1906

The dawn of Alzheimer’s disease

A German physician’s study of a woman with memory loss and hallucinations marks the beginning of research into the disease that came to bear his name.

On 3 November 1906, an audience of psychiatrists in Tübingen, Germany, were the first to hear the story of Auguste Deter. She had been admitted to Frankfurt Psychiatric Hospital five years earlier with memory loss and other cognitive symptoms. On examination of her brain, physician Alois Alzheimer discovered the amyloid plaques and neurofibrillary tangles that are hallmarks of what we now call Alzheimer’s disease.

1984

Identifying amyloid-β in brain plaques

Evidence mounts that these peptides are the key component of plaques associated with Alzheimer’s and might give rise to the disease.

The amyloid-β peptide that makes up plaques in the brain was identified in 1984, nearly 80 years after Alzheimer’s disease gained its name. The discovery of amyloid-β led to the hypothesis that the disease might be caused by a build-up of this peptide in the brain — an idea that remains at the heart of research today.

1985

Disentangling tau pathology

The protein tau is identified as the core component of the neurofibrillary tangles — nearly 80 years after the structures were found in the brains of people with Alzheimer’s disease.

Soon after the characterization of amyloid-β, scientists unmasked the protein that makes up the neurofibrillary tangles spotted by Alois Alzheimer. At the heart of these tiny thread-like structures is tau — a protein that has been implicated in the stabilizing of the microtubules that help cells to maintain their shape, and which is abnormally phosphorylated in the brains of people with Alzheimer’s disease.

1987

Finding the first Alzheimer’s gene

Mutations in the gene encoding APP, the precursor to amyloid-β, are found to underpin some cases of familial Alzheimer’s disease.

About 5–10% of cases of Alzheimer’s disease are genetically inherited. In 1987, the gene encoding amyloid precursor protein (APP) was the first to be identified as a cause of familial disease. APP is located on chromosome 21. People with Down’s syndrome have an extra copy of this chromosome, and as a result they often develop amyloid-β plaques similar to those seen in Alzheimer’s.

1991

The Braak staging system for Alzheimer’s disease, developed by Heiko and Eva Braak at Goethe University Frankfurt, Germany, enabled researchers to better track disease progression. It defines six stages of disease propagation according to the presence of neurofibrillary tangles in different areas of the brain. The spread of tangles from the entorhinal cortex (stages I–II) to the hippocampus and limbic regions (stages III–IV), and then to the neocortex (stages V–VI) correlates with disease progression and the severity of cognitive impairment. Read the paper

1993

A major genetic risk factor for late-onset Alzheimer’s disease

The APOE gene, which codes for a fat-binding protein in the brain, is identified as a strong risk factor for the most common form of the disease.

Late-onset Alzheimer’s disease, which manifests after the age of 65 and accounts for around 95% of cases, is thought to arise from a combination of environmental and genetic factors. In 1993, researchers identified a version of APOE — a gene involved in transporting fats in the brain — that substantially increases the risk of developing late-onset disease.

1995

The first transgenic animal model of Alzheimer’s disease was developed by introducing human mutant amyloid precursor protein (APP) into mice. Known as PDAPP mice, the animals accumulate amyloid-β in the brain over time and experience age-dependent neurodegeneration and cognitive decline — as is seen in people with Alzheimer’s. The mice were the first of a long line of still-ongoing efforts to accurately model the disease. Read the paper

1995

Revealing the most common cause of early-onset Alzheimer’s disease

The presenilin genes are identified as leading causes of familial disease, shedding light on an enzyme at the heart of amyloid-β production.

Mutations in the APP gene, discovered in 1987, are responsible for only a small proportion of cases of early-onset Alzheimer’s disease. In 1995, efforts to identify more causal genes found success when two groups independently implicated mutations in the presenilin genes, PSEN1 and PSEN2. Researchers would later show that these genes encode the catalytic component of the enzyme γ-secretase, which is involved in generating amyloid-β.

1999

A vaccine raises hopes of treatment for Alzheimer’s disease

Immunizing mice against amyloid-β is shown not only to prevent plaques forming, but also to clear away existing deposits.

By the turn of the century, momentum had built behind the amyloid hypothesis and many researchers thought that preventing or clearing the build-up of amyloid-β in the brain might provide a way to treat Alzheimer’s disease. Researchers at Elan Pharmaceuticals in California, led by Dale Schenk, were the first to successfully clear amyloid plaques from the brains of mice, by raising antibodies against amyloid-β.

1999

Identifying the key enzyme β-secretase

BACE1 is revealed to be the missing protease responsible for producing amyloid-β from its precursor protein.

It was clear by 1999 that amyloid-β was formed from the cleavage of amyloid precursor protein (APP), but the enzymes responsible for these crucial cuts had not yet been identified. The first, γ-secretase, was localized to the presenilin genes that had been implicated in Alzheimer’s disease in 1995. The identity of the second enzyme, β-secretase, emerged in October 1999.

2004

The radioactive imaging tracer Pittsburgh compound B (PiB) enabled researchers and clinicians to non-invasively detect and track amyloid deposits in the human brain. The compound made it possible to definitively diagnose Alzheimer’s disease using positron emission tomography (PET) imaging. Before this development, only postmortem analysis of brain tissue could confirm a diagnosis. Read the paper

2008

Exploring the role of inflammation and immunity in Alzheimer’s

Genetic evidence kick-starts research into the involvement of microglia cells and the innate immune system in the development of the disease.

Over time it became clear that the amyloid hypothesis alone could not fully explain Alzheimer’s disease. In 2008, researchers provided evidence suggesting that the immune system also plays a part. The team identified mutations in two receptors — CD33 and TREM2 — found on the surface of immune cells known as microglia that increase the risk of late-onset disease by as much as 200%.

2013

Genetic risk factors for Alzheimer’s uncovered by large meta-analysis

A study of nearly 75,000 people doubled the number of areas of the human genome that were known to be associated with late-onset disease.

By 2013, the list of genetic risk factors for late-onset Alzheimer’s disease – the most common form of the condition – had grown to include 11 areas of the human genome. In October of that year, that number doubled when a large group of researchers from North America and Europe identified a further 11 genetic variants that were associated with the disease.

2020

A blood-borne biomarker for Alzheimer’s disease

The discovery and validation of a diagnostic marker in plasma could be an important step for monitoring disease progression.

Positron emission tomography (PET) imaging and markers in cerebrospinal fluid can be used to diagnose Alzheimer’s disease and monitor its progression, but these techniques are expensive and can be difficult to perform. In 2020, researchers demonstrated the accuracy of perhaps the most useful biomarker yet: a form of the protein tau that can be detected in a simple blood test.

2021

Anti-amyloid antibodies take a bumpy road to the clinic

The arrival of the first disease-modifying therapy for Alzheimer’s was significant, but it was not met with the joy that might have been expected.

After decades of work, aducanumab became the first disease-modifying therapy for Alzheimer’s approved by the US Food and Drug Administration, in 2021. But the approval of this anti-amyloid antibody proved controversial, with many researchers questioning the therapy’s ability to slow cognitive decline. Aducanumab was discontinued in 2024, and has been superseded by lecanemab and donanemab — similar therapies with promising data behind them.

How Alzheimer’s mutates the immune system

Genomicist David Gate explains how neurodegenerative disease can alter immune function, and why this might provide a route to treatment.

Detecting Alzheimer’s 20 years before onset

Early signs of Alzheimer’s disease can be spotted decades before symptoms appear, say Shuheng Wang and Bote Zhao at Capital Medical University in China.

How to battle Alzheimer’s in Africa

Neuroscientist Chi Udeh-Momoh describes how efforts to promote healthy brain ageing through a range of physical and mental interventions are being adapted for use in Africa.