApoE

• Diverse roles beyond immune function such as sculpting developing neuronal circuits to guiding learning-associated plasticity

• Represent 10% of CNS cells