Alzheimer's disease: an animated, cited guide

This page needs JavaScript for its animations. The outline and key answers are below, and every claim in the full version carries a numbered citation.

Not medical advice. Alzheimer's Companion is an educational synthesis of published literature. It does not replace a clinician.

What is in it

What Alzheimer's is Dementia versus Alzheimer's, who it affects, the numbers.
The brain that forgets Where it starts and how it spreads, stage by stage.
Amyloid, animated From one protein cut to a plaque, and the debate about it.
Tau and the tangle How a scaffold protein turns into a tangle and spreads.
Microglia and the lost synapse Inflammation, pruning, and the strongest link to memory loss.
Genes and inheritance APOE, the dominant families, Down syndrome, and what a test means.
Twenty years before symptoms The biomarker cascade, in order.
Stages and symptoms From no symptoms to severe dementia, function by function.
Diagnosis and biomarkers Criteria, scans, spinal fluid, blood tests and screening tools.
The differential Delirium, vascular, Lewy body, frontotemporal and reversible causes.
Cholinesterase inhibitors and memantine Inside the synapse, and what the benefit really is.
Anti-amyloid antibodies over time Lecanemab and donanemab over 18 months, ARIA and the debate.
Beyond memory Agitation, mood, psychosis and sleep, and the drug cautions.
Lowering the risk The 14 modifiable risk factors and what trials show.
Living with dementia and caregiving Planning, safety, caregivers and the end of life.
Nursing care Assessment, giving the medicines, communication, documentation.
Toward a cure The pipeline, prevention trials, and the evidence for each route.
History and people From Auguste Deter in 1901 to the antibodies.
Flashcards and mnemonics Flip cards by topic.
Quiz Questions with explanations.
Glossary Every term, searchable.
Sources Every reference behind the app.

Part 1 · The disease

Microglia and the lost synapse

Memory depends on synapses, the contact points between neurons. In Alzheimer's they are lost early, and the brain's own immune cells help remove them. Press play to watch a patch of tissue change, then try the two switches.

Scenario

Timeline

Schematic, not to scale. The synapse count is illustrative; the two ticks on the bar are measured human values.

Synapses track memory best

In 1991 Robert Terry's group counted synapses, plaques and tangles in the brains of 15 people with Alzheimer's and 9 controls, and compared each with how the person had scored on cognitive testing. Switch the measure on the x-axis and watch the cloud change shape. ⁴⁸⁴

Plot cognition against

Build

Points are schematic, drawn to show the pattern, not Terry's data. The r of 0.96 is the published value.

The other cells, and the other diseases

Established

Astrocytes react too

Activated microglia release IL-1α, TNF and C1q, which push astrocytes into a reactive state, named "A1" in 2017, that supports neurons less well. Such astrocytes were abundant in Alzheimer's brains. ³¹²

Debated

But "A1" and "A2" are too simple

A 2021 consensus statement criticised binary astrocyte labels (A1 versus A2, good versus bad) as oversimplified, and recommended describing reactive astrocytes with several measures at once. ¹⁴³

Established

Microglial genes carry risk

TREM2 R47H raised risk about 2.9-fold. Other rare variants in microglial genes point the same way: PLCG2 P522R is protective (odds ratio 0.68), ABI3 S209F (1.43) and TREM2 R62H (1.67) raise risk. ^263,464 More in Genes and inheritance.

Association only

A leaky barrier, early

Breakdown of the blood–brain barrier in the hippocampus was found in people with early cognitive problems, whatever their amyloid and tau status. The authors propose it as an independent early marker; the study shows association, not cause. ³⁷⁵

Most brains with Alzheimer's have something else too

Alzheimer's rarely travels alone in older brains. Each figure below comes from a different group of people, so the percentages cannot be added or compared directly.

Finding	How often	In whom	Source
Pure Alzheimer's pathology, nothing else	30%	The 50 people with dementia among 141 community autopsies; more than half had several pathologies	⁴⁵³
Alzheimer's plus infarcts (strokes)	38%	Same community autopsies; more than one diagnosis nearly tripled the odds of dementia (OR 2.8)	⁴⁵³
Infarcts, moderate-to-severe CAA, atherosclerosis, arteriolosclerosis	each >30%	Religious Orders Study / Memory and Aging Project brains; each explained 20–30% of decline when present	²⁰⁹
Some cerebral amyloid angiopathy (CAA: amyloid in vessel walls)	85–95%	People with Alzheimer's	^114,209
Moderate-to-severe CAA	13%	Mayo brain bank	²⁰⁹
LATE (TDP-43) enough to be linked to impairment	about 25%	Community autopsy brains	³⁷⁸
Alpha-synuclein (Lewy) co-pathology	41–55%	Alzheimer's brains in 766 autopsies	⁴³²
TDP-43 co-pathology	33–40%	Same 766 autopsies; linked to age and APOE ε4	⁴³²

Exam hookMixed pathology is the rule in old age, not the exception. LATE (limbic TDP-43) causes an amnestic dementia that mimics Alzheimer's, staged amygdala, then hippocampus, then middle frontal gyrus. ^378,453

Sleep and the "glymphatic" system

Mostly rodent · contested

The mouse findings

In mice, fluid enters the brain along spaces around arteries and leaves around veins. Deleting the astrocyte water channel AQP4 cut solute clearance by about 70%. Sleep widened the space between cells by about 60% and sped amyloid clearance, and sleep restriction increased plaques. ^247,269,526

Contrary evidence

Other labs disagree

An independent group found transport in brain tissue fitted diffusion, not flow, and did not depend on AQP4. A 2024 mouse study found clearance was lower, not higher, during sleep and anaesthesia. ^354,467

Small human studies

What people show

One night without sleep (7 people against 17 controls) slowed clearance of a tracer from most brain regions. Sleep deprivation raised spinal-fluid amyloid by 25–30%, but mainly through more production, not less clearance. ^129,330

Where this leaves it

That sleep affects amyloid levels is better supported than any specific glymphatic mechanism in human Alzheimer's. That is a synthesis across the studies above, not any single study's conclusion. Meningeal lymphatic vessels, described in 2015, may be another drainage route; their role in humans is unknown. ^330,467,475

In plain wordsPoor sleep and amyloid are linked. How the brain "washes" itself at night is still argued about, mostly from mouse studies.